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Regiegroep Life Sciences & Health

Innovation contract 2012 from the topsector Life Sciences & Health Investing in research, development and innovation for a healthy and prosperous Netherlands March 2012

Regiegroep Life Sciences & Health

Foreword by Rob van Leen Maintaining and improving an ageing population's quality of life while keeping healthcare affordable and sufficiently staffed is one of the "grand challenges" of our time. It is also a major opportunity for the knowledge economy and for the Life Sciences & Health industry in particular: innovations in Life Sciences & Health can help overcome this grand challenge, and these innovations will find ready demand in the health and healthcare market, one of the largest and fastest growing markets in the world. The Dutch Life Sciences & Health "topsector" is in a unique position to develop such innovations. The Netherlands has an outstanding industry, a world-leading knowledge base in fundamental and applied science, an excellent infrastructure of university medical centers and hospitals, entrepreneurial insurers, a well-organized healthcare system, health foundations, patient organizations and cooperative regulatory authorities – all working together in a unique infrastructure of public-private partnerships. The Regiegroep Life Sciences & Health endorses the Dutch sector's endeavor to seize this social and economic opportunity for the coming decade. This innovation contract (IC) marks a next step in public-private partnerships within the topsector Life Sciences & Health. Much has already been achieved in recent years, but much more is yet to be gained. We must focus our efforts on where they matter most, socially and economically; we must improve partnerships and find new partnership models to combine knowledge and strengths; and we must accelerate the development and delivery of cost-effective health solutions. The topsector's achievements in recent years have been enabled by a government dedicated to knowledge building and public-private partnerships in Life Sciences & Health. We understand the budgetary constraints in the context of today's uncertain economic climate, but Life Sciences & Health represents a long-term window of opportunity that can help put our economy back on course. Continued investments are necessary. By advancing this promising industry, the productivity of our working population and the affordability of our healthcare will be improved and safeguarded. Other countries around us have recognized this opportunity; the UK government, for example, is investing hundreds of millions of pounds extra in the life sciences industry to improve patient care and fund new medical breakthroughs. There is a clear governmental responsibility to invest in this topsector, and if it does so it will benefit greatly. Hospitals, patients, insurers, public health providers and others will have access to better treatments, more efficient solutions and innovative approaches, all of which are needed to contain rising healthcare costs. Every euro spent on R&D in life sciences will see a return on investment within our own public healthcare system as well as within the global health arena. With its topsector policy, the government has given considerable momentum to the Life Sciences & Health sector. After the delivery of the topsector plan, the topsector Life Sciences & Health mobilized itself again to develop the required roadmaps and realize this IC. This work continues as roadmaps and plans are being further developed. A great deal of time and energy has been invested and many stakeholders have committed to this work in one way or another. Expectations are high: the topsector expects the government to co-invest significantly in research and innovation. We challenge the government to go beyond its current policy of relabeling existing budgets and really commit for the long term to our biggest challenge and biggest opportunity: innovative solutions for high-quality, affordable, labor efficient healthcare thanks to a thriving Life Sciences & Health sector. Together we care. On behalf of the Regiegroep Life Sciences & Health, Rob van Leen, chair of the Regiegroep

Regiegroep Life Sciences & Health

Background The Life Sciences & Health "topsector" plan In June 2011, the Life Sciences & Health sector presented its "topsector" plan to the Minister of Economic Affairs, Agriculture and Innovation. The topsector plan is a vision and an action plan for the Life Sciences & Health sector drafted in cooperation with and supported by many stakeholders in the field. It provides recommendations for the government's industrial and innovation policies. The government's response in its white paper In September 2011, the government reacted to the Life Sciences & Health's topsector plan, as well as to the eight other topsectors' plans, through a white paper ("industriebrief"). Among other requests, the white paper asked the topsectors to develop innovation contracts (ICs): frameworks set by the sectors in which the key players in the sector commit to investment and in which the government is asked to coinvest. The Life Sciences & Health topsector plan and the white paper can be found at www.top-sectoren.nl. The Life Sciences & Health "Regiegroep" Following the topsector plan, the Life Sciences & Health sector established the "Regiegroep", or steering group, which facilitates the implementation of the topsector plan (see regiegroeplsh.nl and Cahier no. IV). The Regiegroep brings the various perspectives of the topsector together, working with taskforces to mobilize the field's knowledge and implementation power. The Taskforce Roadmaps Following the government's request for ICs, the Regiegroep set up the Taskforce Roadmaps. This taskforce was asked to coordinate the design of roadmaps that pave the way for public-private partnership within the topsector. The roadmaps form the core of this IC, which in turn complies with the topsector plan's vision and action plan. Innovation contract or covenant This document is not a contract in the strictest sense of the word. It is not legally binding. It is a covenant that describes the topsector's scope (roadmaps) and the commitment of the key players to public-private partnerships. Actual contracts will be made at the level of individual partnerships in which participants will sign legally binding consortium agreements. The taskforce's approach – the first version of the IC, January 10, 2012 The Taskforce Roadmaps initially sketched the outlines of the strengths of the topsector's innovation infrastructure around which possible roadmaps could be developed. For each strength, a roadmap was then developed by a private-public team of experts set up by the taskforce. Each team was led by a Taskforce member, and companies (including SMEs) played a significant role in each team. The teams and the taskforce enlisted broad input for the roadmaps through online consultation rounds, a discussion session with the entire field (~550 people gathered on December 19), and the mobilization of community networks. The roadmaps developed by the teams were brought together as the basis for the first version of the IC that was shared with the government on January 10, 2012. The composition of the teams and Taskforce Roadmaps can be found in Appendix A.

Regiegroep Life Sciences & Health

The taskforce's approach – this version of the innovation contract After the development of the roadmaps and the first version of the IC, the Taskforce Roadmaps was discharged. Several activities, however, continued for the development of this version of the IC. The roadmap leaders continued to feed the enthusiasm in the topsector for public-private partnership and the IC, and obtained additional commitment for the roadmaps. Furthermore, under the supervision of the taskforce's chairs, six examples of health solutions to randomly chosen disease areas were developed to exemplify the connection between each roadmap and the topsector's contribution to society and economy. The development of each example was led by an expert in the specific disease area and was done in close collaboration with the roadmap leaders. Finally, the financial sections of the IC were further developed. On behalf of the Regiegroep This IC is presented to the government on behalf of the Regiegroep Life Sciences & Health and its "kernteam" (core team). Several Regiegroep members participated in the Taskforce Roadmaps. Stakeholder commitment This IC demonstrates a large commitment of companies, research institutes and other stakeholders to invest in public-private partnership. Many participated in the development of the roadmaps, 408 of them signed letters of intent or support, and proposed new public-private partnerships. And many currently invest in ongoing partnerships. Work in progress: a "rolling agenda" and shaping the governance This IC is a work in progress. Its structure follows the model formulated by the Ministry of Economic Affairs, Agriculture and Innovation. The roadmaps are in constant development and thus represent a "rolling agenda". Periodically over the coming years, the roadmaps and commitment to the topsector will be updated and refined, and connections with other topsectors detailed and strengthened. Importantly, the topsector is shaping a sustainable governance structure to execute this IC. Reading instructions This IC starts with an executive summary that communicates the main messages. Chapter 1 describes the vision and strategy, which have already been detailed in the topsector plan; this document provides a summary and explains the connection between the topsector plan strategy and this IC. As an integral part of the topsector's strategy, it is recommended that the topsector plan is read prior to this document. This IC has four main sections: the agenda of the topsector (chapter 2), how the sector is further developing its governance (chapter 3), the topsector's commitment (chapter 4), and the request to the government (chapter 5). Chapter 2 is built around ten roadmaps; detailed descriptions of roadmaps are of special interest to the expert reader and are provided in section 2.2. Five examples of health solutions for priority disease areas that connect roadmaps are provided in section 2.3, demonstrating the topsector's direct economic and social relevance. The document concludes with background information on the current situation (the starting point, chapter 6) and several appendices.

Regiegroep Life Sciences & Health

Summary Vision and strategy Each year, one hundred thousand Dutch people diagnosed with cancer face the fight of their lives. Two out of five will lose it. Some eight hundred thousand men and women in the Netherlands are likely to see their diabetes lead to cardiovascular problems, retinal damage and/or (chronic) kidney failure. A million more people are developing diabetes as we speak. Such diseases not only impact a person's quality of life, but also his or her ability to work. Of all the "grand challenges" of our time, the biggest may be health related: how do we maintain and improve the quality of ever longer lives, without running out of the money and people to do it? Collective spending on Dutch healthcare and (mental) welfare has grown from 11% of GDP in 2000 to 15% in 2010, which equals about EUR 90 billion. Employment in the care sector has increased by ~40% from 2000 to 2010. If this growth were to continue in an uncontrolled fashion, it could collapse our healthcare system. Much has been said and written about this challenge, and we agree there is cause for concern. But we are also inclined to take an optimistic view. We live longer lives – and that is wonderful. Better yet: today’s challenges are tomorrow’s opportunities. Costeffective healthcare innovations can help us live not just longer, but also healthier and more productively lives – while containing healthcare costs and creating huge opportunities for (new) international business and trade. That is the vision of the topsector Life Sciences & Health: to increase health and wealth for both our society and the economy by turning our biggest challenge into our biggest opportunity. The topsector aims to develop cost-effective health solutions and accelerate their delivery. The topsector aims for a paradigm shift: where in the past innovations often added to healthcare costs by making more treatment possible and thus generating additional demand, tomorrow’s innovations must also reduce costs and labor. That is not a paradox, but a genuine possibility. This innovation contract (IC) contains several examples. To name a few: •

•

Breast cancer is the main cause of cancer-related deaths in women and its incidence is expected to grow by 26% towards 2020. In 2010, about 13,000 Dutch women were diagnosed with breast cancer and about 3,000 died of this disease. Optical imaging can guide surgeons to more completely excise the entire tumor and avoid 23% of repeat surgeries – i.e. improved quality of life at lower costs 2.3 million Dutch people suffer from rheumatic disorders. For the 150,000 with the most severe form, rheumatoid arthritis, no cure exists. Currently, 30% of rheumatoid arthritis patients on biological pharmaceuticals do not respond to treatment. Innovations that reduce the time to predict treatment success from six months to six weeks would save EUR 4,500 per patient on inefficient treatment Dementia is the epidemic of the 21st century. Today’s 250,000 patients in the Netherlands will double by 2040 – and they will require long-term, costly, laborintensive care. Delaying the onset of dementia by a mere five years will reduce prevalence by 50%. With annual costs currently at EUR 3.6 billion in the Netherlands alone, the savings potential is staggering

The topsector Life Sciences & Health, with its innovative industry, excellent knowledge base and strong tradition of collaborative and integrative development, is a vital contributor to the future health and wealth of the Netherlands. The topsector invests over EUR 2 billion in R&D in the Netherlands each year and is becoming a globally recognized stronghold of open innovation. It already accounts for 2.5% of GDP.

Regiegroep Life Sciences & Health

The topsector has developed this innovation contract as part of its action plan (see the Life Sciences & Health "topsector plan" of June 2011). This innovation contract brings together over 400 public and private signatories, an unprecedented number of parties, to create focus and build critical mass around those research and innovation areas in which the sector is strong and can have both societal and economic impact. The topsector Life Sciences & Health cannot solve health challenges alone. Individual lifestyle choices, collective priorities and the organization, funding and efficiency of our healthcare system must also play major roles. The Life Sciences & Health topsector plan and the ensuing innovation contract presented here are far from the whole answer – but they are, we would argue, indispensible parts of that answer and may guide others to contribute.

Actions This innovation contract sets out to deliver integrated solutions to health challenges. To illustrate our approach we have randomly selected six disorders with a high disease burden: breast cancer, infectious diseases, rheumatic disorders, dementia, diabetes and Parkinson’s disease. For each we have detailed potential solutions and quantified their benefits. To enable integrated solutions to these and other diseases, we have developed ten roadmaps to guide research and innovation. The roadmaps are designed to address priorities in health outcomes (age-related, chronic, acute, infectious, orphan and neglected diseases) and along the healthcare chain (from prevention through diagnosis to cure and care). The roadmaps represent the areas in which public and private parties are committed to co-innovate and ask the government to co-invest. Companies, research institutes, practitioners, patient organizations, health foundations, health insurers, regulators, and many others have contributed and endorsed these roadmaps that are the core of this IC. Seven roadmaps (1 through 7) are product-oriented. They are supported by two that deliver health technology assessment (8) and enabling technologies & infrastructure (9). The latter also links to other topsectors with a strong life sciences component, such as Agro-food, Horticulture and Chemistry. A final roadmap (10) is centered around diseases that cause a high burden mainly in the developing world, but for which the developed world can make strides in solving. 1. Molecular diagnostics: Development of candidate biomarkers into validated molecular diagnostics for clinical use 2. Imaging & image-guided therapies: Development of imaging applications for more accurate and less invasive diagnosis and treatment 3. Homecare & self-management: Development, assessment and implementation of technologies, infrastructure and services that promote clients’ abilities to live independently and manage their own care, adequately supported by healthcare professionals 4. Regenerative medicine: Development of curative therapies for diseases caused by tissue damage and ensuing organ dysfunction, through repair or renewed growth of the original tissue or replacement by a synthetic or natural substitute 5. Pharmacotherapy: Discovery, development and stratified use of new, safe and (cost-)effective medicines in order to cure or prevent progression along the healthcare chain 6. One health: Development of solutions like vaccines, optimized antimicrobial use and early warning systems that improve health status of humans and animals by

Regiegroep Life Sciences & Health

coupling the know-how and infrastructure available in the human and veterinary/agricultural domains 7. Specialized nutrition, health & disease: Researching specialized nutrition for nutritional intervention as part of integrated health solutions in terms of prevention, cure and care of chronic, acute and rare diseases 8. Health technology assessment & quality of life: Development of methods and knowledge for health technology assessments in which the impact of health innovations on quality of life, cost-containment and productivity is assessed 9. Enabling technologies & infrastructure: Development and offering of expertise and infrastructure in cutting-edge molecular life science technologies (e.g. next generation sequencing, proteomics and bioinformatics), in biobanks and in ultramodern research facilities, all readily accessible to industry and academia, and with existing, strong links to other topsectors (Agro-food, Horticulture, Chemistry, Biobased Economy and High Tech Systems and Materials) 10. Global health, emerging diseases in emerging markets: Development and delivery of solutions to diseases associated with poverty, which affect more than 2 billion people in the developing world This IC provides the initial details of these roadmaps, which will be rolling agendas periodically updated in the coming years. The roadmaps have been based on combined private and public strengths on which the topsector in recent years built focus and mass and can therefore form internationally competitive partnerships. Moving forward the topsector Life Sciences & Health will also shape public-private partnerships at the interface with other topsectors. Examples include the interface with the topsector Agro-food within the specialized nutrition and one health roadmaps, and the interface with the topsector High Tech Systems and Materials within the imaging and homecare roadmaps.

Structure and governance The topsector Life Sciences & Health has implemented the proactive governance structure proposed in the topsector plan. This structure consists of a Regiegroep and a core team which are responsible for the continuity of the topsector and the implementation of the topsector plan. The Regiegroep works with (temporary) taskforces to implement the plan, such as the Taskforce Roadmaps, which developed this IC. The topsector aims to bundle different public stimulus funds and instruments to act together. The topsector is currently designing a light organization for the public-private innovation infrastructure that will guide the distribution of resources in open competition in order to create focus and mass and to support the most promising public-private partnerships that contribute to the topsector's goals. Three main sets of selection criteria for resource distribution refer to social, economic and scientific merits. The administrative function should be responsive to different types of partnerships and stimulate SME participation. It should be set up to support partnerships in the long term, requiring the ability to include different types of funding from different sources.

Commitment of the topsector In this innovation contract, the topsector Life Sciences & Health demonstrates its strong commitment to public-private partnerships. As of the closure date, February 15, 2012, 408 letters of intent or support were received from organizations in the topsector, corresponding to an intended new investment of EUR 293 million in public-private

Regiegroep Life Sciences & Health

partnerships over multiple years, EUR 130 million of which from private parties. An inventory of public-private partnerships resulted in the identification of 263 initiatives that involve about 800 organizations. The topsector already invests substantially in ongoing public-private partnerships, and several partnerships have recently been developed and are ready to start. Based on the commitment of organizations in the topsector, an indicative financial plan has been developed for investments in public-private partnerships in the coming years. The financial plan describes the potential to grow to new investments of EUR ~350 million per year by 2015/2016, 40% of which are from private resources.

Request to the government The topsector Life Sciences & Health asks the government to support this IC, to continue to invest in public-private partnerships, and to create a more sustainable funding base to support public-private partnerships in the future. The topsector asks the government to make new investments growing to EUR ~100 million public stimuli that can be distributed by the topsector in open competition and EUR ~100 million in kind participation in partnerships by public research institutes by 2015/2016. The topsector understands the present budgetary constraints that make it difficult to fully cover the governmental part of the financial plan on a short notice. Therefore, the topsector Life Sciences & Health urges the government to provide at least EUR 20 million in public stimuli in 2012 as soon as possible; this will enable the topsector to invest freely available resources in open competition in new public-private partnerships in 2012, thus giving the topsector the opportunity to materialize part of the new private commitment and to start implementing the IC. Public organizations that are part of the topsector policy are addressed individually for their contributions. TNO, RIVM, KNAW and DLO are asked to maintain or increase current levels of investments in the topsector Life Sciences & Health and to keep contributing in kind to public-private partnerships. The ministries and the intermediary organizations NWO, ZonMw and STW are requested to carry the investment for public stimuli. The topsector also asks the government to maintain current levels of competitive funding for research and innovation in Life Sciences & Health at research institutes through the "tweede geldstroom". The government is asked to participate in partnerships as a cooperative regulatory authority and launching customer of new products in their first phases of deployment, and enable investments of others through e.g. fiscal support for health foundations and incentives for foreign organizations investing here and Dutch organizations participating in international programs. Finally, the government is asked to design dedicated policies and financial instruments for supporting Life Sciences & Health SMEs.

The starting point The topsector is in a good position to take this next step in public-private partnerships. Through its TTIs and NGI, the topsector has already initiated many successful publicprivate partnerships. New outstanding initiatives such as IMDI have arisen. Funding organizations like NWO, ZonMw and STW play an important role in stimulating academic research and its transfer into industry and healthcare. UMCs have been expressly designed to translate research findings into medical and technical practice, in most cases in collaboration with TUs and WUR, and in some cases in collaboration

Regiegroep Life Sciences & Health

with general hospitals. Strong regional clusters, in which public and private players work together, have been built with clear focus. Dutch industry and academia are heavily involved in European/international research and innovation programs, and organizations like health foundations invest profoundly in research and innovation. The topsector will build on these solid foundations as it looks to the future.

The topsector Life Sciences & Health shows its commitment to invest in the economy and our society, and asks the government to participate. With the government's support, the topsector aims to match technology push and market pull in a strong public-private innovation infrastructure to create a flourishing, knowledge-based Life Sciences & Health industry. And this industry, in turn, will drive economic growth and will meet the needs of society, thereby assuring the delivery of cost-efficient health solutions that really make a difference in improving quality of life and supporting the affordability and labor efficiency of healthcare. An unprecedented number of private and public parties in the topsector have been mobilized around the biggest challenge of our time. It is now in the hands of the government to build on this momentum, seize the opportunity and co-invest in the future of our society and economy.

Regiegroep Life Sciences & Health

Table of contents Foreword by Rob van Leen ........................................................................................... 2 Background .................................................................................................................. 3 Summary ...................................................................................................................... 5 Table of contents ........................................................................................................ 10 1. Vision and strategy – for a healthy and prosperous Netherlands............................. 12 1.1 Vision and ambitions ......................................................................................... 12 1.2 Strategy ............................................................................................................. 14 2. Actions – ten roadmaps developed by the topsector ............................................... 16 2.1 Roadmaps based on strengths, priorities and connections ................................ 16 2.1.1 Roadmaps combine private and public STRENGTHS ............................ 16 2.1.2 Roadmaps respond to PRIORITY disease areas/disorders .................... 17 2.1.3 Roadmaps address PRIORITIES along the healthcare chain ................. 19 2.1.4 Roadmaps CONNECT to create integrated solutions ............................. 20 2.1.5 Six detailed EXAMPLES demonstrate priority and connection ................ 23 2.1.6 Other CONNECTIONS ........................................................................... 24 2.2 Ten roadmaps detailed ...................................................................................... 26 2.2.1 Molecular diagnostics ............................................................................. 27 2.2.2 Imaging & image-guided therapies ......................................................... 32 2.2.3 Homecare & self-management ............................................................... 40 2.2.4 Regenerative medicine ........................................................................... 46 2.2.5 Pharmacotherapy ................................................................................... 52 2.2.6 One health .............................................................................................. 60 2.2.7 Specialized nutrition, health & disease ................................................... 68 2.2.8 Health technology assessment & quality of life ....................................... 81 2.2.9 Enabling technologies & infrastructure .................................................... 86 2.2.10 Global health, emerging diseases in emerging markets ........................ 98 2.3 Six disease examples detailed ........................................................................ 105 2.3.1 Breast cancer ....................................................................................... 106 2.3.2 Infectious diseases ............................................................................... 111 2.3.3 Rheumatic disorders ............................................................................. 116 2.3.4 Dementia .............................................................................................. 120 2.3.5 Diabetes ............................................................................................... 125 2.3.6 Parkinson's disease .............................................................................. 130 3. Structure and governance – a proactive topsector ................................................ 135 3.1 Organization of the topsector Life Sciences & Health ...................................... 135 3.2 Organization of the public-private innovation infrastructure of the topsector .... 136 3.3 Value creation ................................................................................................. 138 3.4 Monitoring progress ......................................................................................... 139

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4. Commitment – a strongly committed topsector ready to invest ............................. 140 4.1 Commitment of the topsector........................................................................... 140 4.2 Indicative financial plan based on the sector's commitment ............................. 142 5. Request to the government – invest with us in health and the economy ............... 145 5.1 Request to the government to invest in public-private partnerships ................. 145 5.2 Request to individual organizations that are part of the topsector policy to invest in public-private partnerships ................................................................................. 146 5.3 Other requests to the government and public organizations ............................ 147 6. The starting point – unique foundations for partnership ......................................... 149 6.1 National research and innovation programs .................................................... 149 6.2 Regional innovation programs ......................................................................... 152 6.3 International innovation programs ................................................................... 153 6.4 Other innovation programs .............................................................................. 154 Appendix A: Composition of the Regiegroep, taskforce and roadmap teams ............ 156 Appendix B: Letters of intent and support ................................................................. 159 Appendix C: Inventory of new and ongoing public-private partnerships .................... 174 Appendix D: Participants in public-private partnerships............................................. 183

Regiegroep Life Sciences & Health

1. Vision and strategy – for a healthy and prosperous Netherlands The topsector Life Sciences & Health, with its innovative industry and strong knowledge base, is a vibrant sector in the Netherlands. It stands at the center of one of the "grand challenges" of our time: to secure high quality, affordable and adequately staffed healthcare. The topsector envisions a healthy and prosperous future for the Netherlands, and sees itself playing a crucial role in its realization. It is in tackling this challenge where the economic opportunities for the industry lie. In its topsector plan and resulting action plan of 2011, the sector set out how it aims to enhance the quality of life, the sustainability of healthcare, labor productivity and innovative enterprise in the Netherlands. This innovation contract gives body to part of this action plan by drafting the framework in which private and public partners will come together to develop cost-efficient health solutions and accelerate their delivery to patients and other end-users. By involving end-users in the earliest phases of development, the actual use of these solutions will be assured.

1.1 Vision and ambitions The topsector Life Sciences & Health set out its vision and ambitions in its topsector plan. A brief summary follows below. For details, please refer to the complete topsector plan.1 The topsector Life Sciences & Health – a vibrant sector In the Netherlands, Life Sciences & Health is an innovative and technology-intensive sector focused on human and animal health. The sector is made up of companies and research institutes in fields ranging from medical technology and (clinical) ICT to (bio)pharmaceuticals and regenerative medicine. Vibrant local clusters exist, each with its own focus and strengths. The Life Sciences & Health sector plays a significant role in the Dutch economy, accounting for 2.5% of GDP and 2.5% of the workforce, and provides solutions to a healthcare and welfare sector, its customer, which is responsible for about 15% of GDP, or EUR ~90 billion of collective spending in the Netherlands. The knowledge base upon which the Life Sciences & Health sector stands is first-rate. Dutch science is among the top 4 in the world. University medical centers (UMCs) lead international rankings in clinical research and technical universities (TUs) and the Wageningen University for Healthy Food and Living Environment (WUR) are at the forefront of health-related technology. Knowledge-based companies like Philips, DSM, MSD Animal Health and Crucell are global leaders in their fields. Over EUR 2 billion is invested each year in Life Sciences & Health R&D by companies and research institutes, making it the second-largest R&D investor among the topsectors. That investment is increasingly made in the model of open innovation, where companies innovate together and with research institutes, sharing benefits and costs. Over the last five years alone, companies, research institutes and the government have invested EUR ~1 billion in open innovation through public-private partnerships. The Netherlands' infrastructure for open innovation and the translation of knowledge into (clinical) application has become internationally recognized. Dutch companies are competing and partnering at an international level, and have been involved in the biggest biotech deals in Europe. Our innovative SME base is being continuously bolstered by this increased international business activity, and the Netherlands is becoming a global stronghold of open innovation in Life Sciences & Health. 1

Topsectorplan Life Sciences & Health, Voor een gezond en welvarend Nederland, 2011

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The knowledge base and open innovation infrastructure are, however, under pressure. Public investments are falling significantly behind other countries and much has been built on temporary funds. Continuity, focus and bundling of investments are needed to preserve this engine of innovation. Vision – a healthy and prosperous future "Health" is no longer seen as the mere absence of disease or disorder, but as the capacity to cope, adapt and self-manage, even in the presence of disease or disorder. This vision focuses healthcare not merely on the cure of acute threats, but also on preventing disease through lifestyle management and early detection, and on improving quality of life through long-term care when needed. But expanding healthcare from cure (which is already exploding itself), to the “pre-cure” and “after-cure” phases imposes an ever increasing economic burden on society. The demand for healthcare is growing rapidly, not only because there are more opportunities for cure and care, but also because population ageing and affluence mean we need more and want more. At the same time, ageing is shrinking the Dutch labor population, resulting in lower availability of healthcare workers. Healthcare thus faces the challenge to raise productivity levels while at the same time managing costs and labor, and is in danger of collapsing under this growing burden. The topsector sees itself playing an important role in facing this challenge and achieving a healthy and economically prosperous Netherlands. For the topsector Life Sciences & Health this is not only a large social challenge, but also a major economic opportunity. By developing and supplying cost-efficient innovations, the topsector can enhance the quality of life, the sustainability of healthcare, labor productivity and innovative enterprise in the Netherlands and abroad (see figure 1). That is where the business is and how competitiveness of the Life Sciences & Health industry will grow. Social and economic demands

Products and technologies

Economy

Health

Society

Applications

> Healthcare

Prosperity

SUSTAINABLE HEALTHCARE Tempered growth of healthcare costs through costefficient solutions

BUSINESS ACTIVITY Companies prospering on the (inter)national markets

Self-management

LIFE SCIENCES & HEALTH

Targeted therapies

A more productive population within and beyond healthcare

Prevention

PRODUCTIVITY

Longer, healthier lives

Early diagnosis

QUALITY OF LIFE

> > Medical (Bio)technology pharmacology

> > > >

Diagnosis (e.g. Lab-on-chip) (Molecular) imaging techn. Techno/ Minimallyinvasive techn. logy …

> > > >

Patient information/ biobanks E-health Clinical decision support …

Medicines Vaccines "Biologicals" …

Regenerative medicine

> System biology > ...

> Biomaterials for implants > Stem cell therapies > …

Figure 1. Seizing economic opportunities and answering social challenges (figure from the topsector plan) Ambition – the Life Sciences & Health sector as a global leader By 2025, the Dutch Life Sciences & Health sector will be among the global leaders. To achieve this ambition, the topsector aims to rapidly increase the size of the industry, R&D employment, the R&D portfolio and exports. The topsector plan describes these objectives in detail. Underlying the sector's success and rapid growth will be innovative products and solutions that achieve fast and effective application in the Dutch and international

Regiegroep Life Sciences & Health

healthcare markets. For this, the sector must have at its disposal an innovation system with a large and continuous influx, rapid throughput and evaluation, and high output. And therein the sector must focus on where it is inherently strong, where there is enough critical mass, and where there is market demand or a strong demand for a global public good – a translational approach that accelerates development and (clinical) implementation of health solutions.

1.2 Strategy The Life Sciences & Health topsector plan lays out an action plan to realize its ambitions. That action plan identifies the conditions (the "critical preconditions") necessary for the topsector to succeed (see figure 2). This IC outlines the steps to be taken towards a number of these conditions by guiding research and innovation through ten roadmaps. Roadmaps are the innovation themes of this topsector and provide the framework in which the government is asked to invest. A shared public-private innovation infrastructure Innovation in Life Sciences & Health is not a linear process. Clinical demand (from patients and medical professionals) forms the basis of research, and clinical practice plays a central role throughout the process of development, testing and approval. Entrepreneurs, healthcare providers, patients and (non)clinical scientists must therefore work closely together from beginning to end. This is a demanding process. Innovations often involve large risks and investments, and go beyond the knowledge and resources of individual organizations. A shared public-private innovation infrastructure that brings all stakeholders together, and which accelerates the development and (clinical) application of health innovations, is therefore indispensible. To realize the critical precondition in the topsector plan "a shared public-private innovation infrastructure", this IC guides the focus of the innovation infrastructure through ten roadmaps (chapter 2), sketches the outlines for the public-private innovation infrastructure's organization (chapter 3), and creates commitment for partnership (chapter 4). Proving grounds as a promising concept for public-private partnership The Netherlands can be the world’s workshop for health solutions. We have a unique infrastructure to identify, inoculate and monitor large numbers of (selected) people over long periods of time, and expertise in disease areas and clinical trials. For example, we are running the largest ever vaccine study in the world (80,000 people, for pneumococcus). One of the topsector plan's actions is to seize this opportunity by setting up "proving grounds" ("proeftuinen") in which promising innovations are being developed, tested, monitored and validated in an apt and optimized environment. Proving grounds create not only social value (affordable health solutions and labor productivity in healthcare) but also economic value: for companies that market their validated innovations as well as for contract/clinical research organizations that support the testing stages. This IC foresees proving grounds as an increasingly frequent model for public-private partnerships. The roadmaps guide their scope, and this IC shows commitment from the many stakeholders that are needed for successful proving grounds. This includes commitment from users that create demand and support testing; commitment from health insurers that finance innovation, supply data and expertise for research and analysis, monitor and evaluate health solutions, and stimulate rapid uptake in the reimbursem*nt packages; and commitment from regulatory authorities and government

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that create fast procedures for clinical research, conditional reimbursem*nt and public purchasing policies. A strong knowledge base A high influx of new insights and promising ideas into a shared public-private innovation infrastructure strongly depends on the continuity of a knowledge base that is not only world leading, but is also open to (innovative) entrepreneurs. A strong, accessible knowledge base is one of the critical preconditions in the topsector plan. Fundamental research is a cornerstone of innovation. It provides the creative and scientific basis for applied research activities in the roadmaps. To maintain the excellence and expertise of the workforce that is employed by private enterprises, it is a main task of publicly funded research institutes to provide internationally competitive, high-quality education and fundamental research training that is independent of commercial influence. In line with the topsector plan, this IC argues for maintaining sufficient investments in this important task. Through the involvement of research institutes in the development of the roadmaps and the articulation of areas where significant fundamental research is required, this IC aims to pave the way for easier and more effective use of fundamental research results in public-private partnerships.

APPLICATION of medical solutions in the HEALTHCARE SECTOR*

DEVELOPMENT of new MEDICAL SOLUTIONS*

DEMAND and MARKET driven

NL Life Sciences & Health sector among the global leaders

GENERATION of new IDEAS

KNOWLEDGE driven

IDEA GENERATION

DEVELOPMENT

APPLICATION

Increase the number of promising ideas

Accelerate the development process and heighten the chance of success

Accelerate and broaden effective application (nationally and internationally)

1 Demanding Dutch market with a portal into Europe and the rest of the world

2 Optimized legal and regulatory landscape 3 Enough well educated, entrepreneurial people 4 Good accessibility to the right capital 5 Strong, accessible (fundamental) knowledge base 6 Shared public-private innovation infrastructure 7 The Netherlands as one self-organized Life Sciences & Health sector * The terms medical solutions and healthcare sector are used broadly in this figure, and include self-management, veterinary solutions, etc.

Figure 2. Critical preconditions for the topsector to realize its ambitions (figure from the topsector plan)

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2. Actions – ten roadmaps developed by the topsector The topsector Life Sciences & Health has developed ten roadmaps to guide research and innovation. These roadmaps represent the areas in which private and public parties (companies, research institutes, practitioners, patient organizations, health foundations, health insurers, regulatory authorities, etc.) are committed to coinnovation, areas in which the government is asked to invest. Roadmaps have been identified based on combined private and public strengths. They are being detailed and executed to respond to priority disease areas/disorders and priorities along the healthcare chain (from prevention through diagnosis and cure to care). Roadmaps connect with each other to form integrated solutions to health challenges. This is illustrated by six detailed case examples of integrated health solutions for several randomly chosen, high-burden diseases. These cases also demonstrate the impact of the topsector Life Sciences & Health and public-private partnerships therein on quality of life, affordability of healthcare, productivity and business activity. The roadmaps will also be increasingly connected to other topsectors such as Agro-food and HTSM. 2.1 Roadmaps based on strengths, priorities and connections The roadmaps – the focal points of the public-private innovation infrastructure of the topsector – are based on strengths, health priorities and connections: • STRENGTHS of the topsector: areas where there is innovative industry and demand from industry which can be coupled with a strong knowledge base and through which economic and scientific value can be created (section 2.1.1) • PRIORITY of the health challenges and solutions to which the roadmaps respond, in terms of quality of life and affordability/productivity of healthcare, through which social as well as economic value can be created (sections 2.1.2 and 2.1.3) • CONNECTIONS between and within roadmaps to achieve integrated solutions to health challenges (sections 2.1.4) Detailed descriptions of the roadmaps are provided in section 2.2. Detailed examples of the development of integrated health solutions for randomly chosen diseases which connect roadmaps are provided in section 2.3 and are summarized in 2.1.5. Section 2.1.6 discusses other connections such as those with other topsectors. 2.1.1 Roadmaps combine private and public STRENGTHS Ten roadmaps have been defined which combine the strengths of industry and (applied) research institutes. Within these subjects the topsector has built focus and mass in recent years and can form internationally competitive partnerships. Seven of the ten roadmaps represent product groups (1-7). Two roadmaps deal with supporting fields of health technology assessment, quality of life, enabling technologies and infrastructure (8-9). One roadmap has been developed to offer a platform on which the knowledge and competencies of Dutch companies and research institutes can be connected to global emergencies (10). The ten roadmaps are: 1. Molecular diagnostics: Development of candidate biomarkers into validated molecular diagnostics for clinical use 2. Imaging & image-guided therapies: Development of imaging applications for more accurate and less invasive diagnosis and treatment 3. Homecare & self-management: Development, assessment and implementation of technologies, infrastructure and services that promote clients’ abilities to live independently and manage their own care, adequately supported by healthcare professionals

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4. Regenerative medicine: Development of curative therapies for diseases caused by tissue damage and ensuing organ dysfunction, through repair or renewed growth of the original tissue or replacement by a synthetic or natural substitute 5. Pharmacotherapy: Discovery, development and stratified use of new, safe and (cost-)effective medicines in order to cure or prevent progression along the healthcare chain 6. One health: Development of solutions like vaccines, optimized antimicrobial use and early warning systems that improve health status of humans and animals by coupling the know-how and infrastructure available in the human and veterinary/agricultural domains 7. Specialized nutrition, health & disease: Researching specialized nutrition for nutritional intervention as part of integrated health solutions in terms of prevention, cure and care of chronic, acute and rare diseases 8. Health technology assessment & quality of life: Development of methods and knowledge for health technology assessments in which the impact of health innovations on quality of life, cost-containment and productivity is assessed 9. Enabling technologies & infrastructure: Development and offering of expertise and infrastructure in cutting-edge molecular life science technologies (e.g. next generation sequencing, proteomics and bioinformatics), in biobanks and in ultramodern research facilities, all readily accessible to industry and academia, and with existing, strong links to other topsectors (Agro-food, Horticulture, Chemistry, Biobased Economy and High Tech Systems and Materials) 10. Global health, emerging diseases in emerging markets: Development and delivery of solutions to diseases associated with poverty, which affect more than 2 billion people in the developing world 2.1.2 Roadmaps respond to PRIORITY disease areas/disorders An ageing population and the rise of chronic disease threaten to collapse our healthcare system. Particularly in terms of quality of life and the affordability and adequate staffing of healthcare, the entire healthcare chain is under pressure (examples are quantified in figure 3). The topsector aims to address priority disease areas/disorders to maintain the quality and sustainability of healthcare, and has developed the roadmaps to target these health challenges. Some examples include: •

•

The homecare & self-management roadmap includes the targeting of high cost/burden diseases such as COPD through the development of systems that measure health/disease indicators to enable patients to manage their medical condition themselves with professional support, which would result in fewer hospital visits and thus in lowered healthcare labor demand and costs The imaging & image-guided therapies roadmap targets, among other issues, the number one cause of death, cancer, by looking at imaging tools for accurate surgical removal of tumors and new imaging-guided radiation therapies using particles that can accurately target a tumor and leave surrounding tissue healthy; the last prevents secondary tumors at later age, reducing future healthcare costs The specialized nutrition, health & disease roadmap includes the development of nutritional products that provide precursors that the brain needs to synthesize building blocks of membranes and synapses in order to improve brain function in (early phases of) neurodegeneraton such as in dementia, a major cause of healthcare cost and disease burden The regenerative medicine roadmap aims in part to address high cost/burden chronic diseases like cardiovascular disorders by producing patient specific bioactive implants for tissue like heart valves but also for bone, cartilage (articular cartilage, intervertebral disc, meniscus), muscle, lung, intestine and gastrointestinal tract organs (pancreas/insulin-producing cells, liver)

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Cost vs. burden of a selection of diseases Cost [EUR m/year] 5,800 Dementia

Learning disabilities

1,800

Coronary heart diseases Stroke

1,600 1,400 1,200

Diabetes incl. complications Asthma and COPD

Alcohol or drug addiction

1,000

Hearing disorders Schizophrenia Osteoarthritis

800

Depression

Vision impairments Lung infections and influenza Renal disease Breast cancer Rheumatoid arthritis Heart failure Lung cancer Colon and rectal cancer

600 400 200

Anxiety disorders

0 0

50,000

100,000

150,000

Source: RIVM, kosten van ziekten, 2007; RIVM, ziektelast in DALY's;

Labor handicap [# people x 1000 of ages 15-65 with disease/handicap of duration >6 months]

Causes of death [# deaths x 1000 in 2010] Total

136 44

Cancer 39

Cardiovascular 13

Respiratory 8

Mental health disorders

External causes Digestive organs

Other

Source: CBS

200,000 250,000 300,000 Burden [Disability-adjusted life years]

Neck/back complaints Problems in the legs or feet Problems in the arms or hands Mental health problems Migraine/severe headache Bronchitis, asthma or CARA Cardiovascular disease Stomach or bowel problems Hearing problems Diabetes Other complaints Life-threatening illness Severe skin disease Epilepsy

919 691 614 410 359 255 247 236 144 124 120 88 76 36

Source: RIVM, kosten van ziekten, 2007

Total cost of care 100

Distribution of costs over healthcare services

Cost [EUR billion] (left axis)

16%

Share of GDP (right axis)

14%

60 12% 40 10%

20 0 1972 1980

1990

2000

8% 2010

Source: CBS

Total Hospital care and medical specialists Elderly care Medicines, supportive materials Public welfare Emergency care Handicapped care Mental health Other healthcare services Management Public healthcare and prevention Ambulences and transportation

100% 26% 19% 12% 11% 9% 8% 6% 3% 3% 2% 1%

Source: RIVM, kosten van ziekten, 2007

Employment in the care sector [Full time equivalent, FTE] 1,000

14%

FTE in care sector *1000 (left axis) Share of the care sector in total FTE in the economy (right axis)

800

12%

600 10% 400 8%

200 0 1970

1980

1990

2000

6% 2010

Source: CBS

Figure 3. Examples of health challenges quantified for the Netherlands – illustrative, not exhaustive

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2.1.3 Roadmaps address PRIORITIES along the healthcare chain Adequate response to health challenges demands new cost-effective applications and processes in the healthcare chain, from prevention through diagnosis and cure to care, which contribute to the following priorities: • Keep people healthy as long as possible: Prevention is better and cheaper than cure or care, as it maintains a high quality of life and keeps people out of the hospital, the largest of the healthcare costs (figure 3) • Diagnose early, before complications arise: The more an illness develops, the higher the disease burden and costs are for healthcare system • Individualize treatment for best results: Treatments that are fine tuned to the individual improve treatment results and prevent unnecessary actions from being taken, reducing healthcare costs and improving quality of life • Treat with minimal side effects: Minimally invasive methods ensure that the patient heals faster and therefore returns to his/her activities sooner – thus reducing the disease burden • Replace or repair bodily functions: Regaining bodily function similar to its original healthy state significantly improves the quality of life of many patients, keeping them out of long-term, expensive care situations • Move from care to cure (unmet needs): Applications that make chronic disease treatable, reduce costs, improve productivity and offer patients better quality of life • Reduce symptoms, slow down disease: A priority for many chronically-ill patients is the ability to enjoy their lives more and longer • Enable chronic patients to stay at home: Making it possible for chronically-ill patients to function in their own homes not only contributes significantly to their quality of life, but also potentially means significant cost and productivity savings PREVENT

DIAGNOSE

CURE

CARE

PRIORITIES ALONG THE HEALTHCARE CHAIN Keep people healthy as long as possible

Diagnose early, before complications arise

Individualize treatment for best results

Treat with minimal side effects

Replace or repair bodily functions

Move from care to cure (unmet needs)

Reduce symptoms, slow down disease

Enable chronic patients to stay at home

ROADMAPS

Figure 4. Roadmap themes and their relation to priorities along the healthcare chain The roadmap subjects chosen have the potential to address one or more of these priorities along the healthcare chain. Figure 4 summarizes the relationship between the roadmaps and these priorities, for example: •

Biomarkers developed in the molecular diagnostics roadmap not only enable "early diagnosis, before complications arise" as one of the priorities along the healthcare chain, but also "keep people healthy as long as possible" through identification of

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• •

risk factors and "individualize treatment for best results" by supporting treatment choice and monitoring treatment results A main concern of the pharmacotherapy roadmap is to reduce the total costs of the healthcare system by developing medication that prevents progression of a patient along the healthcare chain, thus addressing all priorities along the chain The one health roadmap develops solutions to improve human immune competence to reduce the disease burden and to keep people healthy, as well as early warning systems for early diagnosis

2.1.4 Roadmaps CONNECT to create integrated solutions The applications that will be developed within an individual roadmap may represent only a partial solution to a health challenge. For example, a diagnostic tool by itself does not improve a patient's life or reduce healthcare costs. Costs and employment savings and a higher quality of life, rather, are optimized when applications (and thus roadmaps) are connected to form integrated solutions to priority health challenges throughout the healthcare chain. Note that integrated solutions are seen in the global context; by no means should all elements of a solution be developed by the Dutch Life Sciences & Health sector alone. The topsector is connecting roadmaps, examples include: •

•

• •

•

Individualized or optimized treatment requires companion diagnostics to predict which treatment will work in someone or what kind of dose is needed. The roadmaps molecular diagnostics, pharmacotherapy, one health and enabling technologies & infrastructure are thus linked Image-guided therapies are an integral part of the regenerative medicine strategy, since they are essential for the accurate delivery of cells, biomaterials and combinations thereof, connecting the roadmaps regenerative medicine and imaging & image-guided therapies The important theme of healthy ageing connects many roadmaps. For example, improving the quality of life of elderly suffering from multiple chronic diseases requires integrated solutions that combine nutrition, pharmacotherapy, molecular diagnostics and imaging techniques, self-management and ICT tools to reduce symptoms, slow down disease, monitor disease progression, keep the patient longer at home, and prevent other health issues. The theme directly plays into the second largest cost driver of our healthcare system: elderly care (figure 3) Along the same lines, major diseases like cancer, cardiovascular disease and dementia require multiple connections between roadmaps, as illustrated with detailed examples in section 2.3 and summarized in section 2.1.5. Technologies and solutions developed in several roadmaps can be used in the global health roadmap to tackle diseases in developing countries. For example, knowledge from the one health roadmap could shed light on diseases that arise in developing countries where humans and animals often live in close proximity The roadmap health technology assessment & quality of life is by nature connected to all other roadmaps providing the knowledge to assess cost-efficiency The roadmap enabling technologies & infrastructure offers the platform for optimizing the accessibility and quality of cutting-edge molecular life science expertise and technologies, and biobanking infrastructure, which can be applied in all roadmaps and in several other topsectors (see box on enabling technologies & infrastructure) Refinement, reduction and replacement of animal experiments (3R) are addressed by a majority of the roadmaps. Innovative 3R models improve the predictive value of the (pre)clinical development and accelerate the creation of integrated health solutions (see box on 3R).

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BOX – Enabling technologies & infrastructure (ET&I) Establishing a next generation life sciences technology research infrastructure in the Netherlands The roadmap enabling technologies & infrastructure ensures that existing expertise and facilities in biobanking (DBH) and in cutting-edge life science technologies (DTL) are actively embedded in the topsector Life Sciences & Health. DTL brings together genomics/next generation sequencing, proteomics, metabolomics, bioimaging, bioinformatics and systems biology. ET&I effectively bridges the Life Sciences & Health research infrastructure with other topsector agendas, aiming to establish a framework of interconnected national facilities of top quality. Thus, technology and infrastructure investments are optimally tuned to the priorities of Life Sciences & Health and other topsectors, linked to the international technology arena, while combining scientific excellence with the availability of high-end technologies through accessible facilities.

Life Sciences & Health roadmaps Global health

HTA & quality of life

Specialized nutrition

One health

Pharmacotherapy

Regenerative medicine Homecare & selfmanagement Imaging & imageguided therapies Molecular diagnostics

Enabling Technologies & Infrastructure

ICT BioBased Economy

Dutch Techcentre For Life Sciences Molecular Life Sciences technology research infrastructure

DFF

Set up as a national facility • Active embedding in the Life Sciences & Health roadmaps and other topsectors • Collection of Dutch nodes in international life sciences research infrastructures • Delivering excellence in technology research to academia, industry and publicprivate partnerships • Sustaining a strong and visible biobanking and life sciences technology community in the Netherlands • Driving technology research and (open) innovation programs Proposition to tune sector-funding instruments • Towards coordinated and cross-sector investments in accessible facilities • Budget for technology use and data stewardship in research proposals (and evaluations)

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BOX – Refinement, Reduction and Replacement (3R) of animal testing within the topsector Life Sciences & Health, across roadmaps and disease areas Animal testing is costly and time consuming. Moreover, it is increasingly considered unethical and can even be in conflict with certain EU legislation. It has also been realized that current animal-based predictive tests for human drug safety and efficacy are not sufficiently reliable. Development and implementation of innovative models and technologies in biomedical research that (i) predict health developments, (ii) prevent adverse health effects, (iii) shorten the time to “first-into-human” phase, and (iv) are non-animal-based, are urgently needed. For neurological diseases, cardiac diseases and cancer, embryonic stem cell-derived neurons, cardiomyocytes and hepatocytes have already been shown to provide predictive models which are valuable alternatives to animal models. To advance the translation of in vitro (outside the body) predictive biomarkers, molecular diagnostics, cell assays, etc., it is important that cells and tissues from relevant patient groups, including patients showing adverse drug reactions, become available, preferably through dedicated, high-quality biobanking. This will lead to better risk assessment strategies and safer chemicals (pharmaceuticals, cosmetics, industrial chemicals, food ingredients) which may increase quality of life, reduce health risks for patients, consumers and employees, and thus reduce healthcare costs. Other innovative methods such as -omics, systems biology and tissue culture provide insight into basic mechanisms in humans, both healthy and diseased. Cell and organ cultures, for instance, are used in pre-clinical developments of joint diseases like rheumatoid arthritis and osteoarthritis. This increase in knowledge of human biology will eventually replace animal experiments. After all, ultimately we develop treatment methods and medicine to treat diseases in human, and not in (healthy) laboratory animals. 3R alternatives are based on transdisciplinary initiatives. Different disciplines will seek out and work together to arrive at an integrated result not only in the research community, but also with other parties. Public-private partnerships have already demonstrated their ability to increase the development of such models and technologies. A good example is the Netherlands Toxicogenomics Centre (NTC), which is an existing private-public partnership in which Dutch toxicology groups working in the public domain collaborate with multiple national and international industrial parties and governmental authorities. NTC organizes research on alternatives to animal testing with regard to human safety. In the past ten years, private partners from the pharmaceutical industry (MSD, GlaxoSmithKline, Astra Zenica), health foundations (Hartstichting, Koningin Wilhelmina Fonds), animal welfare organizations (Stichting Proefdiervrij, Dierenbescherming) and small and medium enterprises (Notox B.V.) have participated in the ZonMw programs on 3R. In the program “Meer Kennis met Minder Dieren”, 80% of the recently submitted proposals involve the industry. Research on alternatives to animal experimentation directly connects to Life Sciences & Health roadmaps on enabling technologies, pharmacotherapy, molecular diagnostics, regenerative medicine and nutrition. Furthermore, it connects to other topsectors, e.g. Chemistry and Agro-food, as well as to the umbrella ICT roadmap. Special attention will be given to connect the various activities in this area and to implement results from one roadmap into another.

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2.1.5 Six detailed EXAMPLES demonstrate priority and connection To convincingly show that the topsector addresses major (health) priorities through connecting roadmaps, six examples have been detailed further. These examples detail integrated solutions along the healthcare chain for randomly chosen, high-burden diseases: breast cancer, infectious diseases, rheumatic disorders, dementia, diabetes and Parkinson's disease. The examples demonstrate the major impact that the topsector and its public-private partnerships has on society and economy: on quality of life, the affordability of healthcare, productivity and business activity. Some highlights are provided in figure 5; details can be found in section 2.3. Health challenge

Solution

Benefit (example)

Roadmaps

Breast cancer Number 1 cause of cancer-related death in women: 327,000 deaths and 1.35 million new cases every year. 26% more new cases expected in 2020.

Combinations of new biomarkers, imaging techniques and drugs, which support early detection and optimal treatment (surgical and non-surgical) tailored to patient and tumor.

Optical imaging can guide surgeons to obtain tumor-free margins. This can avoid up to 23% of the repeated surgeries.

Developed around: • Molecular diagnostics • Imaging • Pharmacotherapy

Infectious diseases

Antibiotic resistance is increasing. The prospect of untreatable infections caused by pathogens that rapidly cross species and country borders is no longer hypothetical.

Better surveillance, improved diagnostics, optimal use of antibiotics, prevention of resistance transmission and infections, and the development of new antibiotics.

The Netherlands is home to leaders in antibiotic resistance control. Solutions appeal to international markets, incl. BRIC countries that face large problems with antibiotic resistant bacteria.

Developed around: • Molecular diagnostics • Pharmacotherapy • One health • Specialized nutrition • HTA & quality of life • Global health

Rheumatic disorders

2.3 million Dutch patients of which 150,000 with the most severe form, rheumatoid arthritis, for whom no cure exists. 50% of patients are under 65, heavily affecting the working population.

Early stage biomarkers and new medicines are required to detect the disease up to ten years earlier, stop progression and eventually cure the disease.

30% of patients on biologicals do not respond to the treatment. A reduction from 6 months to 6 weeks for prediction of treatment success saves EUR 4,500 per patient.

Developed around: • Molecular diagnostics • Imaging • Homecare • Regenerative med. • Pharmacotherapy • HTA & quality of life

Dementia

Epidemic of the 21st century: 250,000 Dutch patients, doubling towards 2040. Patients need costly, laborintensive care; affordability and availability coming under pressure.

Unraveling the origins of disease to find solutions to delay onset and progression, and supporting selfmanagement, i.e. through an online ehealth patient portal.

Delay of disease by 5 years reduces prevalence by 50%. With current cost of EUR 3.6 billion per year in the Netherlands, this would save several billions of Euros.

Developed around: • Molecular diagnostics • Imaging • Homecare • Specialized nutrition

Diabetes

800,000 Dutch patients increasing by 10% annually and the onset of type 2 diabetes occurs at ever-younger age; causing high (in)direct costs and significantly reducing our workforce.

New methods to predict and prevent type 2 diabetes, cell therapies to cure type 1 diabetes, and eHealth solutions for better personalized follow-up are required.

Dutch export products of better prediction, therapies and follow-up improve the quality of life, repair the mismatch between number of patients and care providers, and cut the costs for diabetes.

Developed around: • Molecular diagnostics • Regenerative med. • Homecare • Pharmacotherapy • Specialized nutrition • HTA & quality of life • Enabling tech & infra • Global health

Parkinson's disease

50.000 Dutch patients, doubling towards 2013. Patients need laborintensive and costly care. The annual direct costs in the Netherlands are EUR 180 million.

Combination of primary and secondary preventative measures (e.g. nutrition) personalized treatment, self-management tools, and specialized networks like ParkinsonNet.

ParkinsonNet reduces healthcare costs, by as much as EUR 20 million annually. It also reduces complications: e.g. the number of hip fractures is reduced by 50% in ParkinsonNet regions.

Developed around: • Molecular diagnostics • Imaging • Homecare • Pharmacotherapy • Specialized nutrition • Enabling tech & infra

Figure 5. Disease example highlights

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2.1.6 Other CONNECTIONS Next to connecting private and public strengths within the roadmaps, and connecting roadmaps to create integrated solutions, the topsector Life Sciences & Health is making connections on many other levels, summarized in table 1. SUBJECT OF CONNECTION Accelerate implementation

Different stages of R&D National innovation programs

EU/ international themes

Regions

Other topsectors

BRIEF DESCRIPTION The topsector aims to connect all stakeholders necessary to accelerate actual (clinical) implementation by connecting companies and research institutes in public-private partnerships not only with each other, but also with users (practitioners/patients), payers (health insurers), regulators, applied research institutes, health foundations and other relevant stakeholders. Many such parties are already involved in existing public-private partnerships, and have participated in designing the roadmaps. This acceleration to (clinical) implementation through public-private partnerships will be an important factor in the implementation of the roadmaps. The roadmaps connect different stages of R&D. Roadmaps involve activities across the entire innovation chain, from fundamental research to strategic and applied research, development and implementation of health solutions. The roadmaps connect existing and new national innovation programs. For example, the enabling technologies & infrastructure roadmap connects various technology partnerships in the Dutch Techcentre for Life Sciences, integrates several biobanking initiatives, and connects the technology program with biobanking. Roadmaps aim to connect and strengthen the most successful activities in ongoing programs, as well as to start up new, promising activities that will fundamentally contribute to the roadmaps. Roadmaps are closely linked with EU themes. Roadmaps include ongoing European initiatives that link the Dutch innovation infrastructure to other countries, like the EATRIS initiative led by the Netherlands, BBMRI, the European and Developing Countries Clinical Trials Partnership, and the many Dutch participants in consortiums under the Innovative Medicines Initiative. The Dutch Federation of University Medical Centers (NFU) is one of the frontrunners in detailing the EU grand challenge of healthy ageing through its position paper on the matter (see the box on active and healthy ageing). The topsector will collaborate with other topsectors and government to design an adequate interface between the Dutch and EU policies in order to tap into important EU funding sources. Several roadmaps are closely linked to global health priorities, in particular the UN Millennium Development Goals that are related to health, nutrition and strengthening pharmaceutical innovation, and could be linked to funding opportunities provided by global health organizations and the World Bank. The roadmaps also connect to activities underway in various regions. For example, the ultra-high throughput screening facility at the Life Sciences Park in Oss aims to support the Dutch life sciences community as a whole. And the regional initiatives Immuno Valley and Utrecht Life Sciences are growing to become a national network within the one health roadmap. Roadmaps connect to other topsectors, for example: • The roadmaps imaging & image-guided therapies, molecular diagnostics, and homecare & self-management are closely linked to the High Tech Systems & Materials (HTSM) topsector and the theme of nano and micro technology. HTSM develops high-tech instruments like imaging equipment and microscopes, which the Life Sciences & Health sector uses to develop and deliver clinical applications. The topsector Life Sciences & Health already has much experience in shaping publicprivate partnerships at the interface with HTSM and will continue to do so. Existing examples include CTMM, IMDI and Cyttron II (see chapter 6) that have close connections to HTSM and involve many partners that are active in both topsectors

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Social research

The roadmaps specialized nutrition, health & disease and one health are closely connected to the Agro-food and Horticulture topsectors. Knowledge and applications developed in these roadmaps and in these two topsectors can be transferred and shared • Aspects of the roadmaps enabling technologies & infrastructure and homecare & self-management are closely connected to the umbrella roadmap of ICT that covers all topsectors. The ICT umbrella roadmap is a supplier, particularly of bioinformatics and ICT solutions for healthcare like eHealth. Implementation aspects will be specifically addressed in the topsector Life Sciences & Health • The roadmap enabling technologies & infrastructure is interconnected with all other topsectors that have a strong molecular biosciences component (see box on enabling technologies & infrastructure). The expertise networks and facilities in this roadmap closely interact with technology approaches in the topsectors Chemistry (and its biobased economy roadmap), Agro-food and Horticulture, and they link to High Tech Systems & Materials and ICT. These topsectors and cross-sector agendas have contributed to the development of this Life Sciences & Health roadmap Other examples can be found in the roadmaps. Discussions with other topsectors on coordination of such connections are ongoing. This IC also argues for connections with the social research agenda. Life Sciences & Health research and innovation is linked to social research and public dialogue. Social sciences play a leading role in the discussion about quality of life and the redesign of life career. As an example, the Center for Society and the Life Sciences was established under the Netherlands Genomics Initiative (NGI) to connect life sciences research at NGI to social research, ethics, public dialogue and education. Another example is the relevance of the 3R theme (alternatives for animal testing) in social research and public dialogue. The roadmaps provide questions for partners in social research and public dialogue, and they can provide answers (and questions) to the topsector. Increased cooperation between Life Sciences & Health and social research is promising and should be established in public-private partnerships that are executed as part of the roadmaps. Along these lines, the Humanities division of NWO will invest in public-private partnerships that address ethical and social questions regarding science and technology in the topsector Life Sciences & Health and several other topsectors.

Table 1. Themes of connections

BOX: EU grand societal challenges: Active and healthy ageing The European population is ageing rapidly. This poses a formidable socioeconomic challenge, mainly through the burden it places on care systems. Yet it also presents great opportunities for citizens and businesses. Innovation for ageing well can improve the quality of life of citizens and enhance the competitiveness of EU industry as it opens up new markets. In 2011 the European Innovation Partnership on Active and Healthy Ageing (EIP AHA) pilot was launched. The EIP AHA creates a platform where public authorities, private partners, professionals (doctors, researchers), (representatives of) the public and public-sector organizations meet and exchange views and concepts. The EIP AHA aims to increase the healthy lifespan of EU citizens by 2 years by: •

Improving the health and quality of life of European citizens, and particularly of older people

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• •

Supporting the long-term sustainability and efficiency of Europe’s health and social systems Fostering the growth and expansion of EU industry in this field

These ambitions connect well to those of the Dutch topsector Life Sciences & Health, and there is much to gain in connecting the topsector and the EIP AHA. The activities that the AHA proposes to overcome this grand challenge link well with the roadmaps of the topsector Life Sciences & Health. For example, one of the seven EIP AHA activities that were started in 2012, "finding innovative solutions to better manage our own health and prevent falls by older people" is a solid match with the roadmap homecare & selfmanagement. Overall, the EIP AHA not only links to several of the roadmaps of the topsector Life Sciences & health, it also connects Life Sciences & Health with the topsectors Agro-food and High Tech Systems & Materials. From its start, the Netherlands has shown great interest in participation in the EIP AHA. Representatives of Dutch stakeholders in the biomedical sector have contributed broadly to the consultation EIP AHA in January 2011 through participation in working groups and expressing commitment for the program. The eight University Medical Centers have developed a common position paper and a long term research & innovation agenda to contribute to EIP AHA. Through its topsector policy, the Netherlands is in a frontrunner position within the EIP AHA. 2.2 Ten roadmaps detailed This section details the ten roadmaps of the topsector Life Sciences & Health. Each description follows the same structure: the roadmap's goals (what it wants to achieve), activities (how it will achieve this), case (why it wants to and is able to achieve this) and connections (how it connects with existing partnerships, other roadmaps, other topsectors, etc.). Roadmaps represent rolling agendas The roadmaps in this IC represent rolling agendas. Over the coming years, roadmaps will be updated continuously, and focus and connections will be further strengthened. Importantly, focus around priority health challenges with integrated solutions will be shaped in the execution of the roadmaps. To assess their impact, three sets of criteria will be applied, referring to social, economic and scientific merits. Aside from being a separate roadmap, health technology assessment is thus a tool that is used in all roadmaps to measure the cost-effectiveness of new interventions. The topsector has recently gained much experience with assessing social merits through methodologies developed by the Dutch Advisory Committee on Health Research in its report Medical products: new and needed!, and by involving users in public-private partnerships.

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2.2.1 Molecular diagnostics

1. GOALS Important issues and challenges in the further development and dissemination of new diagnostic tests based on molecular information are: • The high number of candidate biomarkers identified in academia that do not progress to molecular diagnostic tools in clinical use • There is limited integration of molecular diagnostic technologies and tools to provide straightforward diagnoses in a complex biological context • Currently, there is a considerable disconnect and lack of integration between the science-driven discovery of molecular diagnostics, subsequently the development of a robust diagnostic, clinically validated test, the clinical application of such a biomarker test and last but not least clinical adoption including reimbursem*nt. • The coming decade new technology (e.g. high throughput genome sequencing, digital pathology) will result in massive data with unclear clinical relevance; this requires prioritized research efforts to transform this in valuable individualized clinical information • All diagnostic test should have the intention to be developed into an in-vitro diagnostic device meeting all regulatory requirements (which are, at this point in time, highly insufficient for fast market penetration of these tests) The ambition should be to define and implement a generic framework in NL that facilitates the development of candidate biomarkers into validated molecular diagnostics in clinical use (including screening programs), involving all stakeholders from the start in this process to ensure an integrated process from clinical needs to discovery and development resulting in reimbursed clinical application. It should be absolutely clear that all the stakeholders agree that the anticipated diagnostic test will serve an unmet medical need, has a high clinical additive utility and is commercially viable. In the process, the 3R goals will be served. In the end, this will result in the clinical application of specific molecular biomarkers for improved diagnosis and screening, patient segmentation and monitoring of therapy, ultimately contributing to cost-effective improvements of patient outcomes and quality of life.

2. ACTIVITIES Initial focus and being able to quickly assimilate new insights in technology and molecular biology to the major healthcare challenges will be essential to become successful in molecular diagnostics. Critical aspects are • The identification of biological imbalances that drive clinical phenotypes, and the realization that this may be different between individual patients. • The development of molecular read-out of disease biology that can provide important clinical information that affects the diagnosis, prognosis, triaging (prediction) and treatment of patients. • A successful molecular diagnostic pipeline based on an integrated approach that starts with a well-defined clinical need that drives biomarker discovery and development, and ends with a reimbursed diagnostic test that is being applied in clinical use. • Application of such generic framework involving all key stakeholders is not limited to specific disease areas.

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Molecular diagnostic read-out methods include a variety of technology platforms including e.g. simple laboratory tests and high-content imaging modalities. Biomarker based diagnostic tests hold great promise for increasing costeffectiveness in healthcare by facilitating personalized therapies

The molecular biomarkers involved in molecular diagnostics address defined clinical needs like: • (Genetic) predisposition for disease • Screening/early detection of disease • Prognosis for the individual patient • Pretreatment classification for personalized therapy/prediction of response to therapy • Early therapy response monitoring • Follow-up and early detection of recurrence of the disease Direct benefits of an operational molecular diagnostic development pipeline for the aforementioned needs will result in: • Improved and personalized patient care • More specific and earlier treatment based on individual case • Prevention of (serious) adverse side effects • Reduction in healthcare costs and increase in quality of life The separate steps that can be identified in the molecular diagnostic development pipeline include: • Discovery of biomarkers (‘Omics’, imaging, literature, etc) • Development of initial diagnostic test (prototype) • Discussion with the appropriate bodies to agree on development strategy leading to registration and reimbursem*nt at the start of the development pipeline (precompetitive procurement!) • Performance of prototype validation and cost effectiveness (including access to high quality clinical samples) • Optimization of the prototype and development of the full (IVD) diagnostic test that meets regulatory requirements • Analytical and clinical validation of diagnostic test • Standardized application in clinical setting • (GMP) production facilities for molecular kits

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The process to convert these steps into one integrated pipeline includes: • Define and standardize the molecular diagnostic development pipeline from discovery to a reimbursed clinical service that will contribute to a cost effective health solution • Involve key stakeholders in building such integrated pipeline • Ensure early buy-in of end users (patients, clinicians, healthcare insurance) • Support particularly those projects that demonstrate the added value in society and health The required conditions and enabling technologies are: • Accessible collections of well-defined biosamples (biobanks) • Accessible data sets with clinical/phenotype annotations • Appropriate and accepted molecular read-out technologies • Facilitating IT infrastructure • Appropriate Quality Assurance Besides the technical challenge in Molecular Diagnostics to obtain the “highest level of information from the smallest amount of sample”, the major roadblocks for an attractive R&D “ecosystem” are predominantly related to guidelines, inappropriate or lacking regulations and a reimbursem*nt system unable to accommodate the evaluation ad implementation of complex molecular diagnostic products. Ultimately, the compelling arguments for increased investments in Molecular Diagnostics and the rationale for its use are: • Cost containment by early detection allowing secondary prevention and early treatment of less advanced (and less costly) disease states • Keeping patients as active society members (labor participation) for longer time • Defining target population avoids unnecessary treatment and prevents toxicity from treatment • Monitoring results avoids unnecessary continuation of ineffective treatment and also avoid Rx related complications

3. CASE A. Priorities Priority setting in this Roadmap is directly related to addressing a therapeutic area that has a high medical need for improved application of molecular diagnostics and should involve all parts of the molecular diagnostic development pipeline with a phased but connected approach from discovery to application and implementation of effective healthcare solutions (including screening programs). An important aspect will be to use molecular diagnostics to bridge research to clinic, thus also reducing animal experimentation following 3R guide lines. B. Strengths Scientific landscape in Netherlands The public-private partnerships that have been operational in NL since 2006 have changed the mindset of researchers and industry towards an integrated team approach. Experts in their individual disciplines work closely together towards an innovative solution that would not have been possible by the separate parts. Several

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groups have succeeded in creating highly effective multi- and cross disciplinary teams where industry meets academia. This is unique in the world. Technologies Within these partnerships, much expertise has been built around basic research, biomaterials, clinical applications, shared infrastructure and enabling technologies (ESFRI (EATRIS, BBMRI. ELIXIR, ECRIN), PSI, PALGA, etc). The Netherlands has state-of-the-art molecular diagnostic activities closely integrated with clinical practice within the setting of the UMCs and through the public-private partnership network. Based on a firm academic presence in molecular biology, a spectrum of small and medium enterprises form an excellent industrial base for innovations focused on unmet clinical needs. Dutch research groups are highly productive in both application development and biological discovery. The continued development of technologies within the NGI technology centers has brought the field to a level that allows molecular diagnostic development with methodologies that have proven to be robust. The implementation of this knowledge and the technical capabilities to improve health in real life is still a major hurdle. Applied research institutes, the government, payers and patients should help implementing these findings. Provided that the molecular diagnostic development pipeline can now be extended to clinical care and reimbursem*nt involving key stakeholders as we propose in this Roadmap, these characteristics put the Netherlands in an excellent position to be an example worldwide of integrated applied diagnostic development.

4. CONNECTIONS There are direct links with other top sectors, e.g. High Tech Systems & Materials (nanomedicine) and DTL (enabling technologies). The roadmap team consulted the topsector High Tech Systems & materials roadmap healthcare. The companies involved in both topsectors are compatible and synergy can be established with this topsector in the form of joint public private partnerships. Molecular diagnostics comprise the tools that enable improved biological and clinical research. As such, this Roadmap relates to many other disciplines and stakeholders in the Life Sciences and Health Sector: • Enabling technologies and infrastructure: application of technologies, biobanking, digital pathology (BBMRI, PALGA, data analysis into the integrated molecular diagnostic development pipeline.) • Imaging and image-guided therapies: application of the developed integrated molecular diagnostic development pipeline into imaging applications in healthcare. • ICT and clinical decision support: application of molecular diagnostic information into clinical decisions, supported by ICT e.g. electronic medical record, TraIT/DISC/DTL. • Pharmacology & pharmacotherapy, Regenerative medicine, Nutrition & health: flow of candidate biomarkers into the integrated molecular diagnostic development pipeline to mature into robust tests that support research in these Roadmaps • One Health: molecular diagnostics of infectious agents becomes more important due to the emergence of resistance. • Health economics: application of health technology assessment to support selection of those therapeutic areas based on calculated costs and effects • Ethics: involvement CSG (Center the Society and the Life sciences), VSOP (Vereniging Samenwerkende Ouder- en Patiëntenorganisaties) and other

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organizations addressing societal impact and acceptation of new healthcare solutions Many different stakeholders are directly involved in and impacted by the development and implementation of molecular diagnostics: (e.g. Nederlandse Hartstichting (NHS), Koningin Wilhelmina Fonds (KWF) , Diabetes fonds, Nierstichting, Reumafonds, etc.) The Royal Netherlands Academy of Arts and Sciences (KNAW) recently installed a committee on market access and reimbursem*nt of therapeutic innovations (including molecular diagnostics). The present initiative and the KNAW effort will be bundled. A large number of on-going public-private partnerships within the existing TTIs (CTMM, BMM, TI Pharma) are engaged in all kind of activities directly related to Molecular Diagnostics. There is a need for further coordination and integration between different programs that range from biomarker discovery to diagnostic assay development and implementation, particularly in the area of technology adoption, access to biobanks and data handling (TraIT, DTL, NBIC, Parelsnoer, eSience). Other relevant initiatives comprise the TNO programs “Preventie en Therapie Opmaat” en “3R”, as supported by ministry of VWS, the NGI and ZonMw LifeSciences@work program and the ZonMw program Translational Research. Relevant European programs include Biomedical ESFRI programs for infrastructure (e.g. EATRIS, Elixir, BBMRI), IMI (OpenPhacts).

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2.2.2 Imaging & image-guided therapies

1. GOALS Medical imaging enables earlier, more accurate and less invasive diagnosis and eliminates the need for unnecessary invasive interventions resulting in patient’s quality of life improvement and cost containment. (Quicker, cheaper, without causing new trauma, with less or no hospitalization, risk of infection or need for medication). Diseases can be treated more effectively when diagnosed at an earlier stage. Personalized, tailored approaches can delay the onset or progression of a disease or even prevent it. In addition, medical imaging forms the corner stone in many therapeutic applications in different clinical domains both in the planning, such as radiation therapy and various surgical areas, as well as in the actual treatment, including: • catheter based interventions in cardiology (coronary but also transcatheter/transapical valve replacement), vascular, neurology, electrophysiology and oncology as well as • direct targeted therapies, brachy therapy, biopsies, drainages and others • minimal invasive surgery. Fusion of diagnostic and minimally and non-invasive therapeutic procedures will transform many of the current clinical practices. This imaging roadmap aims to initiate a fundamental transformation in the traditional development chain with all stakeholders involved: researchers and developers in the scientific area and in the industry as well as end users (healthcare professionals, providers, patients) having all a more active role in the research and development imaging based healthcare solutions. This arrangement has two main advantages: imaging devices will be better suited to the needs of end-users, and the efforts for research and development will be allocated more efficiently. Imaging provides early diagnosis (prognosis), elucidation of disease mechanisms, drug development, risk assessment (population based imaging), treatment selection (prediction) and response monitoring as part of integrated care. Imaging applications have become an important integral part of different stages in the care cycle and will have a major impact on delivery of health cure and care. In conjunction with increasing technical achievements, these new opportunities will have to be validated with existing technologies and compared with current standards. Physicians do not always select the most clinically and cost-effective solution to specific problems while new treatments may provide better outcomes. Unexpected findings further accelerate diagnostic and therapeutic healthcare costs and induce over-medication. At the same time one should qualify the significant potential of modern imaging in patient selection, prediction and prognosis (and the associated potential cost savings). A thorough Health Technology Assessments (HTA) and taking into account the patient’s values will be an important determinant for the prioritization and monitoring of this imaging roadmap.

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2. ACTIVITIES Over the last decades, imaging applications have become an integrated part of the disease management of patients rather than a diagnostic tool alone. Optimal benefit from new developments in imaging technology will require: • the appropriate infrastructure for new imaging applications as well as their integration in the entire patient care cycles • an adequate assessment of the impact on healthcare of various imaging technologies • fast and reliable feature extraction and image analysis. A number of specific imaging applications can be identified that will impact patient care and cure in which the Netherlands excels both in fundamental research and the translational of new findings and technologies to the clinic. A. Diagnostic Imaging High Definition Imaging Optimal sensitivity and specificity are the key elements in imaging for an early, accurate and robust assessment of pathology. Different technologies may be used for their own intrinsic strengths. All major application areas in the life sciences will benefit from higher spatial and more specific functional and metabolic information. Understanding the pathophysiology of disease at the pre-symptomatic stage, more accurate patient stratification, assessment of disease progression and treatment response monitoring are absolute priorities in facing the enormous burden in the ageing population. For many diseases, however, imaging markers are not yet investigated sufficiently for application in clinical practice. Research into the imaging targets in many diseases is needed as well as development of the imaging technology itself. Hybrid Imaging The capability of instantaneous fusion of anatomic and functional data with hybrid imaging technology and simultaneous scanning will substantially increase our capabilities for the quantitative assessment of “anatomo-molecular” information. Furthermore, multi modal imaging and navigation technologies are developed to expand the interventional domain towards tissue ablation and replacement, endovascular embolizations & recanalisations, treatment of arrhythmia & heart failure and many other major clinical applications Flow and functional imaging are provided in the interventional room to have those readily available during the procedures in order to improve procedural planning, navigate & deliver devices, assess procedural outcomes and predict (long term) treatment results. Tracer development & Molecular Imaging Molecular imaging is of value for sensitive visualization and quantification of critical disease targets and targeting molecules - either drug candidates or diagnostic agents at high resolution and low concentrations. As such, molecular imaging is of high utility for initial diagnosis and prognosis, treatment selection and guidance, outcome monitoring, and new drug development. Key in molecular imaging is the exploitation of critical biomarkers involved in pathogenic processes, and the development of disease specific, and process or pathway specific probes (to study pharmaco*kinetic, toxicological and efficacy related processes herein collectively called “tracers” that can be used in nuclear (PET, SPECT), radiological (MRI and US) and/or optical procedures. It opens business opportunities for the production of complete systems for

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nuclear imaging (e.g. SPECT and PET) and radionuclide therapy comprising radionuclides, radionuclide generators and new nano-scaled targeted carriers. Feature extraction and image analysis In order to cope with the advances in imaging technology, including the generation of multiple image types with increasing resolution and number of images, robust feature extraction and image analysis becomes mandatory. This includes modeling of physiological data and image analysis algorithms. The goal is to enhance quantification to improve accuracy and reliability of sensitivity and specificity measures in detection, diagnosis and treatment follow-up. Real-time image registration and visualization techniques to support image-guided interventions require advance processing of complex data. Innovation could, e.g., be induced by steering the analysis using models of anatomy, pathology, expert knowledge on function and physiology or human observer characteristics, or by supervised classification of structures using large-scale annotated image data bases. The latter class of methods would also - in the long run allow translation of results from clinical population imaging studies to personalized risk management. Using deformable registration algorithms combined with direct imageguidance advanced imaging techniques could enable true image-guided interventions by immediate feedback of treatment progress and treatment outcomes. B. Theranostics The advent of image-guided interventions is expected to help society cope with the challenges and trends of the coming decades. The major advantages of non and minimally invasive techniques are not only beneficial to the patients due to a reduced risk of acquiring infections, a shortened recovery time, and a shorter hospital stay, often with same day discharge, which leads to a faster return to everyday life, but also reduced labor time for the nursing staff. With increased sensitivity of modern imaging devices, disease can be detected much earlier, allowing pathological tissue to be removed either by image-guided radiotherapy, trans arterial interventions, open surgery or minimally-invasive techniques such as endoscopy or laparoscopy. Treatment planning Many new image-guided therapy approaches are being developed that will substantially change the preferred treatment procedures for many different disease areas. The Netherlands is a pioneer in the development of image-guided radiotherapy applications such as Cone beam CT guidance and more recently the application of fully integrated real time MR guidance for radiotherapy. In addition, combinations of imaging modalities and real-time fusion of images will also enable a broader spread of imageguided radiotherapy to clinics without direct dedicated access to integrated imaging with treatment delivery. Image guidance here may not only result in more accurate (and more cost effective) procedures, but may result in therapeutic applications for disease targets previously not suitable for image-guided curative therapies. New imaging techniques will play a crucial role for the adoption of many new, emerging imageguided therapies (e.g. proton therapy) like dual energy CT, proton radiography and ToF PET. Image-guided surgery An alternative (emerging) therapeutic imaging route is image-guided surgery. With this technology the surgical intervention is guided by real-time visualization of the areas of interest using functional parameters. Preferably, such procedures are planned using the highly accurate preoperative imaging findings obtained via SPECT/CT, PET/CT, and/or MRI. In the last years the clinical value of intraoperative radioguidance,

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fluorescence guidance, and/or the combination thereof via the use of (multimodal) tracers has been demonstrated for a number of indications. Optical guidance using (targeted) fluorescent dyes also allows more accurate tissue removal (e.g. with sufficient tumor-free margins.) This will substantially reduce further disease proliferation and (co)morbidity by prevention of unnecessary radical surgery. To this end new imaging tracers, imaging modalities, and imaging procedures are currently being evaluated in both the preclinical and clinical setting. Minimally invasive interventions The Netherlands is leading in the development of new devices and procedures for minimally invasive interventions and its introduction into the clinic. The intensive national collaboration on this topic brings together expertise in miniaturization of (steerable) instruments, optical sensing technique, biomaterials, ergonomics, haptics as well as clinicians who are playing a leading role in their clinical discipline. Related business development expertise and an extensive network of companies promise a significant market share with new products and services. Navigation with steerable instruments in a complex space with moving vital structures requires innovative man-machine interaction technologies where 3D visualization essential for precise guidance. Augmented reality through overlay CAT or x-ray images on the patient supports the surgeon while performing his minimal invasive intervention. Endoscopic tip-functionality is increasingly enhanced with diagnostic and interventional qualities: high-resolution imaging at the ‘tip’ of the instrument and narrow band imaging (OCT, IVUS, photo-acoustic imaging, optical techniques) enable characterization of local tissue e.g. atherosclerotic plaque or tumor. Image-based therapy A further step is when imaging itself is used not only to plan, but also execute (and monitor) the treatment. Such image based therapies have been developed in the last 30 years mainly for applications in the vascular field. Also today there are important new vascular developments but recently such techniques are increasingly applied in other medical fields as well. E.g., an important new development in the vascular field has been trans arterial renal artery denervation by RF ablation as a new treatment for therapy resistant hypertension. This technique holds a promise for the treatment of heart failure and renal failure. A perfect example of image based therapy in the oncologic field is integrated MR-High Intensity Focused Ultrasound (HIFU), currently being used in the clinic for ablation of uterine fibroids and palliative treatment of bone metastases, but soon to be introduced for other organ disease treatments as well. This technique can also be used for targeted drug delivery: the local release of potent new therapeutics for more effective treatment with fewer side effects. Other examples comprise Image-guided transarterial chemo-, and radio-embolization techniques as well as thermal ablations which provide new and effective treatments with minimal side effects to reduce hospitalization and expedite revalidation. Additional examples are transcatheter/transapical valve replacement, (T)EVAR, PFO/septum closures, cardiac ablation & CRT (arythmia), stem cell therapies, stroke treatment (recanalization techniques), Uterine Fibroid embolisations, C. Pre-clinical and cellular imaging To date, the resolution of imaging tools is such that small laboratory animals can be monitored and studied along the line of technology applications already used in man for more than 30 years. Multimodality techniques, combining strengths of the various technologies at high resolution in vivo will improve understanding of physiological

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processes in fundamental research. The use of clinically available modalities increases the translational power of preclinical disease models and pharmaco*kinetic research in laboratory animals. For drug development, efficacy, kinetics and safety testing, this non-invasive preclinical research is of prime importance, enabling rational treatment and drug development. These studies will enable a better translation from animal to man, contributing to more efficient drug development pipelines and a reduction of animal studies (3R) as imaging allows for longitudinal studies. High resolution techniques as small animal SPECT, small animal PET and optical imaging using bioluminescence and/or fluorescence have opened the door to studying cells, tissues and organs in the context of a systems biology setting. Moreover, these techniques have allowed monitoring all kinds of cellular and molecular events in vivo with the ability also to interface with other in vivo imaging modalities such as CT and MRI. These technologies provides ample opportunities for public-private collaborations in drug screening and drug development. The next step up for imaging in understanding the fundamental biology of disease processes is the linkage of organ imaging techniques to digital pathology and optical Advanced Microscopy. Advanced Microscopy in particular provides the resolution to reveal the molecular and cellular details necessary for understanding the biological mechanisms of human diseases, pre-clinical drug screening and optimization of treatment approaches. Moreover, there are many more ways of learning about the kinetics and molecular interactions of bio-molecules inside living cells. Examples include single-molecule visualization, which can report on molecular transport, diffusion, or activity. Especially for rare events which can nonetheless be instrumental in determine cellular fates (e.g. specific DNA repair), visualization at this level is crucial. Some typical examples of Advanced Microscopy include high-resolution light-optical techniques (e.g. STED, PALM, FLIM, FRET, etc.), electron microscopy and combinations of these. Applying these, and other Advanced Microscopy techniques to human model systems, e.g. cellular co-culture models, tissues or 3D reconstituted organs, can be used to better predict the human situation and increase the efficacy of the pharmacological interventions, implementing cost-effective approaches. In addition, recent breakthroughs in Advanced Microscopy and intraoperative spectroscopy increasingly provide opportunities for direct integration of distinct imaging technologies. This is exemplified by Intravital Microscopy, by which optical methods are employed to detect cells and tissues in animals and humans, which can be combined with the monitoring of metabolic and signaling activities. Of crucial importance for further integration is the development of new multi-modal probes that can be visualized by distinct imaging technologies, allowing direct data correlation at multiple levels, from intracellular to whole organisms. D. Cost containment, clinical evaluation and validation For societal acceptance and effective cost containment there is an increasing need to develop diagnostic algorithms for the appropriate application of new and existing medical imaging and image-guided technology. This pathway will redirect the autonomous trend of technology push towards clinical demand driven R&D. Every new diagnostic imaging or minimally invasive device, algorithm or biomarker should be an improvement on existing technology (which is not self-evident) in terms of reduction in morbidity, mortality, patient comfort and/or cost. Current models for the critical assessment of new products in development in terms of their economic and clinical value (early Health Technology Assessment (HTA)) are insufficient. An integrated

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approach is needed when assessing new technology, i.e., the use and (de)implementation of new and old technology as part of diagnostic strategies is a recognized determinant of overall cost-effectiveness of healthcare. Devices and biomarkers that can show that individuals have a non-existent or negligible risk of developing a disease over the next five or ten years allow them to be excluded from further monitoring and (expensive, invasive) testing. There is an immediate need for low cost, high sensitivity prognostic and predictive tests to exclude diseases (reassuring patients, reducing medicalization and containing healthcare cost.) A limited number of high-end university diagnostic centers (that will contain all procedures for primary diagnosis, starting from a clinical question and resulting in a final diagnosis – preferably within one day) can serve the entire population, while follow-up diagnostic care remains an intramural procedure. This will even further strengthen the position of the Netherlands for large population studies and the creation of an effective development infrastructure for medical technology.

3. CASE A. Priorities • • •

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•

Increased sensitivity and specificity of diagnostic imaging and personalized treatment strategies will contribute to earlier diagnosis, better patient triaging, shorter hospitalization and decreased (co-)morbidity. Selective usage of increasingly expensive smart drugs is possible by selecting drug-responders using (molecular) imaging and by monitoring treatment response continuously. “Theranostics”, the merger of non- and minimally-invasive surgical procedures and interventions (“Incisionless Surgery”) will introduce a new spectrum of treatments that will substantially decrease the burden patients are face during highly invasive procedures as well as costs associated with long hospitalization periods. “One stop shop” procedures will expedite the diagnosis-cure cycle. Use of high resolution imaging modalities in pre-clinical research will increase understanding of physiological and pathological processes and improve efficacy of drug development The next generation imaging systems generate a high volume of data which can be combined with other data from multiple sources and gather that information into discrete items in order to achieve inferences, which will be more efficient and clinical relevant than if they were achieved by means of disparate sources. In the future, (bio)medical data from genomics, proteomics, metabolomics, cellomics, digital pathology bridging in-vivo and ex-vivo elements and morphological imaging will merge in a 4 dimensional dataset by which health and disease can be characterized, predicted, monitored and treatments simulated. Complex, largescale, collaborative simulations are becoming more and more crucial for decision making in healthcare. This requires a ICT infrastructure which can handle algorithms, methods and tools and provide immediate access to large compute and storage systems (computers, grids, clouds) for such computations required for clever decision making (roadmap Enabling Technologies & Infrastructure). Functional and Flow imaging, as an adjunct to morphological imaging and the use of feature extraction and decision support systems, will allow better assessment of function and performance of organs and tissue allowing better treatment planning, execution and outcome assessment Advanced navigation techniques based on mutually registered multimodal sources and support of robotics will allow more accurate interventions

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Affordable and small scale integrated (multi-modality) imaging systems may come available for community care centers with easy-to-use handling and stepwise decision support. Expertise will be provided by interconnected specialists in excellence centers. This will help the implementation of integrated care and providing imaging facilities in community care settings, accompanied with support from experts. The development of these next generations of service network based imaging systems, anticipate on global trend of downsizing institutional care and creation of lean but smart connected healthcare centers.

B. Strengths Imaging represents one the most prominent industrial activities in the Dutch Healthcare system. Medical Imaging alone represents an annual 3.2 B€ turnover and 180 M€ R&D investments in the Netherlands (10% of the entire global medical imaging (40 B€) and radiotherapy (3 B€) market). Many industrial players and SMEs in the Netherlands play a key role in the imaging and image-guided interventions field. New initiatives should be tailored towards the development of imaging and medical devices that are requested by physicians and patients (a shift in focus from push-driven innovation towards pull-driven innovation) and include valorization as an integral component of the program. This involves the creation of start-up companies from academic research and new business opportunities for existing companies that are based in the Netherlands. In addition, public-private initiatives will contribute to improving the attractiveness of the knowledge infrastructure in the Netherlands, thereby stimulating foreign companies to invest in or open up new research and development or production facilities in the Netherlands. Public-private partnerships in imaging and image-guided therapeutics have been operational since 2006 which has resulted in several successful multi-disciplinary public-private consortia comprising all Dutch industrial and academic centers of excellence. These consortia operate at the forefront of innovations in one of the fast growing markets in healthcare and represent one of the few areas with a sustainable leadership position for Netherlands.

4. CONNECTIONS There are direct links with other top sectors, High Tech Systems & Materials in particular. Whereas HTS&M primarily focuses on technology development, the LS&H sector will address the development of new integrated healthcare solutions based on new enabling technology within the constraints of the most important clinical and societal opportunities and challenges. Within the sector, imaging and image-guided therapeutics have direct links with Molecular Diagnostics (target finding and validation, biomarkers), Regenerative Medicine (tissue regeneration, cell tracking), Pharmacotherapy (companion diagnostics and surrogate endpoints), One Health (animal imaging) and Specialized nutrition, health and disease (food and cognition, metabolism). Management of imaging data combined with other patient related information (clinical, -omics) is crucial. Current initiatives (TraIT, DTL (NBIC)), as represented in the enabling technologies & infrastructure roadmap, should have direct links with new public-private imaging initiatives.

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Many different stakeholders are directly involved in and impacted by the development and implementation of imaging and image-guided therapy: Nederlandse Hartstichting (NHS), Koningin Wilhelmina Fonds (KWF) , Diabetes fonds, Nierstichting, Reumafonds, etc. A large number of on-going public-private partnerships within the existing TTIs (CTMM, Cyttron) are engaged in all kind of activities described in this roadmap, as well as the four IMDI-CoREs for imaging (CMINEN, MDII, IDII, Quantivision) and minimally invasive technology (NIMIT, MITeC) and initiatives like the TNO programs “Preventie en Therapie Opmaat” en “3R”, as supported by ministry of VWS. At Technology Foundation STW a number of public private partnerships that can be linked to the LSH Imaging & Image-guided therapies roadmap are currently running as projects within the Open Technology Program (OTP) or as Perspectief program (e.g. Cardiovascular Risk Management ‘CARISMA’ and ‘Nanoscopy’). Even more so, as a result of existing incentives to create public-private consortia, there is a clear trend in the Netherlands showing increased scientific collaboration, pooling of technology, clinical data sharing as well as joint “on shoring” of private commitment for additional public-private collaborative programs. Imaging in particular is an area where many of these new “hubs” and open access facilities are being formed (e.g. Dutch Imaging Hub (molecular imaging), VISTA (ultra high field MRI), Image-guided Surgery Network Netherlands, iThermoNano, MITeC, PRIME, etc.). This roadmap aims to stimulate further collaboration and integration of excellence and expertise for an optimal ecosystem for innovation and valorization of image based healthcare solutions. Finally, the roadmap stimulates alignment with relevant European programs such as the Biomedical ESFRI programs for infrastructure (EATRIS, Eurobiomaging with the Dutch initiatives connected with these European programs: EATRIS-NL and NLBioImaging AM.)

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2.2.3 Homecare & self-management

1. GOALS The objective of the group establishing this roadmap is for people to age healthily, to help them to remain independent and active, contributing to and participating in society, and to support them to live in their own home as long as possible, despite disease or disability. Mobility is key to achieve this goal. Diagnosis, treatment, rehabilitation and care should take place in their neighborhood if possible, engaging the patient and his environment. This can be achieved by developing, assessing and implementing technologies, (built and ICT) infrastructure and related services that promote clients' abilities to live independently and self-management. In addition, by supporting healthcare professionals in the development and application of efficient and suitable care in or close to the home. The roadmap Homecare and Self-Management delivers solutions that address the main challenges of the Dutch (and global) healthcare system: shortage of healthcare professionals and increasing costs of healthcare. Core to this roadmap is the development, assessment and implementation of solutions which contribute to a sustainable healthcare system for people with one or more chronic diseases and/or disabilities. From the client's point of view, this means tailored (or personalized) solutions enabled by new technologies. But it also requires an alignment in attitude and skills of professionals, and the organization of the healthcare system and supporting services to make self-care and self-management feasible in daily life and activities, in line with the individual wishes, (dis)abilities, and (health) skills of the client. Social innovation is necessary to support the needed cultural shift and organizational change. The Netherlands has the knowledge, capacity and position to form strong consortia in which businesses, patient and client organizations, healthcare groups, research institutes, health foundations and other relevant stakeholders co-create appropriate solutions that enable this transition. Health insurers and municipalities are joining forces to make sure these solutions can be funded, supported and stimulated by the responsible national bodies (e.g. from a regulatory and organizational point of view). The themes described below indicate in which areas the Netherlands excels and which groups are active and are eminently suited to deliver viable solutions to meet the challenge.

2. ACTIVITIES Four themes have been identified covering areas in which Dutch stakeholders hold strong positions and have the ability to develop and implement meaningful innovation in healthcare, briefly described below. A. Prevention and early diagnosis in primary and decentralized care This theme involves early detection and diagnose people with a high risk profile, using tools like home tests and preventive medical examination. Examples include the detection of groups at high cardiometabolic risk, or frail elderly, and early detection of (pre)diabetes at people with obesity. Solutions must also be developed that influence behavior and lifestyle (health promotion) in such high-risk groups, with the goal to

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retain good quality of life as long as possible. People's motivation and behavioral change plays a major role in this theme. B. Monitoring physiological, behavioral and functional parameters relevant to treatment, assistance or support of clients, their informal caregivers and/or their professional healthcare providers By monitoring, interpreting and assessing relevant parameters for the client and by making this information available to him/her (personal health records), clients can follow their own health status as part of tailored, if not autonomous, support from "remote" healthcare professionals. Decision-supporting protocols then advise and guide clients and healthcare professionals (shared decision support). Examples include behavioral monitoring in elderly with dementia, fall prevention in frail elderly, monitoring of COPD or chronic heart failure, blood sugar monitoring for diabetes, and ambulatory monitoring of blood pressure in people with severe hypertension. The monitoring also emphatically includes feedback to the client and/or the caregiver to support treatment. The combination of self-management, telecare and telerehabilitation results in the integrated and effective coordination of care, as is necessary for complex care of clients. Patients with neurological diseases (stroke, Parkinson's, MS, Alzheimer's, etc.) demand long-term and knowledge-intensive care. For these patients, the integration of monitoring (with the help of diagnostic robots and neuro-imaging) and treatment (making use of neuroplasticity) is important, i.e. the treatment is continuously adjusted according to how the patient is responding to the treatment. By using these techniques, care can take place in the home or in outpatient facilities rather than in the hospital, which reduces the costs of care for these large patient groups. By building intelligent systems and adding alarm functions to them, remote preventative treatment, such as the adjustment of medication, can be achieved, preventing, or at least reducing the impact of exacerbations of disease. It is essential to provide effective remote disease management solutions to control chronic diseases and to prevent the acute and dangerous situations that would necessitate (expensive) hospital admission. C. Remote treatment and assistance Many types of remote care are being made possible thanks to visual communication, internet-based education and treatment programs, serious games, personal medical records, etc. Motivation and behavioral aspects of clients and healthcare professionals require specific attention. The e-Health National Implementation Agenda (NIA) gives direction to this theme. This theme also includes devices which make homecare and rehabilitation possible, such as the portable artificial kidney or devices for treatment of respiratory disease at home. This requires that remote treatment and assistance are combined with an integrated coordination of care and (chronic) treatment. D. Support for functioning and participating in daily life This theme deals with the development of solutions that support daily life activities and make it possible for people to stay active and independent. This includes both domotics and newer areas like care robotics (e.g. service robots), sensor technology (e.g. the use of wireless sensor networks) and innovative prostheses and orthoses. It also includes (technological) solutions that support work and job search, whether paid, as caregiver or as volunteer, and/or provide the necessary education and training.

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Each theme addresses healthcare solutions and technologies at an internationally competitive level. Consortia of companies, patient and client groups, healthcare organizations, healthcare professionals, research institutes, and other relevant stakeholders which have committed themselves to the goals of this plan, will implement these programs. The results will lead to products that are applied widely across the (international) healthcare market, based on sound expertise and with demonstrated added value. The table below outlines the schematic "playing field" for this roadmap. This will be completed with public-private consortia. Of particular relevance is the co-creation of integrated solutions that address the entire care spectrum, and which can be used effectively by healthy people, by patients and by caregivers and healthcare professionals. Attention is also given to ethical and social aspects. The roadmap has received an impressive and broad support from groups active in this area, comprising all stakeholders involved. A total of 64 consortia covering a large part of the playing field have reacted to the call for expressions of interest in the roadmap Homecare and Self-Management. The consortia comprise about 200 public and private partners, and have indicated a total commitment of 13,5 M Euro in 2012.

Prevention and early diagnosis

Monitoring of functions

Remote treatment and assistance

Support of daily activities

Research (basic, strategic, experimental, evaluations, HTA, implementation, ethics) Development of applications Testing beds, living labs Valorization and commercialization Normalization/standardization Quality and safety

3. CASE The demand for healthcare is rising due to the ageing population and to the rise in chronic diseases as a result of unhealthy lifestyles and improved life expectancy of (chronic) patients suffering from severe diseases. For the Netherlands it is estimated that more than 4.5 million people suffer from one or more chronic disorders2. In 20 years, the number of over-65s in the Netherlands will increase by half to 21%. The number of people with chronic diseases will continue to rise until 2025, between 30% and 70% depending on the specific disorder, with particularly high increases for cardiovascular diseases, dementia, cancer, diabetes, COPD, rheumatism, kidney damage and depression2. About 8% of the population, especially the elderly, has

RIVM, Nationaal Kompas Volksgezondheid, Chronische ziekten en multimorbiditeit, Bilthoven, 2010

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several chronic diseases at the same time: co- and multimorbidity3. These problems are also seen in other European countries and in the US and Japan, but also in emerging economies like Brazil, Russia, India and China. Chronic disorders severely impact the burden of disease and thus also professional care needs and medical expenses. For example, psychiatric diseases – like depression and anxiety – account for a substantial portion of the Dutch burden of disease (DALYs) and contribute to about 30% of all productivity losses due to sick leave and reduced efficiency at work. Nearly 2 million adults in the Netherlands suffer annually from subclinical or clinical depression, amounting to EUR 3.98 billion in medical expenses and productivity loss4. The increase in the incidence of chronic disease also impacts participation and labor productivity. It is not only the treatment that is costly; the loss of mobility puts the patient at risk of syndromes like obesity and heart disease, and as a result the elderly can at some point no longer live independently, resulting in a further increase in costs and demand on professional support. The total burden on Dutch society of chronic medical conditions in the labor active part of the population only is estimated to 21.8 million working days, or EUR 5.3 billion5 lost. In the Netherlands, 1.2 million people work in healthcare. Between 2007 and 2025, this workforce will shrink by 10% as a result of demographic developments. If we combine this workforce reduction with the anticipated additional demands on the healthcare system, then 55 out of 145 clients in 2025 will not receive professional care, if we would continue to offer healthcare in the current manner. A shortage of 40%!6 The result is a large gap between demand of healthcare workers and available caregivers. New healthcare concepts and modalities, which support people in their ability to live independently and which support the work of healthcare professionals and other care providers, are vital. Where possible, this requires a transition from hospital care to primary care and welfare, and from professional care to self-management and informal care. The demand for healthcare must be delayed or prevented as much as possible. Technology, including ICT, plays a major supportive role here. Training and education of clients, caregivers and professionals is crucial. Scientific evidence indicates that self-management leads to better quality of care, at higher efficiency and at lower costs. This transition is an enormous challenge for the healthcare sector, and it is a fantastic opportunity for business. It empowers the citizens and their society. New products to support self-management and independency must be developed, for the Dutch as well as the international market. The Netherlands can take a leading position internationally in the development of homecare solutions. The combination of internationally leading companies, SMEs, excellent research institutes and a professional healthcare sector in the Netherlands is very powerful. Its high population density in combination with an excellent ICT 3

Hoeymans N (RIVM), Schellevis FC (NIVEL), Wolters I (NIVEL). Hoeveel mensen hebben één of meer chronische ziekten? In: Volksgezondheid Toekomst Verkenning, Nationaal Kompas Volksgezondheid. Bilthoven: RIVM, Nationaal Kompas Volksgezondheid\Gezondheid en ziekte\Ziekten en aandoeningen\Chronische ziekten en multimorbiditeit, 12 december 2008 4 Smit et al., 2006; Cuijpers et al., 2006 5 Ron de Graaf, Marlous Tuithof, Saskia van Dorsselaer, Margreet ten Have, Verzuim door psychische en somatische aandoeningen bij werkenden, Trimbos, Utrecht, 2011 6 STG/HMF, Ruimte voor arbeidsbesparende technologie om in 2025 voldoende zorg te bieden, Leiden, 2008

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infrastructure puts the Netherlands in a good position to become a global leader. This will be even more strengthened by the support of health foundations and health insurers' funds, and by active support of the relevant regional and national governmental bodies, accelerating introduction, acceptance and reimbursem*nt of the novel approaches.

4. CONNECTIONS This roadmap should be seen as one with the healthcare roadmap in the HTSM topsector, which brings together technological innovation with demand, development, application and valorization. Of particular relevance are the subjects rehabilitation techniques, home and community care, ICT and mechatronics and robotics. There is additional synergy with a number of roadmaps within LSH (specialized nutrition, molecular diagnostics, pharmacotherapy, HTA/quality of life, enabling technologies & infrastructure). There are also linkages with the ICT theme (personal medical records, prospective internet use, data storage and exchange, privacy and security, normalization and standardization) and with the topsector Creative Industry (serious gaming, Dutch Health Hub). There are clear links between this roadmap and other initiatives such as: • The IMDI initiative of NWO/ZonMw (the IMDI CoREs – CCTR and SPRINT – fit directly within this roadmap and there are overlaps with CoRE Neurocontrol). • The Interactive Care Platform research program (which aims to create innovative solutions for patients with chronic disorders, particularly diabetes, chronic heart disease and COPD), carried out by Stichting Zorg Binnen Bereik (established by Philips and Achmea) in cooperation with research institutes, patient organizations and healthcare providers throughout the care spectrum. • EU research agendas/programs (e.g. "A strategic implementation plan for the European innovation partnership on active and healthy ageing, a digital agenda for Europe, eHealth Action Plan 2012-2020"). • The "Brainport 2020 agenda". • The Ministry of Education, Culture and Science its profiling policy with regard to HBO and MBO education. • Advice of the self-management core group and the National Self-management Action Program. • The 2012 policy plan of the Ministry of Health, Welfare and Sport, VWS (incl. National Institute on Quality of Healthcare/care standards). • The 2012 policy plan of the Ministry of Social Affairs and Employment, SZW (sustainable employability). • The SZW and VWS "labor saving in healthcare" knowledge investment program. • The e-Health National Implementation Agenda (NIA) 2012-2015 drawn up by the NPCF, KNMG and ZN.

BOX – public private partnerships submitted to this roadmap Ninety public-private partnerships were submitted to this roadmap. The following is a summary of our initial conclusions with regard to these partnerships: • The partnerships can be classified at three levels: o Consultancies (patients and providers are often involved here) o Cooperations (companies and research institutes) with international connections and European and global possibilities

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Independent initiatives (projects, some disease-specific and some technology-specific) Many activities center around this roadmap, be it from research institutes, SMEs, insurance companies or patient organizations Interestingly, many initiatives focus more on the technology itself than on client behavior (self-management support) or on fitting said technology into healthcare and into (care) organizations (social innovation) On average, the actual involvement of patients and professionals/care providers in the public-private partnerships is limited In the public-private partnerships submitted, there are a few large partnerships, but more often many smaller proposals (in terms of size and/or scope/objectives) in the form of (temporary) projects. As such, there are various patient portals, technological innovations and research projects We consider the sustainability of the initiatives a central condition of the high-quality knowledge development, application and valorization that the Ministry of Economic Affairs, Agriculture and Innovation seeks. The right combination of techniques, knowledge, motivation and patient & professional involvement, and good boundary conditions (infrastructure, financing, etc.) can lead to the realization of the roadmap’s ambitions. There is a lot to be gained when projects (possibly parallel to each other) join together or connect to larger and more sustainable partnerships of entrepreneurs, research institutes, patient organizations and care providers Most proposals pay little attention to the business case. We therefore think it is important to conduct integrated HTA research in which accessible data plays a decisive role. Without a proper business case a proposal should not receive funding o

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2.2.4 Regenerative medicine

1. GOALS The aim of Regenerative Medicine is to extend healthy lifespan through healthy ageing by developing curative therapies for diseases caused by tissue damage and ensuing organ dysfunction. Through Regenerative Medicine approaches, normal organ function would be restored through repair or renewed growth of the original tissue or replacement by a synthetic or natural substitute. Regenerative Medicine solutions are particularly urgent for congenital disorders and chronic diseases of ageing but a variety of diseases may benefit from Regenerative Medicine approaches. These include, but are not limited to, diseases of the heart muscle and valves, skin, articular and intervertebral cartilage, bone defects, intestine and digestive organs, central nervous system, blood and immune system and kidney. Regenerative Medicine will contribute to cost-effective healthcare by replacing existing, less effective and more expensive therapies and decreasing pressure on the healthcare system through reduction of patients requiring chronic therapy. Regenerative Medicine takes full advantage of contemporary developments in stem cell and molecular biology, epigenetics, genomics and proteomics and biomaterials and bioengineering, while seizing new opportunities as they emerge from advances in molecular diagnostics, image-guided therapies for the minimally invasive treatments and novel drugs.

2. ACTIVITIES Regenerative medicine is an emerging discipline that aims to restore tissue and organ function after damage caused by disease or injury. Approaches presently under investigation employ the complete multidisciplinary toolbox of contemporary cell and molecular biology, materials science and bioengineering; including cell and gene therapy, the use of synthetic and natural biomaterials, small molecules and growth factors. Regenerative medicine solutions are particularly urgent in congenital disorders and the chronic diseases of ageing but those secondary to acute diseases, like diabetes and kidney failure, which create lifelong healthcare requirements, are also high on the agenda. Clinical areas that have the greatest impact on society because of their high prevalence, morbidity and mortality include: Cardiovascular disease which results from damage to heart muscle, the vascular system and cardiovascular structures like valves and can manifest as heart failure, stroke, myocardial infarction and chronic limb ischemia. More than 1 million people in the Netherlands suffer from cardiovascular diseases, hypertension, diabetes and hypercholesterolemia being risk factors that are often compounded by lifestyle factors and ageing so that present expectations are of epidemic proportions in the coming decade. Prognosis is poor because of limited options to replace or repair myocardium, blood vessels and valves, to control inflammation and fibrosis and to reduce risk factors adequately. Few treatments are in the pharmaceutical pipeline and research is needed urgently to address the unmet need. Musculoskeletal diseases are one of the most common causes of chronic pain and physical disability accounting for over 50% of chronic disease in the elderly. This is largely caused by bone and cartilage defects, degeneration or trauma, while underlying

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diseases such as osteoarthritis and osteoporosis will affect articulating joints, spine and supportive structures such as (long) bones. Further, increased mobility of our society will lead to an increased incidence of musculoskeletal trauma, and increased cancer survival will lead to more patients requiring treatment for musculoskeletal metastatic disease, both requiring new regenerative based solutions. Chronic diseases of internal organs, afflicting almost all of the elderly and affecting for example the respiratory system (asthma, COPD, fibrosis), liver (alcohol, viruses, toxins, metabolic syndromes), pancreas (diabetes), intestine (inflammatory bowel disease, Crohn’s Disease), kidney and urogenital tract/organs (failure, infection) and extending to secondary complications of diabetes (to the vasculature, kidney, eye), cancer (e.g. destruction of salivary gland by radiation, loss of tissue by surgery, chemotherapy), defects in the immune system (infection, inflammation) and blood (leukemia/bone marrow). An individual has a lifetime chance of 50% of contracting cancer, most of which will result in some form of tissue damage, including to the skin (burns, ulcers). Diseases of the nervous system, like Parkinson and Alzheimer, have a huge impact on healthcare costs. More recently recognized neural diseases and disorders which may affect the working population, not just the elderly (depression, schizophrenia, ADHD, autism, Huntington’s Disease, ALS and spinal cord injury) are included for which the lack of human model systems has proven an obstacle for developing new treatments. Diseases of the blood system are widespread, and of all clinical problems, anemia is the most frequent. Blood cell diseases include leukemias and lymphomas (requiring the most intensive and expensive treatments), inflammatory based diseases, clotting defects, aberrant immune responses, autoimmune disease and in transplantation scenarios, graft rejection. As the pivotal organ system for regenerative medicine, there is a need to reduce the health burden by, for example, immune therapy, control of inflammation recruitment of endogenous stem cells, addition of exogenous therapeutic cells and improved blood transfusion products. Basic Research • Identify circulating or resident endogenous progenitor- and stem cells that give rise to the mature cells of adult organs and tissues such as the heart, valves, vascular system, skin, eyes, bone, cartilage, glands, lung, kidney, intestine and organs of the gastrointestinal tract (liver, pancreas) and the recruitment of these cells. • Elucidate the mechanisms underlying cell homing, lineage fate decisions, progenitor cell proliferation, differentiation and recruitment in tissue repair, cell-cell and cell-matrix interactions under physiological and pathological conditions with view to implementation in regenerative therapies and harnessing endogenous repair processes that include paracrine effects activated in response to injury and ischemia. • Identify targets for development of drugs that (i) control angiogenesis and vasculogenesis, vessel maturation and function with view to tissue vascularization, (ii) control the release of progenitor cells from bone marrow to enhance tissue and organ repair, and (iii) stimulate local proliferation of progenitor cells (e.g. satellite cells for muscle repair, heart progenitors for heart repair). • Develop technology for the expansion of human (post-natal) stem cells, (induced) pluripotent stem (iPS) cells and their differentiated derivatives in culture. • Develop technology for controlling the expression of specific disease-associated genes, including gene-transfer vectors, artificial sequence-specific DNA modifying

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• • • • •

enzymes, gene-editing technology, RNAi technology, and other nucleic acid based drugs. Identify mechanisms underlying (patho-) physiological tissue repair, including fibrosis. Establish the role of inflammation and the immune system in tissue degeneration, regeneration and repair including the hematopoietic system and immunotherapy. Investigate the self-organization of (stem) cells and extracellular matrix molecules in the formation of functional tissues. Investigate and modify signaling pathways that alter tissue behavior. Develop biomimetic materials that mimic complex biological molecules, to guide and instruct cells in situ in functional regeneration and activate endogenous repair.

Strategic Research • Development of (biomaterials based) off-the-shelf technologies for in situ tissue regeneration and repair. • Investigation of cost-effective cell-based therapeutic strategies, including comparisons of heterologous and autologous cell effectiveness and safety. • Establish patient stratification methodologies to predict the outcome of regenerative therapies. • Integration of genetic modification, imaging, stem cell and biomaterial manufacturing technologies to produce patient specific bioactive implants for tissues like bone, cartilage (articular cartilage, intervertebral disc, meniscus), heart valves, muscle, lung, intestine and gastrointestinal tract organs (pancreas/insulinproducing cells, liver). • Development and evaluation of materials or material coatings for the controlled spatial and temporal delivery of cells, genes, pharmacological agents and/or bioactive molecules to affect biological functions, such as cell growth, inflammation and the immune response, and prevent biomaterial-associated infection. • Concurrent development of materials and material processing technologies such as electrospinning, three dimensional printing, photolithography, fused deposition molding and micro-fluidic particle production for implementation in tissue mimics. • Development of human disease models based on complex cell mixtures, as appropriate in “Organs-on- Chip” formats or microfluidic/microfabrication devices and including cells from different genetic/ethnic backgrounds, or 3D organ structures, to simulate (patho) physiological mechanisms. A major goal would be scaled production for safety pharmacology and drug discovery and development of screens for clinical trials “in a dish”. This may implicitly reduce the need for animal experiments (3R’s). • Ethical guideline development on regenerative medicine for clinical applications in adults, children/parents and animal experiments. Experimental Research • Translation of research towards clinical application by establishing the safety, feasibility and efficacy of new therapeutic strategies currently being developed in patients. • Development of a robust decision protocols to translate new therapies to clinical application. Systematic reviews of animal experiments may be valuable in this respect. “Proeftuinen” • Application of recently developed biomaterials to designated orphan disease indication. • Application of bioartificial organs as an intermediate step to organ replacement.

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Application of in vitro assays for the screening of drugs and compounds in safety pharmacology and drug discovery. High-throughput screening of biomaterials as appropriate, in combination with cells, bioactive molecules, antigens and modified surface architecture. Cell expansion technologies in multiple bioreactors and automated formats using robotics as appropriate.

3. CASE A. Priorities • •

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Decrease pressure on the healthcare system by reducing the need for chronic therapy, the number of patient-doctor encounters, hospital admissions and longterm care requirements. Cost-effective therapies by employing minimally invasive technologies to reduce pain and hospitalization time and cost, and enhance recovery speed. In addition, the objective is to deliver off-the-shelf technologies when possible, or procedures that require minimal handling of autologous cells to minimize GLP/GMP incurred costs. An example: for diabetes the costs of lost productivity in 2010 are estimated at € 5-6 billion thus accounting for more than 50% of total costs (10-11 billion). [Diabetes Care in the Netherlands, improving health and wealth. Booz&Co 2011] Maintain healthy workforce by developing cures or delaying degeneration rates, thus improving quality of life, extending healthy life expectancy and increasing independent mobility of patients Regenerative medicine will address unmet clinical needs. Examples include: o Heart failure: approximately 50% of patients die within 5 years of an infarct from heart failure, while regenerative therapies for the myocardium are still lacking o Valve, bone and cartilage replacement: tissues that have can follow the anatomical growth of patients are urgent for many ailments and accidents of childhood. o Long-term complications of diabetes: prevention of renal failure, cardiovascular disease and retinopathy. o Parkinson, Alzheimer, Huntington, ALS: may all be curable CNS diseases. o Age related deafness and blindness might be curable. o Muscle regeneration in the elderly by enhancing satellite cell function. o Osteoarthritis: alternatives to prosthetic replacement at the end stage of disease would be asset for treating the elderly. o Low back pain resulting from intervertebral disc degeneration which may not only affect the elderly but also a growing proportion of the workforce as obesity increases. Replace existing therapies that are less effective or associated with detrimental side effects. Examples: o Recipients of current heart valve replacements still have reduced life expectancy compared to healthy individuals of the same age. Replacement with living valves could overcome these limitations and would be better suited to children in which growth results in ill-fitting replacement valves. o Insulin therapy in case of diabetes is cheap but does not prevent long-term expensive and chronic complications. o Hemodialysis therapy does not replace all functions of the kidney: patients develop complications due to the incomplete removal of uremic waste and the lack of endocrine and metabolic renal functions. Implantation of de novo

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renal tissue and autologous vascular grafts for vascular access, may improve the health of patients on dialysis. Portable dialysis devices would reduce psychological problems associated with device dependence. B. Strengths •

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Recently published market reports predict that the regenerative medicine market will grow from $1,6 billion to $15-20 billion over the next 15 years. (http://www.fiercebiotech.com/story/regenerative-medicine-could-be-20b-market15-years/2010-04-23). Not only SMEs, but also Big Pharma have started to invest in regenerative medicine (Genzyme 2008, Novartis and Pfizer 2009, Cephalon 2010). Previous and current Private Public Partnerships (DPTE, SCDD, TeRM, BMM, NiRM, DCTI) in the Netherlands have identified the strengths of combined private and public partnerships in the field of RM through a succession of competitive open calls. Both large and, in particular, small and medium sized enterprises have entered the emerging RM field. This has resulted in an effective network of publicprivate partners. Proven collaboration between engineering schools and university medical centers. Strong collaboration with healthcare foundations, patient advocacy groups and charities. An example of economic value creation: o diabetes: the ideal treatment/cure is new insulin-producing cells in the body. Improvement of health of diabetes patients may lead to € 1,5-2 billion of economic benefits in 2020. [Diabetes Care in the Netherlands, improving health and wealth. Booz&Co 2011] Academic strengths: According to a recent KNAW report evaluating the status of Regenerative Medicine in the Netherlands, scientists have excellent national and international reputations in research on stem cell biology and biomaterials. Regenerative Medicine in the Netherlands can consolidate this leading position by integrating these disciplines even further, training a new generation of researchers and implementing state-of-the-art methodologies of cell and molecular biology, proteomics, medicinal chemistry, bioengineering and materials science. The Netherlands is among the global top 10 in Regenerative Medicine publications, and in the top 5 in the EU. [Royal Netherlands Academy of Arts and Sciences, Well underway. Opportunities for regenerative medicine in the Netherlands, Amsterdam, KNAW 2009; Foresight studies no 14.]

4. CONNECTIONS •

•

Molecular diagnostics may enable the early detection of diseases. The probability of the success of regenerative therapies is significantly increased if diseases can be diagnosed at an early stage of their development. The earlier the disease is detected, the more likely it is that the endogenous repair mechanisms can be activated for tissue repair. In addition, some diseases that maybe candidate for regenerative medicine therapies, such as local drug delivery or cell therapy, are currently difficult to diagnose and may only be detected outside the “ window of opportunity” for treatment. Image-guided therapies are an integral part of the regenerative medicine strategy, since they are essential for the accurate delivery of cell, biomaterials and combinations thereof. The targeted therapies employ minimally invasive or non-

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• • • • •

• •

invasive technologies to reduce pain, and hospitalization time and cost, and enhance recovery speed. Remote sensing enables monitoring of the efficacy of the new therapies developed, while minimizing hospitalization of the patients. Pharmacotherapy may deliver new compounds to support local regeneration and repair mechanism. Regenerative medicine tools and devices may enable the early assessment of drug safety and efficacy in realistic (human) disease models. Enabling technologies, such as (epi)genomics, proteomics, bioinformatics and systems biology are important tools to develop regenerative medicine therapies. TNO programs “personalized medicine and therapy” and “3R” as supported by the Ministry of VWS. The Regenerative Medicine field is an emerging domain with excellent opportunities for new business creation, and the Netherlands has an excellent track record in this respect. The market is projected to grow from $1.6 billion to $15-20 billion in the next 20 years. The Regenerative Medicine roadmap specifically addresses congenital disorders and age-related diseases and is well equipped to participate in future EU calls in this domain. Regenerative Medicine is integral to the public private partnerships BMM, TeRM and NIRM. The budget of BMM is 90 M€, and has a projected end date June 2014. TeRM has a total budget of 25 M€ with an end date of December 2012. NIRM has a budget of 84 M€ and a projected end date of December 2015. ZonMw fosters three programs on Translational research that are relevant for regenerative medicine: Translational Adult Stem Cell Research program, with a total budget of 23.5 M€ and an end date of December 2022, the translational gene therapy research program with a total budget of 15.6 M€ and an end date of December 2015 and the Open Translational Research program (structural program).

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2.2.5 Pharmacotherapy

1. GOALS Pharmacotherapy: chemical and biological health interventions The roadmap pharmacotherapy covers all disease types, including orphan/rare diseases, as defined in the disease / solution matrix. Its main contribution to cost effective healthcare solutions is through the discovery, development and efficient use of new, safe and (cost-) effective medicines in order to cure patients or prevent their progression along the healthcare chain and to improve their quality of life. Therapeutic modalities include small molecules, biologicals, biosimilars and other advanced therapies. Long term (and chronic) treatment and hospitalization are the main expenses (74%) in Dutch healthcare1) whilst only 9% is related to pharmacotherapy. Investment in new pharmacotherapeutic approaches can significantly contribute to (cost-) efficiency increase and improvement of healthcare especially for chronic and hospitalized patients. Additionally, continuous learning from healthcare practice and working on an innovative regulatory environment stimulates the cost efficiency of healthcare. This roadmap contributes to wealth in terms of economic activity, employment and productivity.

2. ACTIVITIES The need for new pharmacotherapeutics in all disease types and areas that contribute to cost-effective healthcare is characterized by four main goals: 1. To address clear unmet medical needs (currently there is no treatment available); 2. To improve current treatments with insufficient (cost-) effectiveness; 3. To improve current treatments with an insufficient safety profile; 4. To achieve an optimal treatment of patients (with e.g. a stratified approach). Activities will focus on three aspects: A. fundamental research B. experimental R&D C. creating a stimulating environment for R&D. The third activity (‘proeftuin’) may prove ideal for connections with other roadmaps. Within this roadmap, the research activities are connected by translational research programs and an overall support by the roadmap Enabling Technologies & Infrastructure. A. Fundamental research The early stages of drug discovery include the identification of an appropriate disease model, elucidation of the biochemical basis of disease, finding the associated drug targets and the subsequent validation of these targets for drug intervention. Once the disease model is established and the drug targets are identified, lead identification and optimization will deliver the first molecular (chemical or biological) entities to modulate the drug targets. Especially for the development of pharmacotherapies addressing unmet medical needs (amongst others, orphan diseases), there is a clear need for fundamental research dealing with e.g. the determination of mechanisms of action, target finding, side effects and validation. New Molecular Entities including advanced therapies often result from findings in fundamental research. Patients’ needs regarding pharmacotherapy are achieved in collaboration with the relevant patient organizations.

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B. Experimental research & development Once the disease model is established or known from previous research, the main focus should be on the development of new and/or optimized treatments. This includes the identification and optimization of new leads, full in vitro and in vivo pharmacology and toxicology studies, as well as formulation and administration strategies and the development of innovative enabling technologies (e.g. modeling and simulation techniques). Currently, innovative treatment options, such as the development of designer therapeutic antibodies, gene- and cellular therapy or miRNA based therapeutics, are driven by SMEs in close interaction with academic researchers. These areas of research can be largely covered by experimental research and development as is currently efficiently performed within the TTIs of the Life Sciences and Health sector and within other initiatives such as NGI. The experimental research and development needed to drive innovation and use of its outcome for the benefit of patients has a high public interest and is largely driven by private partners, sometimes in collaboration with public and private health charities and patient organizations. Innovation e.g. within SMEs dealing with rare / orphan diseases can contribute to the efficiency of R&D in other disease areas. An important part of this activity is to develop new concepts to assess toxicity and efficacy at an early stage, thereby also helping to identify risks as early as possible (especially in conjunction with lead optimization strategies). These technologies will enhance the efficiency of R&D by reducing the risk of unexpected side effects. It also includes the development of methods for Phase 0 testing and methods that reduce animal testing (3R methods) as described in the Enabling Technologies and Infrastructure roadmap. In addition, implementing pharmacogenomics and predictive biomarker strategies are needed for stratified treatment of patients (e.g. next generation sequencing), further improving the health benefits of pharmacotherapy and reducing the burden of the therapy for the patient. This connects with the roadmaps molecular diagnostics, molecular imaging and Enabling Technologies and Infrastructure (DTL) and will (together with these roadmaps) improve the safety and efficacy of future medicines. Optimization of pharmaceutical formulations (e.g. protein stability, formulations for increased absorption, etc) contributes to an increased accessibility in lower developed countries and leads to a better and improved treatment for patients in Europe. C. ‘Proeftuin’ as innovative and supportive environment for research and development Fundamental and experimental research has to take place within an environment that stimulates and supports innovation. Parts of this research can be performed in the socalled ‘proeftuin’ setting and include research in the orphan disease area, supported by the Orphan Diseases and Business initiative. This setup also provides the opportunity to acquire Health Technology Assessment (HTA) data in a real life setting. A transparent validated database is important to formulate medical needs and to derive data on potential new (pharmacotherapeutic) approaches, this links to the HTA / Quality of Life roadmap. In this particular context, the roadmap Pharmacotherapy highlights two ‘needs’: (1) continuous learning from healthcare practice and (2) an innovative regulatory environment.

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(1) Continuous learning from healthcare practice: When new solutions are used in clinical practice, the actual effectiveness and safety of medical interventions, as well as their economic benefit, can be determined. This calls for close cooperation with the roadmap Enabling Technologies and Infrastructure, with an integrated approach to address societal issues for governance evoked by the integration of highly diverse data-sets. Rich, integrated real-world data-sets (e.g. biobanks and other epidemiological databases) allow for the monitoring of new medical interventions and are essential tool for these assessments. Robust assessments of these existing data can be provided by modeling and simulation technologies. The Netherlands has a strong tradition in this area (e.g. TI Pharma project Sustainable Orphan Drug development through registries and monitoring), and continues to invest to stay at the cutting edge internationally. In the future, we will use these increasingly advanced datasets to both improve clinical practice and to provide leads for new innovative products within the scope of this roadmap but also in other ones (e.g. Molecular Diagnostics, ICT & Clinical decision support). For example, the validation and use of biomarkers, pharmacogenomics and diagnostics (combined with better and more specific treatment) will facilitate cost-effective treatments of the appropriate group of patients and help to identify directions for new therapies. Furthermore, it allows for optimization and optimal use of existing therapies using real life data. Alignment between clinical practice and drug product developers can catalyze innovation in the field of e.g. better drug delivery forms, biomarkers in terms of effectiveness and safety, and IT solutions to support the full potential of chemical and biological health interventions. (2) An innovative regulatory environment: Pharmacotherapeutic interventions are, justifiably, among the most regulated products in society. Regulation may contribute to innovation by giving patients access to the treatments that they require, while at the same time protecting society against unwarranted risk. In this context, an ideal regulatory system should be: • Extensive where needed, lean where possible; • Able to adapt to the requirements for individual technologies (‘tailor made regulation’); • Able to learn and improve continuously; • Able to translate or communicate knowledge to and with healthcare professionals and patients.

While ample evidence is available from ‘regulatory science’ and changes to the regulatory system are implemented, there are still many opportunities for improvement. This will be high on the agenda for the future. It should be noted that some changes can be made at the national level, but many regulations (both ‘hard’ and ‘soft’) originate at the European level and require complex policy processes that involve all stakeholders to achieve change. Here, the Netherlands has the possibility to play a key role, in agenda setting, facilitation and providing credible evidence for change. For example, the Dutch Medicines Evaluation Board (CBG-MEB) has included the ambition to reduce the regulatory burden where it is possible and acceptable from a public health perspective in its Strategic Business Plan. Regulatory innovation requires the optimal use of available regulatory data (for example, the late stage clinical studies will provide valuable information regarding current regulatory policies and procedures). But also data from healthcare practice (1) is of high value here. Keeping up with the best science and technological advances,

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development and validation of new methods to assess the benefit-risk and studying the regulatory systems in terms of impact on patient safety, public health and innovation is the core of regulatory science. Relevant platforms to fuel innovative thinking in these three areas are built in e.g. the TI Pharma Escher project. Moreover, it should be noted that activities cannot just focus on new molecules. A better understanding of the mode of action of drugs in humans provides clues for innovative new indications for registered drugs. The current therapeutic arsenal can be applied to new indications or used in a more optimal fashion (for example by developing new formulations or delivery systems). Furthermore, new formulations and routes of administration of existing drugs may improve therapeutic outcomes or lead to new indications for existing drugs. Learning from clinical practice and building an innovative regulatory system can also be of value to the patient and the overall healthcare system. It is therefore essential to have continuous, adequate and sufficient access to real life data from patient registries and registries with (related) data from healthy persons and where necessary to improve or set up new documentation systems. These data will prove essential for monitoring and evaluating the impact of novel and existing therapies in societal context (broader than pharmacotherapy alone). These are strong focus points for both TI Pharma’s Mondriaan project as well as ZonMw’s upcoming Goed Gebruik Geneesmiddelen (GGG) or current “Priority Medicines” program and the respective research programs funded by several health charities. By participation in e.g. aforementioned partnerships, patient organizations can deliver a valuable contribution to these programs. Near future and timelines: The development and integration of enabling technologies as well as modeling and simulation strategies is essential to all goals and will be addressed by the separate roadmap ‘enabling technologies and infrastructure’. Based on the outcome of fundamental research and the developed enabling technologies eventually alternative modalities of therapy will reach the patient e.g. through valorization within TTIs and ‘proeftuinen’. Within the pharmacotherapeutic area, many stakeholders are currently working together in the research portfolios of running public private initiatives such as TI Pharma. In terms of timelines and milestones for the next two years, the agreements made within the current public-private programs are considered to have a leading role in guiding the potential initiation of new programs. In potential new programs, the participation of SMEs is of high importance. Moreover the input of healthcare insurance companies and patient- and health organizations will contribute to an integrated approach in addressing medical needs and identifying potential (cost-) effective treatments.

3. CASE A. Priorities The main priority of this roadmap is to reduce the overall costs of the healthcare system by curing or preventing the progression along the healthcare chain by means of chemical or biological therapeutic interventions. New and innovative pharmacotherapeutic approaches will improve the quality of life (efficacy and safety aspect) and reduce the burden of illness in every aspect both for the individual patent as well as for society as a whole. To reduce that burden an integrated approach is

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required aiming for societal embedding of innovations. This will significantly contribute to a healthy society and bring wealth to the Netherlands in terms of employability and attracting foreign investments in the Dutch Life Sciences and Health sector. Priority setting, including patient perspectives, is in line with the recent report by the Dutch Health Council ´Medical products, new and needed´. B. Strengths Change in Business Model: A change is observed in the global business model of Big Pharma companies, moving from ‘in house’ Research and Development to a networked model for Search and Development. This change, occurring on an international scale, is especially visible through the restructuring of R&D activities (e.g. closure of Sandwich site by Pfizer, parts of Oss and Newhouse by Merck, Weesp by Abbott). Recent deals made between Big Pharma and smaller innovative companies illustrate the global change in business model with increasing externalization of R&D. Examples are the deals between Prosensa and GSK (518 M Euro), between Galapagos and Roche (400 M Euro) and between Merus and Novartis (154 M Euro). During the period 2008 and 2010, 6 of the top-10 European strategic alliances were made with companies in the Dutch Life Sciences and Health sector (source: Dutch Life Sciences Outlook 2011). These examples show the bright (economic) prospects of an “innovate, and sell or license” strategy in this sector. Moreover, many international (bio)-pharmaceutical companies outsource pre-clinical research and clinical studies to the Netherlands with its leading university medical centers, some hundred highly qualified hospitals, the highly organized public health system and high quality contract research organizations. A further development of an interconnected network of academia, medical and diagnostic centers, SME and Big Pharma will add to the Dutch innovation potential in developing new therapeutic options. The Netherlands is a pioneer in public private partnerships in Life Sciences: Multilateral collaboration in the life sciences was pioneered in the Netherlands with the initiation of TI Pharma in 2006. Within this PPP, true partnerships between academia, university medical centers, SMEs, regulatory authorities and big Pharma were established. A clear cultural change was observed over the last few years with respect to the interaction between these stakeholders. Successful collaborations in the TTIs deliver valuable results for society, economy and science. Previous proposals (e.g. Drugs Cluster FES 2009) indicate a strong relationship between academic and private partners in order to jointly innovate in this area. Internationally, in calls of the European PPP, Innovative Medicines Initiative (IMI), the Netherlands was the most successful small country in attracting research funds. Scientific Excellence in academia and SMEs: The Dutch Life Sciences and Health sector has an excellent track record with its high quality academic expertise as well as with the initiation and development of SMEs in early stages of drug research. With respect to the number of innovative SMEs, an increase of 8% per year is observed, which is higher than observed for other European countries (source Agentschap NL cluster information and CBS statline). Within the sector, Dutch scientists belong to the most highly ranked scientists in the world (ref 1012 Topsector plan). The scientific excellence is ranked as number 4 in the world (table 1.3 Topsector plan). Dutch academic researchers have played a key role in the development of orphan drugs for rare diseases such as Gaucher disease or Pompe disease. The Dutch spin-offs of the academia in the field of rare diseases are strong in technology-driven research. The Netherlands has a unique, strong and well organized

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healthcare structure. With some hundred hospitals, a well structured first line healthcare system with patients well documented in different databases, this gives the opportunity to develop and efficiently use the ‘proeftuin’ setting. Companies are increasingly seeking to unlock the power of patients and data, working closely with clinicians and researchers 3). All aforementioned situations provide an excellent window of opportunity for the Netherlands to acquire, build and sustain a strong research portfolio in the area of pharmacotherapy with a clear need for public private partnerships.

4. CONNECTIONS Link with other roadmaps: The roadmap Pharmacotherapy closely connects with several of the other roadmaps; amongst others, Molecular Diagnostics, One Health, Global Health, Regenerative Medicine, Imaging & Image-guided therapies, Enabling Technologies & Infrastructure and Specialized Nutrition, Health & Disease. Especially in the field of companion diagnostics (also described under 3.1 Continuous learning from healthcare practice) this roadmap is linked with Molecular Diagnostics and Imaging & Image-guided therapies with e.g. the discovery of new biomarkers and the design of new radiopharmaceutical tracers. Pharmacotherapy is able to support the Global Health roadmap. Innovative technologies, new treatments and e.g. formulation strategies developed within the Pharmacotherapy roadmap can lead to breakthroughs in programs defined within the neglected diseases area such as the euSEND initiative. Enabling Technologies & Infrastructure facilitates new approaches for drug discovery and development and therefore can accelerate developments in areas such as target identification & validation as well as early risk assessment strategies and achieve better use of clinical data for decision making by modeling and simulation. The roadmap Nutrition and Health has several clearly aligned topics with Pharmacotherapy. Research in this roadmap will focus on exploring and establishing in a pharma-like way the therapeutic effects of specialized nutrition as well as to improve pharmaco*kinetics and -dynamics of chemical and biological interventions. In addition, exploring the effects of specialized nutrition for reducing side effects of chemical and biological therapies can lead to a better safety-efficacy balance. Links with other Topsectors: Connections with other Topsectors include e.g. nano/material sciences within High Tech Systems and Materials, in which innovative nanotechnologies for drug delivery and drug release will be developed. Also with the Topsector Chemistry important connections can be made in the area of target finding and validation, lead finding and optimization (incl. safety issues) and the discovery & validation of new analytical techniques for e.g. biomarker research. This includes the roadmap Advanced Materials of the Chemistry Topsector. Links with ongoing programs/initiatives: Regional initiatives currently being developed include the life sciences parks in Oss and Weesp. There are many more regional initiatives important within the context of this roadmap. In Groningen for example, the Healthy Ageing campus brings together

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researchers, entrepreneurs and the public sector in an environment that stimulates open innovation in several disciplines, including pharma. Already in 2006 the LifeLines Cohort & Biobank initiative was started. It investigates a representative sample of 165.000 participants from the three northern provinces of the Netherlands in a unique three-generation design. National initiatives such as the current FES/BSIK-consortia (Virgo, NeuroBsik) and other PPPs such as TI Pharma, CTMM and BMM contribute to the alignment of the national research agenda and with that, increase the effective output (translate scientific output to novel health interventions) of the Dutch life sciences and Health sector. The ‘Innovatiekrediet’ has significantly helped in getting SMEs the support they need for development. Several patient organizations and health charities stimulate research co-funded by SMEs and participate in currently running PPPs. In other national initiatives, such as TI COAST, several sectors including the pharmaceutical sector team up to provide pivotal analytical knowledge and instruments based on fundamental science and to ensuring transfer of analytical expertise between application areas. The recent report by the Dutch Health Council ´Medical products, new and needed´ describes their vision on how the field should develop. Furthermore, it describes how the patient perspective and knowledge could be collected and generates relevant guidance for future drug research and development. The field of Priority Medicines is a.o. addressed by programs within ZonMw (including translational research and orphan diseases) and the extensive research portfolio of TI Pharma (based on the WHO priority medicines report). In a novel, structural ZonMw program ´Goed Gebruik Geneesmiddelen´ attention will be paid to the development of evidence for the rational use of pharmacotherapy. This novel program will also be a PPP with pharmaceutical industries and government participating. It includes building on national patient registries to support “proeftuin” approaches with real life data. The Orphan diseases and Business initiative is supported by several private partners, public partners and patient organizations. The TNO programs “Preventie en Therapie Op Maat” and “3R”, as supported by the ministry of health (VWS), develop together with the (Dutch) Life Science Industry tools and technologies that help driving new product development in a more cost and time effective way. As an example, in terms of participation in European initiatives, the Netherlands was the most successful small country in attracting research funds from the first call of Innovative Medicines Initiative, in the field of Pharmacotherapy. Research projects within these IMI consortia typically include many industrial, academic and other partners (e.g.: • Etox (VU University) • Protect (Utrecht University, University Groningen) • U-BIOPRED (Amsterdam Medical Center; Astma Foundation) • PROactive (University Medical Center Groningen, Astma Foundation) • SafeSciMed (VU University) • EU2P (Erasmus MC, Utrecht University) • BTCURE (Amsterdam Medical Center, Leiden University MC, Tilburg University Brabant) • DDMore (Leiden University) • Open Phacts (Leiden University MC, University Maastricht, VU University) • EUPATI (VSOP).

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References • • •

Rijksbegroting VWS 2011 via http://www.nefarma.nl/website/feiten-encijfers/farmaceutische-zorguitgaven RGO: Gezondheidsraad. Medische producten: nieuw en nodig! Een investeringsagenda voor onderzoek naar innovatieve en relevante medische producten. Den Haag: Gezondheidsraad, 2011; publicatienr. 2011/01 Investing in UK Health and Life Sciences, HM Government report, December 2011.

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2.2.6 One health

1. GOALS The One Health concept is based on the recognition that human and animal health are inextricably linked. Humans and animals have socio-economic interactions through direct physical contact, the food chain and the environment. Therefore, the health and well-being of all species can only be safeguarded by enhancing cooperation and collaboration between physicians, veterinarians, and other scientific health professionals. This will be achieved by effectively coupling the know-how and infrastructure available in the Human and Veterinary/Agricultural domain and will lead to an improved health status of humans and animals at an overall lower cost to Society. To meet this challenge, the One Health Roadmap focuses on the following objectives: • Prevention of infectious and related diseases of humans; • Prevention of infectious and zoonotic diseases of animals • Reducing the burden on humans of antimicrobial resistant organisms • Reducing the infection pressure on food-producing animals; This will be achieved by development and application of tools in the field of: • Vaccines for humans and animals • Other interventions for humans and animals • Extended early warning systems, incl. risk assessment such as diagnostics to identify and monitor infectious diseases in animals and humans and monitor antimicrobial resistance; • Efficient evaluation and monitoring systems for human health impact by animal farming; • Improvement of the immune competence of animals and humans (e.g., intestinal health); • Enabling technologies Together, this will lead to a world leading position of the Netherlands in the field of infectious diseases and expertise and economic activity in One Health solutions.

2. ACTIVITIES

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A. Diagnostics and Early Warning systems Diagnostics are an important tool for obtaining insight in the occurrence, frequency and character of infections as well as in the origin and development of antimicrobial resistance. Three areas of solutions are critical to achieve the One Health objectives: 1. Diagnostic tools to identify new challenges (infectious agents, specific antibodies, specific genes, biomarkers, resistance markers and genes, other health burdens). 2. New technologies and new diagnostic platforms to allow more effective or efficient testing. Examples are: • On-site testing methodology to improve the intervention decision • Qualitative (multi-plex) screening and quantitative confirmation tests • Chain monitoring of animal healthcare treatment and movement from birth to slaughter 3. Development and implementation of risk-evaluation systems and methods to monitor One Health epidemiology. 4. In this area it is critical that the Veterinary- and Human health systems, signals, databases and structures are fully aligned to come to a true One Health approach. B. Vaccine interventions Infections have a major impact on the disease burden in both humans and animals and often are dependent on interactions between humans and the animal world (including wildlife). Increasingly, antimicrobials are loosing their applicability in humans and animals because of increasing antimicrobial resistance development. Some infections are restricted to humans and some in animals. In the One Health concept, pathogens that can be transmitted from animals to humans are preferentially controlled in animals. In addition, common concepts for parallel development of vaccines for human and veterinary application is being sought. There are several benefits to the combined development of vaccines for humans and animals, including spreading risks and combining innovation power. The key reason is that the same technology platforms can be utilized for research and development, but also for production, of vaccines. Animal and zoonotic infections Transfer of infectious agents can either be caused by direct contact with animals, wildlife or pets (e.g., MRSA; SARS, Influenza; Rabies) or through foods produced from animals (e.g. Salmonella, Escherichia coli, Campylobacter, Toxoplasma and Noroviruses). Food-borne infections in the Netherlands annually lead to an estimated 300.000 to 700.000 disease cases resulting in 1000-4000 DALYs with estimated costs associated of about 30 Million Euro (Kennisagenda Voedselveiligheid Min LNV, Rapport DKI nr. 2010/dk132). Besides zoonotic pathogens, also other pathogens are responsible for a considerable disease burden in animals (e.g., mastitis infections, coccidiosis, clostridial infections) and also in these cases antimicrobials are loosing their effect (because of resistance development and political/societal pressure to reduce usage). Availability of effective vaccines against endemic diseases in farm animals is an important tool to lower antimicrobial use in animal husbandry and thereby to prevent further development of antimicrobial resistance. Other tools such as innovative animal housing systems and health management programs can also contribute to lower the impact of infectious diseases in livestock (as specifically addressed in the program of the Topsector Agrofood).

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There is a clear guidance on the priority for the development of animal (zoonotic) vaccines/other interventions. In the Netherlands, the recent Emerging Zoonosis report (RIVM) and a report of the Ministry of EL&I on food animal production related diseases (Bergevoet et al. 2010) give direction to this issue. These priorities can be aligned with EU and OIE/WHO priority settings such as the Discontools and Epizone initiatives and recent EFSA reports (3 Oct 2011). Human infectious diseases In addition to the infectious diseases caused by the above mentioned zoonotic pathogens, human specific agents of particular (onco-)viral, bacterial and parasitic origin are of concern to human health (i.e. HPV, CMV, respiratory pathogens) The need for (cost)effective, efficacious and safe vaccines is evident. The focus within the One Health roadmap would be to combine the know-how and infrastructure for human and animal vaccine development in the areas of molecular mechanisms of antigenic make-up, antigenic variation, infectiology, immunology and molecular epidemiology of specific pathogens and product/technology development. Potentially this could lead to development of the same vaccines for humans and animals. More realistically, use of combined know-how will accelerate development and improve the vaccine profile. In this respect the initiative to see if a broad platform can be formed on strategic vaccine research may be relevant. Emerging and neglected Infectious diseases A specific domain worth touching is the field of infectious diseases that may be of future threat to Western Europe. In many cases they originate from animals and often are vector borne (through bats, ticks and mosquitoes). Examples are Crimean Congo, Rift Valley fever, SARS but also new Influenza viruses, Chikungunya virus, West Nile virus and Japanese encephalitis virus. Climate change will also increase the risk for EU to epidemic malaria, Leishmania, heartworm and Schistosoma outbreaks. Treatment often comes too late or is ineffective, whereas vaccines against many of these threats are yet to be developed. Improvements in this area will need both fundamental research on topics such as antigen selection and antigenic variation, immunology, infection biology, epidemiology, vector-competence, as well as platform-, product- and technology development. Public involvement is essential for this topic since commercial opportunities are limited. Involvement of NGOs could be considered as well to come to a joint effort of public, NGO and private parties. The currently running Castellum consortium project is based on this model and combines the expertise of Industry (MSD) and Governmental organizations (Utrecht University, Central Veterinary Institute, RIVM) to develop vaccines against Rift Valley Fever, Crimean Congo Haemorrhagic Fever and Influenza. Overall, there is strong expertise on prevention, monitoring and treatment of infectious diseases within the human and veterinary arena in the Netherlands, both within Academia (Amsterdam, Rotterdam, Nijmegen, Utrecht) as well as within the RIVM Unit of Vaccinology, and Industry (MSD, Crucell and specialized biotech). Connection of this infrastructure with outside stakeholders such as the EU EATRIS initiative, TRANSVAC, WHO and the Bill&Melinda Gates Foundation is important to further support running programs. C. Tools to prevent and overcome antimicrobial resistance Therapeutic interventions such as anti-bacterials, anti-parasitics and anti-virals are still feasible options to reduce transmission and burden of infection. In order to reduce the risk of resistance new classes of target molecules are needed. It has been estimated

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by the ECDP that in the EU, antibiotic–resistant (AR) bacteria cause about 25.000 human deaths per year and cost about 1.25 billion Euros per year in healthcare expenses and loss of productivity. Clearly antimicrobial resistance within the human population is becoming a more urgent healthcare risk. Although it is believed that the main cause for occurrence of AR-strains lies within the human field of use, evidence shows that transfer of AR strains from animals to humans also play a significant role.. Fundamental knowledge on the transmission routes and risk is lacking. It is a great challenge to combine knowledge and expertise from molecular monitoring, epidemiology and infection biology to provide new solutions. This One Health aspect is an integral part of the Roadmap and innovative solutions to limit/eliminate the transfer are key elements to decrease healthcare costs by prevention. • Models, protocols and programs to support optimal use of antimicrobials (in humans and in animals) • Mechanistic research in the resistance transfer process and molecular epidemiology of antimicrobial resistance. • Further development of new anti-microbials specific for use in humans • Further development of novel therapies and other interventions (“alternatives”) to replace antibiotics in humans and in animals (i.e. phages, peptides). The currently running ALTANT program is an excellent example within the scope of One-Health where novel approaches to antimicrobial therapies and immunomodulation show potential. This also holds for mechanistic work and research currently performed by CVI, RIVM and academic parties. D. Other interventions Tools to enhance natural resistance in humans and animals Recent discoveries corroborate the importance of intestinal health as a crucial factor in resistance to disease, including infectious diseases. More and better defined chemicaland plant derived entities are being discovered acting on the immune and metabolic pathways involved in intestinal health. This is a field where technology and knowledge can be readily combined to develop solutions for both animals and humans. Pre- and probiotics, phytochemicals and defined feed additives are frontrunners of this fascinating new subject of life sciences. Also, microbial exposures which originate from animal contact are known to be associated with protective effects against chronic immunological diseases like asthma. Identification of key organisms and mechanisms may contribute to new interventions. Enabling technologies Developments in vaccines, diagnostics and other interventions depend on a number of enabling technology platforms. Examples of generic necessary technologies are, x– omics, molecular diagnostics, immunology, epidemiology, infection biology, intestinal health and imaging technologies. To be mentioned specific technologies are vaccine platform technologies for parasites, viruses, bacteria, but also oncologic viruses and additional essentials as adjuvants and expression systems. A unique collection of yeasts (CBS) may be instrumental in discovery of new classes of anti-microbials. Another important enabling infrastructure is Virus and Pathogen Discovery. The One Health partnerships will require the involvement of specialized knowledge centers in these areas to effectively execute their programs.

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Reduction, refinement and replacement of animal experiments Reduction, refinement and replacement of animal experiments are not discussed as a separate topic in this roadmap but will be a point of interest or even a requirement for all developments within the One Health program. Furthermore we will evaluate in vitro models for quality procedures regarding vaccine production, for example to test vaccine titers. A unique feature of the One Health approach is the advantage of using data obtained from target animals for veterinary interventions, which may well reduce the number of experimental animals for development of equivalent human applications.

3. CASE A. Priorities On the basis of the key elements of the One Health Roadmap: • Vaccines for humans and animals • Other interventions for humans and animals • Extended early warning systems, incl. risk assessment such as diagnostics to identify and monitor infectious diseases in animals and humans and monitor antimicrobial resistance; • Efficient evaluation and monitoring systems for human health impact by animal farming; • Improvement of the immune competence of animals and humans (e.g., intestinal health); • Enabling technologies the estimated costs to society associated with the human impact of (food-borne) zoonotic and infectious diseases, and increasing antimicrobial resistant bacteria, a priority setting can be achieved in consultation with the key stakeholders. Animal vaccine development will concentrate on vaccines for those infectious diseases with the highest impact in respect to veterinary antimicrobial usage and on zoonotic diseases as these will have the largest economic and Health improvement impact. Priority setting can be on the basis of National (Emzoo, RIVM) and International (EU/OIE) guidance, combined with economic perspective for Industry. We foresee an elaborative consultation, prioritization and evaluation phase. The Castellum consortium has a working program based on the EmZoo priority setting combined with specific evaluation criteria based on feasibility and perspectives. For Human vaccines, the priority may be partially parallel to the Zoonotic agenda for Animal Health, but in addition will be governed by running National and International (WHO/EATRIS/TRANSVAC) programs. Many large and strictly human focused challenges exist in the field. Industry involvement will be evaluated. We foresee a first stage action in the beginning of 2012 to identify the largest opportunities with significant social and economic perspectives. Technology- and animal model sharing between Human and Animal vaccine development may be powerful process accelerators. Any tool, other than the development and application of vaccines, to limit the occurrence and transfer of antimicrobial resistance from animals (direct or through food) to humans will be both very relevant to the animal food producing sector as well as to human health. Continuation and strengthening of existing activities such as ALTANT will be critical. Also, new solutions may come from the knowledge that microbial exposures which originate from animal contact are known to be associated with protective effects against chronic immunological diseases like asthma.

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To achieve the above main One Health programs and support the priorities set , the development and implementation of new diagnostic tools is critical. Next to that Risk assessment models and a closer alignment between the Veterinary and Human epidemiological and diagnostic systems has top priority. Finally, as the remit of this Roadmap is about prevention of costs by implementing measures early in the cost- and value chain, identification of so far underestimated or under-recognized health effects is relevant. Examples of vaccination of animals reducing the infection risk in humans are documented. Vaccination of chickens with a co*cktail of several Salmonella species mid 1990 in UK was followed by a 50% reduction of human cases. The Q-fever vaccine for goats that has been applied in 2009 and 2010, could not be evaluated properly due to culling of all pregnant animals from infected farms, but analysis of the available data indicated that reduction of shedding of Coxiella was achieved in vaccinated animals. (Hogerwerf et al. Emerg Infect Dis. 2011 March; 17(3): 379–386) In Salmons the application of new vaccines, combined with additional other interventions, has resulted in a drop of 80% of antimicrobial usage within 2 years. A recent example of a very costly epidemic has been the 2011 EU E.coli 104:H4 outbreak with a cost of about $2.5 billion in human and economic losses, clearly showing the priority case. B. Strengths Industry related to infectious diseases The Netherlands has a strong position in both human vaccine and veterinary pharmaceutical industries. A top player of the veterinary pharmaceutical industry is MSD Animal Health with headquarters and major R&D facilities in Boxmeer. Other companies such as Merial, Pfizer AH and Elanco-Lilly have offices and invest in collaborative R&D in the Netherlands. Eurovet (Bladel) and Prionics (Lelystad) are examples of members of FIDIN that are developing products for the veterinary and agro industry. The Animal Health Service (Deventer) is a private service organization. Human pharma is represented by the Dutch Vaccine group (covering over 25 companies) including big players such as Crucell (J&J) and by MSD Oss and many biotech firms that produce or develop high tech solutions (antibodies, diagnostics). All major human pharma companies (MSD, GSK, Novartis, Pfizer, etc.) have strong alliances to Dutch scientists and invest in collaborative programs or contract research. Academia and related research-institutions Utrecht University has established in 2010 an open Innovation Center for Research on Zoonosis with a collaborative effort of the Faculty of Veterinary Medicine, RIVM and University Medical Center Utrecht. Universities of Amsterdam (incl. VUmc and AMC) , Rotterdam (Erasmus MC), Leiden (LUMC) and Nijmegen (RUMC) have highly renowned scientists in the field of infectious diseases, microbiology, immunology, immunological disorders and vaccine technology. Artemis is an open Innovation Center for Research in the field of Wildlife Virology. The Central Veterinary Institute (Lelystad) has complementary veterinary knowledge and unique facilities (hBSL3+). The RIVM with its Vaccinology Unit, has core knowledge on Human vaccine development up to Phase I clinical studies. In addition RIVM has a strong signaling and monitoring expertise and is responsible for advising the ministry on public health measures in general and on infectious diseases in specific. Wageningen University is well recognized for its food-related microbiology, intestinal immunology and microbiology.

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The Netherlands has a unique opportunity to post-marketing surveillance of the effects and efficacy of vaccination. Through the cohorts vaccinated in the National Vaccination Program pharmacovigilance data are of great value to optimize the quality of vaccines. Many groups already collaborate in consortia with industry such as Castellum, VIRGO, Immuno Valley, ALTANT and projects of Dutch Vaccine Group. In addition expertise and technology on tuberculosis intervention strategies are strongly integrated in European consortia (e.g. TBVI). TNO have several front-running institutes and departments on complementary technology in diagnostics, immunology and food. It is critical for the success of the One Health Roadmap and the One Health initiative as such, that the knowledge and expertise in human and veterinary health and food production are brought together. This will be the greatest challenge for the coming years. A specific aspect of the Roadmap One Health is that there are important program areas where substantial private funding will not always be obvious. As the societal need does clearly exist this implies that that the balance private to public funding may be driven towards the public domain. Taken together the Netherlands has all the ingredients to obtain a world leader position in the field of One Health and Prevention, at the same time improving the Health status and well being of men and animals and lowering overall healthcare costs to society.

4. CONNECTIONS Connections within the LS&H sector: • Pharmacotherapy (novel antimicrobials) • Enabling technologies (-omics, and alternatives for experimental animal use) • Molecular diagnostics (novel diagnostics and technology) • Imaging (disease discovery) • Global health. The microbiological part of this connects to the Roadmap One Health (e.g. Tuberculosis) • Regenerative medicine (Translational Medicine, Comparative Pathology) • Specialized nutrition (basic immunological principals, animal models) Connections to Topsector Agro-food: • Reduction animal-related food-borne diseases. Agro-food: animal keeping, risk based management, food chain quality, risk based housing and production, resistance breeding, improving health. LSH: novel tools therapies, surveillance, early warning. • Diagnostics (chain quality; on-site). • Food safety • Relation between animal health and human health Connections to other Topsectors: • WATER: environmental spreading of infectious agents • Nanotechnology: diagnostics development, vaccine delivery. Connection to running programs: Public private partnerships: • VIRGO (respiratory virus vaccines)

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• • • • • • • • • • •

Immuno Valley ALTANT (Alternatives for antibiotics in livestock) Castellum (vaccines and monitoring of emerging infections) TI-Pharma projects (a.o. malaria, Chikungunya) PneumoProtect and Pneumovac (improvement human pneumococcal vaccines) ZonMw Program Infectious Diseases ZonMw Program Priority Medicines Antimicrobial Resistance, ZonMw Program Q-fever NWO program Leven in Gezondheid ARTEMIS (wildlife virology, virus discovery) NGI CTMM (a.o.AmpVacs and MARS)

Regional initiatives: • Immuno Valley as a bottom up consortium of >30 industry and academia (PID 2008-2014) but grown as a national organization. • Life Sciences clusters and Science parks of Amsterdam (AIM, ASP), Utrecht (ULS, USP), Flevoland (LSIPF, EDC), Leiden (LeidenBioSciences, LSP), Nijmegen-Oss (SPO), BOM, all are active in the field of vaccines, diagnostics etc. New initiatives: First orientation towards the feasibility of a national knowledge Center on Vaccines International links Key stakeholders in the One Health roadmap activities have a wide range of international connections. They range from EU- and WHO/OIE programs to individual collaborations on specific topics. Funding model for partnerships We foresee a path with emphasis on fundamental knowledge development during the first 2 years with high public involvement backed by specific knowledge from the private partners. This is followed by a path of strategic and industrial research for periods of 5 to 7 years with shared input and risk of public and private partners. For a number of animal vaccines, the stage of development could be reached earlier. This model has proved successful before as in ALTANT.

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2.2.7 Specialized nutrition, health & disease

1. GOALS Reduce the costs and burden of diseases through researching Specialized Nutrition that: • prevents the onset, reduces the severity or delays the progression of chronic diseases; • enhances recovery after acute disease; • provides solutions for a series of rare often inborn (metabolic) diseases • supports and enhances the efficacy of chemical, biological, radio- and surgical therapies. Approach The problem in the treatment of most high-cost, high-burden diseases is the lack of curative treatments as well as the lacking possibility to modify disease course. Current treatments are often modestly effective and sometimes offering only temporary symptomatic relieve. Chronic diseases are in most cases multi-factorial, thus administration of a single pharmaceutical drug might not be effective on its own. Since the development of new drugs is extremely costly, the positive contribution provides by Specialized Nutrition are receiving increasing attention. A recent example is Alzheimer’s disease: where some large pharma cease their development programs for new drugs, Specialized Nutrition has stepped in to develop more effective solutions. The management of these multi-factorial diseases needs a new and integrated therapeutic approach. This new approach is based on appropriate phenotyping and combines not only early diagnostics and pharmaceuticals (chemical and biological therapy) but also Specialized Nutrition and medical care next to a tailored lifestyle (diet nutrition and physical activity). A better discrimination of multivariate phenotypes (including life history, behavior and environment in addition to genotypes) will predict response (responder/non-responder) that will ultimately lead to personalized nutrition and personalized medicine. The new approach requires integrated collaboration between several LSH roadmaps and also includes social innovation. Design, development and prescription of new safe and effective Specialized Nutrition in high-cost, high-burden diseases will offer the advantages of a multi-component, multitarget approach such as: • no or very little side effects, faster recovery, improved quality of life and living independently longer; • increased efficacy of therapies, reduced therapy costs, reduced duration and costs of hospitalization and institutionalization; • prevention of epigenetic/metabolic imprinting diseases. In addition, this approach also has considerable effects on increase of labor productivity.

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2. ACTIVITIES Research themes and corresponding products to be developed: 1. Nutritional intervention through metabolic imprinting Sub-optimal maternal and infant nutrition may affect the development of the immune system, microbiome, cardio vascular and endocrine metabolism, cognition and behavior. This occurs through epigenetic and metabolic mechanisms resulting in immune-related or neurodegenerative diseases or obesity related metabolic syndrome. This theme studies the possibilities of nutritional programming to prevent diseases early and later in life. New and improved nutritional products can be developed for phases that are the window in life for imprinting and programming: pre-conception, pregnancy, lactation and early childhood. 2. Nutritional intervention in disease development This theme researches the possibilities to prevent the onset, reduce severity or delay progression of diseases. The proposed approach should potentially be effective in: neurodegenerative, psychiatric, chronic inflammatory, autoimmune (e.g. celiacy) diseases in metabolic and age-related diseases and diabetes type 1 and type 2. Research will include exploring and establishing in a pharma-like way the preventive and therapeutic effects of lead nutritional ingredients, compositions and formulas. New and improved products can be developed for disease intervention with Specialized Nutrition. 3. Nutritional support during treatment for improved safety-efficacy balance This theme studies the possibilities of Specialized Nutrition to improve the condition of patients before, during and/or after chemical, biological, surgical or/and radiotherapy interventions aimed at enhanced functional outcomes of the interventions. In addition, the possibilities of Specialized Nutrition to limit side effects and/or reduce the dosage (improving safety-efficacy balance) of chemical or biological therapies will be studied. Ad 1. Nutritional intervention through metabolic imprinting Humans are able to adapt to diverse environmental circ*mstances. Type of food, quality, quantity and preparation can largely vary. Although the human gene pool is quite stable, it can adapt to a changing nutritional environment by adjusting gene function via epigenetic 'switches' that can be gradually turned ‘on’ or ‘off’’ via DNA modifications. Most of these switches are set when the cell/organ is being constructed to create the required flexibility in later life, based on the actual exposure to nutrients in early life. Once the cell/organ is fully developed, the switch setting can hardly be changed and thus is set for life. This concept of metabolic imprinting sets limits to the flexibility of our body. This might play an important role in the prevalence of obesity, allergies, autoimmunity, cancer and other metabolic diseases. Fundamental research Research will focus on understanding the circ*mstances, the effectors - in particular nutrients - and the mechanisms that are involved in or responsible for these programming effects. This will reveal in more detail how organ structure and function are being constructed and how their flexibility is set in early life. Specific research of epigenetic mechanisms of immune and intestinal epithelial cells in above mentioned diseases will lead to the identification of new nutritional targets (including microbiota) for treatment as well as biomarkers.

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Strategic research The insights gained in epigenetics research will allow to define Specialized Nutrition concepts (the right amount and quality of ingredients) tailored to the specific needs of mother and child (especially the optimal start in life) and to their environmental circ*mstances. The prospects include tailor-made Specialized Nutritional solutions in early life that also include variation in genetic predispositions for life-long health. • Pre- and postnatal Specialized Nutritional strategies to prevent deficiencies that impact both the incidence and severity of metabolic, immunological, neurological and psychiatric disorders. • Identification of dietary components from breast milk and other food sources such as fruits, vegetables, dairy and fish, that induce long term metabolic effects, structural changes as well as optimal cognitive functioning and balanced immunity in order to prevent metabolic, immunological, neurological and psychiatric disorders. Proeftuin Longitudinal follow-up of existing and new birth cohorts. Ad 2. Nutritional intervention in disease development Two major chronic conditions that ultimately lead to diseases can be distinguished. Firstly, chronic inflammation and loss of immune tolerance predisposing to neuroinflammation and neurodegenerative disease (Alzheimer’s disease, stroke, Parkinson’s disease, age related macular degeneration) and/or leading to high burden chronic inflammatory diseases (i.e. COPD, asthma, inflammatory bowel disease, autoimmunity, musculoskeletal disorders).Secondly, obesity leading to metabolic syndrome and diabetes which accelerates renal and cardiovascular disease. In addition, among certain cancer patients in the early stages of their disease, weight gain is an important side effect of some chemotherapeutic and/or hormonal treatment which may lead to sarcopenic obesity and muscle strength may weaken which leads to dynapenic obesity. The therapeutic window of Specialized Nutritional intervention as adjunct to medical intervention in disease modification lies not only in modifying the primary disease process (i.e. inflammatory processes in the various organs) but also in combating the progressively disabling effects on mobility. The heterogeneity and complexity of the current high burden chronic diseases requires a tailored multi-target intervention approach with Specialized Nutrition. This intervention approach must be aligned to the different disease stages (from prevention to end of life care) and integrated in state of the art medical therapy. The tremendous increase in prevalence and comorbidity of these diseases in particular in the elderly, also requires unraveling common lifestyle induced denominators (smoking, western diet, physical inactivity) and disease specific denominators of metabolic aberrations in aetiology and disease progression. Elite/high level sports require well-designed nutritional formulations that support the continuous improvement of extreme performance. Study of the metabolic processes in relation to nutritional requirements is also relevant for development of Specialized Nutrition for prevention of onset and progression of life style related diseases. Fundamental research • Identification of the potential targets for Specialized Nutrition involved in neuroinflammation and neurodegeneration and of monitoring effectiveness by non-invasive neuro-imaging and novel biomarkers. • Translation of catabolic triggers and their regulation of muscle maintenance (muscle mass and muscle oxidative metabolism) in the different active phases (acute wasting, decreased muscle growth and impaired regeneration during

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recovery) to identify the potential of modulation by Specialized Nutrition as single or multi-component intervention. To studying the effectiveness of novel imaging methods and biomarkers to monitor effectiveness. Identification of the cause and consequences of systemic inflammation in chronic metabolic and inflammatory diseases to identify disease specific or generic targets for Specialized Nutritional intervention. Special focus on the role of inflammation in metabolic disorders (muscle wasting, obesity), chronic inflammatory diseases such as allergy, autoimmunity and cardiovascular diseases. Understanding the loss of flexibility of the body to switch between storage and oxidation of substrates and the flexibility to select substrates (glucose versus fatty acids) for oxidation upon availability - jointly referred to as metabolic flexibility - is severely blunted in obese and insulin resistant subjects. A diabetes prone state of metabolic inflexibility emerges. Identification of new targets for Specialized Nutrition should have the potency to maintain metabolic flexibility in obese and insulin resistant subjects with the aim to prevent development of full blown diabetes. Unraveling the biological pathways that lead to frailty and co-morbidity in age related chronic neurodegenerative and wasting diseases, conditioned by both physical and cognitive dysfunction. Potential mechanisms include but are not limited to inflammation, oxidative stress, autonomic nervous system, hormones and the multiple adaptative mechanisms to physical activity. Unraveling the relation between the composition and functionality of the gut microbiota and systemic diseases like diabetes, metabolic syndrome, (chronic) inflammatory diseases, allergy and diseases related to the proper functioning of the GI-tract. Include a network-based (systems biology) approach to chronic metabolic and inflammatory disorders that links tissue and organ systems as well as intestinal microbiome and will identify new metabolic targets for Specialized Nutrition and biomarkers for these complex chronic diseases at different stages of disease progression that will truly lead to personalized lifestyle and medicine. For this purpose a systems biology supporting technology infrastructure is of importance.

Strategic research Specialized Nutritional therapy in management of neurodegenerative and chronic inflammatory diseases: • Develop Specialized Nutrition that provide precursors that the brain needs to synthesize building blocks of membrane and synapses or to support neurotransmission and related processes in order to improve brain function in (early phase of) neurodegeneraton (Alzheimer’s, AMD and Parkinson’s disease). • Develop Specialized Nutrition that helps to suppress neuroinflammation and systemic inflammation linked to obesity, diabetes and chronic inflammatory diseases as these are predisposing factors for neuroinflammation and neurodegenerative diseases. • Develop Specialized Nutrition interventions to modulate the immune response and enhanced intestinal integrity and signaling as a novel additive approach to the therapy of chronic inflammatory and auto-immune diseases (allergy, asthma, COPD, cystic fibrosis, IBD, rheumatoid arthritis) and to stimulate the immune response in populations at increased risk for infections. • Develop Specialized Nutrition to stimulate proper immune responses in populations at increased risk for infections (such as COPD, HIV, neonates, elderly). • Develop Specialized Nutrition that helps to modulate the chronic malnutritioninflammatory condition that characterizes chronic renal function impairment and its cardiovascular complications, and hence improve immune responses, reduce infection rate, improve the response to pharmacological interventions, and improve outcome.

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Specialized Nutritional therapy in the management of Diabetes: Specialized Nutrition should be developed with the potency to assist in preventing the transition of the pre-diabetic state as accelerator of comorbidity and towards full blown diabetes by: • maintaining metabolic flexibility; • maintaining muscle insulin sensitivity; • maintaining hepatic function and hepatic insulin sensitivity; • maintaining adipose tissue insulin sensitivity • maintaining renal function Specialized Nutrition should be developed to assist in the prevention of cardiovascular complications. Specialized Nutritional therapy in the management of chronic wasting disorders and ageing related frailty: Develop tailored nutritional intervention as single or multi-modal intervention strategy to maintain muscle and bone health and to enhance the efficacy of physical activity in frailty and in the different stages (mild to severe disease and stable versus acute clinical condition) of chronic inflammatory and musculoskeletal diseases. Explore and establish the therapeutic effects of lead Specialized Nutritional ingredients and compositions on the microbiome and its interaction with the host. A balanced microbiota in the human gut is crucial for a healthy life. Variations in the microbiota and impaired intestinal barrier function are associated with disorders e.g. chronic inflammatory diseases, obesity, diabetes. In addition, chemotherapy may severely affect the intestinal microbiota, leading to side-effects such as diarrhea, mucositis and increased risk of infections. It has been demonstrated that modulation of the microbiota can maintain immunological and metabolic homeostasis and prevent and even cure diseases. Therefore, the effect of modulating the microbiota composition by Specialized Nutritional ingredients (for example prebiotic carbohydrates or specific bacterial cultures or fragments) and the possible effects on metabolic and immune status will be explored. The impact of Specialized Nutrition on the restoration of gastrointestinal barrier integrity and the rebalancing of the immune system will be explored. Specialized nutrition can be developed and exploited together with other preventive/therapeutic strategies (lifestyle, pharmaceuticals), fine-tuned to personalized needs. Proeftuin Specialized Nutrition could strongly contribute to the overall goals of LSH by allowing for personalized therapeutic and preventive strategies connected to tailored (point-of care or home-based) diagnosis and adequate ICT-based patient interaction. The implementation of such strategies requires, besides the scientifically established evidence of efficacy of specialized nutrition, also an integrated implementation within a “proeftuin” setting that includes multiple actors (Food and Pharma industry, academic researchers, primary healthcare, healthcare funders, dieticians, lifestyle coaches, diagnostics providers, ICT solution providers, etc). since such a ‘proeftuin’ setting also includes components of other roadmaps and topsectors, this could be an overarching innovation program focusing on personalized preventive healthcare. Specialized Nutritional compositions will be formulated and tested in proof of concept and small clinical studies. Nutritional kinetic studies are of interest to study the absorption, distribution, metabolism and elimination of Specialized Nutritional ingredients. Furthermore, examination of combining pharmaceutical and Specialized Nutritional approaches might reduce side effects and/or improve efficacy of chemical

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and biological therapies. Ad 3. Specialized Nutritional support during treatment providing improved safety-efficacy balance Current therapies for numerous diseases have unwanted risk-benefit ratios. On the other hand aggressive chemical, biological, surgical or radiotherapy interventions have become effective tools in treating a variety of diseases, particularly cancer and severe inflammatory and infectious diseases. However, a large proportion of patients shows little or no response to current pharmacotherapy and due to severe side-effects of these treatments, overall conditions of patients undergoing such treatment are seriously affected. Interventions with Specialized Nutrition can support therapy and positively influence patient outcomes. Specialized Nutritional interventions aim to become an integral part of optimal therapy throughout the patient journey. It is the aim of this activity to study the possibilities of Specialized Nutrition to intervene in diseaseinduced altered metabolism and gut health and to improve the condition of patients preand post-treatment. Specialized Nutrition may limit short and long term side effects and may facilitate completing the therapy or optimizing the dosage of aggressive medication by improved safety-efficacy balance. Fundamental research Treatment of seriously ill patients using aggressive therapies poses real challenges at the start, during and also after treatment. For cancer therapy-related as well as most other illness-related malnutrition requiring specialized nutrition, muscle regeneration requires more fundamental and applied research into the additive effect of nutritional modulation in combination with physical exercise. Final outcome is muscle quality as functionality and quality of life. Cachexia is highly prevalent in the course of chronic inflammatory diseases, various forms of cancer and in severe organ failure. Long term cancer-treatment increases morbidity such as cardiovascular disease, metabolic syndrome and functional decline which can result in decreased quality of life. Specialized Nutrition is likely to reduce this morbidity and even mortality. Studies are needed to identify: • determinants and course of cachexia during cancer treatment; • risk factors for developing less optimal body composition and metabolic syndrome after successful cancer treatment; • determinants of non-malignant DNA-damage in relation to development of less optimal body composition and metabolic syndrome. • Optimal specialized nutrition and medical treatment of patients suffering from complications of abdominal surgery or severe intestinal infection. Strategic research Explore whether the ability of Specialized Nutrition to improve pharmaco-kinetics and -dynamics of chemical and biological (including cell and gene therapy) interventions will result in a better efficacy and quality of life. Explore the ability of Specialized Nutrition to reduce side effects of chemical and biological therapies and to induce a better safety-efficacy balance (e.g. in cancer-cachexia, cancer-related sarcopenic and/or dynapenic obesity or in chemotherapy- or radiotherapy-related severe gastrointestinal mucositis, which is associated with impaired uptake of nutrients leading to an undernourished state). Reduction of such effects will significantly contribute to the efficacy of aggressive medical treatments and enhanced quality of life.

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Proeftuin Specialized Nutrition will be designed to become an integral part of optimal therapy throughout the patient journey. This includes products for patients who suffer from loss of taste, smell and permanent changes in food preferences due to the aggressive treatments. Proof of concept studies and first clinical trials will be conducted. New technologies Innovative technologies assessing risk and safety without animal testing are in development and in some cases already available. Examples of new developments are the TNO research in microdosing; the TNO research for developing in vitro toxicity tests. In the interest of current developments and insights in fundamental research as well as risk- and safety assessments, connecting to these innovative methodologies is important as is the development and use of new technologies in this area to the benefit of this roadmap. 3. CASE A. Priorities Costs and burden Prevalence, costs and burden of most high-cost, high-burden diseases will rapidly increase in the next decades in the Netherlands, in Europe as well as globally. In the following paragraph data are presented on prevalence, direct and indirect costs for some diseases, but these are just an example for most of them. Also examples of burden to patients (disease-related complications and reduced quality of life) are given. These examples will illustrate the urgent need for a new approach and integrated solutions. •

Dementia Global prevalence is expected to increase from 35 million patients in 2010 to 115 million in 2050. In Europe the costs of medication and direct care are estimated to be € 90 billion per year today, but these will dramatically increase towards 2050. Taking also into consideration the huge number of care givers who will be required in the future, the total burden will rapidly increase to a magnitude with which society will not be able to coop anymore. The loss of labor productivity of relatives and other care givers will be huge too. The personal burden to patients and relatives of this devastating disease is nowadays increasingly well understood. There are no effective pharmaceutical treatments available and as a result of disappointing clinical outcomes of many candidate drug therapies, big Pharma is increasingly reducing its R&D investments in this field. A new approach is urgently needed. Specialized Nutrition has shown to be a potentially powerful factor in an integrated solution.

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Chronic Obstructive Pulmonary Disease (COPD) Over 200 million people suffer from COPD, which is expected to become the third leading cause of death in the world by 2030. In the USA, the direct and indirect costs of COPD are already over US$ 32 billion this year but these costs are also rapidly further increasing. In early stage COPD patients there is an increased cardiovascular risk. Currently there are no good pharmaceutical treatments and the need for new and innovative approaches is high

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Diabetes and related renal failure and cardiovascular disease Over 285 million people suffer from diabetes. In Europe this is about 55 million. In the Netherlands 1 million (~8 of 100) persons suffer from Diabetes, of which 25% non-diagnosed (in the USA this is 12 of 100). The larger part of this is type 2, i.e. overweight related. The costs in 2005 were estimated about 814 million in 2005. It is to be expected that the amount of people with diabetes will be doubled in 2025. About 50% of the diabetes patients have complications like cardiovascular diseases (10-43%) or renal failure (5-40%). Diabetes has a high incidence and a high level of complications, which makes it a high burden, high cost disease. An integrated healthcare approach is needed including Specialized Nutrition.

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Disease and age-related loss of muscle mass Global prevalence of sarcopenia in community-dwelling people (mainly western world) is expected to increase from 50 million patients in 2010 to over 200 million in 2050. The costs in the USA only, related to frailty and fractures are estimated to be US$ 19 billion per year and are expected to correspondingly rapidly increase. The most abundant (chronic) diseases such as COPD, cancer, diabetes, CVD and osteoporosis, are also accompanied by accelerated muscle loss usually starting in an early phase of the disease. Loss of muscle mass, strength and function, fractures, costly hospitalization, loss of independence and quality of life are among the individual burdens to the patients. Delay of disease-related loss of muscle mass or restoring muscle mass and function is becoming a key area in disease management. Specialized Nutrition is a key factor in a solution-oriented approach.

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Obesity Obesity is a global problem with major public-health consequences. Although ultimately the increase in obesity is a consequence of secular changes in cultural, behavioral, and lifestyle factors that promote a positive-energy balance, factors in early life are suggested to influence or program the long-term propensity to obesity. Growth and nutrition in infancy and childhood are thought to be particularly influential. Many studies now support this hypothesis and suggest that faster weight gain (the upward percentile crossing for weight) in infancy is associated with a greater risk of long-term obesity. Innovative solutions providing ‘Nutrition for the best start of life‘ seem to be a key factor in an integrated solution.

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Cancer In cancer therapy similar but also additional problems and burdens exist. Cancerrelated cachexia (decreased anabolism and increased proteolysis) is observed in 50-80% of the patients with advanced-stage cancer. Cachexia is responsible for premature discontinuing chemo- or radiotherapy and consequently for 20% of death in cancer. Cachexia is responsible for increase in drug-related toxicity and adverse events and increase in post-surgery complications and longer hospital stay. Cachexia also severely reduces quality of life and reintegration in the labor process. Furthermore, in severe chronic inflammatory diseases, such as COPD, advanced stage cachexia is associated with increased morbidity and mortality.

Need for solution: Specialized Nutritional intervention opportunity The above examples show that much effort is needed to find solutions to counteract the ever increasing costs and burden in these diseases. The overarching problem is that no effective pharmacological treatment exists for most of the mentioned diseases. The nature and cause of these diseases are such that it cannot be expected that a single chemical entity can intervene in processes in which many different intervention targets are involved. Therefore, a new multi-target, multi-component approach is needed in combination with integral therapy and care solutions. These consist of early

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diagnoses, (early) intervention with a combination of pharmaceutical intervention, Specialized Nutrition and/or physical exercise, tailored life style and in later stages rehabilitation. Impact on society: cost/burden reduction on the mid and longer term Specialized Nutritional intervention is promising as it has been demonstrated that in most of the high-cost, high-burden diseases, specific nutritional components have been identified that possess structures that have the ability to: • intervene in the disease cycle; • can initialize metabolic processes involved in restoring homeostasis, neurological processes and cellular and physical functioning; • can act as antigens that can provoke immune modulating responses. Specialized Nutritional intervention as part of an integral approach to counteract the cost increase in healthcare is increasingly gaining more credibility and attention worldwide. Moreover, in some diseases e.g. Alzheimer’s disease, COPD, allergy, cancer, the first positive results of efficacy in combination with little or no side-effects of nutritional intervention have been demonstrated. On the mid term (5 years) the first indications of significant cost/burden reduction may be expected. To reduce the cost and healthcare burden more rigorously on the longer term it is necessary to apply the knowledge generated in Activity 1, metabolic imprinting. Here the problems are tackled at the initial base i.e. at the epigenetic level. The metabolic imprinting by Specialized Nutritional programming, may significantly contribute to the actual prevention of diseases. Economic impact Unfortunately, the prevalence of the described diseases is huge and rapidly growing. However, as a consequence, the emerging therapies offer the opportunity for the Specialized Nutrition industry to develop new products and integrated therapies for large target groups which offer excellent potential for ROI. Moreover, jobs for highly educated people will be created in the Netherlands: PhD and post-doc positions; company positions in R&D and factories (the high-tech factories of the food industry) for development and production of advanced medical and baby nutrition. Also suppliers of special ingredients, packaging materials and production facilities located in the Netherlands will profit from these activities. The opportunity to develop the first highly specialized cluster of economic activities in this field world-wide is within reach. B. Strengths The Netherlands leading The idea of exploring the potential of Specialized Nutritional therapy and developing Specialized Nutrition as part of an integral healthcare solution, emerged in the Netherlands a decade ago. Early collaboration between Dutch industry and academic research groups in the Netherlands and abroad, supported by the Dutch government, has resulted in a leading position of the Netherlands. This is shown by the results of a number of preclinical and clinical explorative studies and recently by the first clinical trials which have been concluded. These showed (even better than expected) positive results in patients with early Alzheimer’s disease, COPD and HIV, confirming the potential of the multi-component, multi-target approach with Specialized Nutrition. As a result of the high prevalence in all described disease areas, the limited number of commercial players and the high entrance barrier of this complex industry, the leading

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position can be consolidated and further expanded when a ‘Top Consortium for Knowledge and Innovation‘ can be established. Strengths companies The current market for this relatively new industry branch is approximately € 7 billion per year. A conservative estimate for growth is a market of € 16 billion in 2016 and € 30 billion in 2025. The main companies in this field that operate from the Netherlands are: • Nutricia Advanced Medical Nutrition • Nutricia Baby Nutrition • DSM • Unilever • RijkZwaan • FrieslandCampina • Newtricious, Winclove, DNAge Products, and 10 other SMEs are already collaborating in this field • Foreign Pharma companies (e.g. GSK) are collaborating in this field via TI Pharma. Strengths academia The life and food sciences in the Netherlands rank very high in international comparisons. Early collaborations between Dutch industry and academia in the field of Infant and Clinical Nutrition, have given the Netherlands a head-start in bridging life sciences and food science. This has resulted in a world leading position of Dutch academic groups, especially in medical and biological sciences and pharmacology of nutrients, especially in the field of fundamental-strategic research for Specialized Nutrition for patients and infants. TNO in its program “Preventie en Therapie op Maat” develops and applies technologies for disease prevention of diseases by means of personalized food. In a number of large EU-projects and other international collaborations with some of the most reputable universities world-wide, Dutch academic groups have a leading position. The Dutch scientific landscape is becoming increasingly attractive to international companies to establish facilities in the Netherlands for R&D in (Specialized) Nutrition. The field of Specialized Nutrition - a multi-component, multi-target approach - is an entirely new approach, especially in the light of contributing to an integral care solution. Consequently, there are sufficient scientific challenges to have the most reputable research groups involved. A number of world leading Dutch companies and academic research groups and SMEs in this field will be involved in an attempt to establish a Top Consortium for Knowledge and Innovation. 4. CONNECTIONS The roadmap ‘Specialized Nutrition, Health and Disease’ has several clearly aligned topics with other roadmaps in the Topsector Life Science & Health: • Homecare & self-management; • Molecular diagnostics; • Imaging and image-guided therapies; • Enabling technologies and infrastructure (DTL and biobanks); • Pharmacotherapy:

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o o o o

improving current treatment showing insufficient efficacy; improving current treatment showing insufficient safety in the treatment of patients; a combination of Specialized Nutrition and pharmaceuticals could results in reduction of side effects of chemical and biological therapies; exploration and establishment in a pharma-like way of the therapeutic effects of lead Specialized Nutritional ingredients could lead to discovery of new targets and lead compounds to be developed into pharmacotherapeutics.

With the topsector Agro-food collaboration already exists. Knowledge and established health effect of Specialized Nutrition and ingredients can serve as topic for further research and development towards food products to maintain health and to aid in preventing diseases. Existing research programs: • Top Institute Pharma: Dutch academia is strongly participating in close collaboration with food industry (Toll like receptor platform; Immunomodulation with Carbohydrates; etc.). • Carbohydrate Competence Centre: UU, WUR, Danone and Friesland Campina are participating in CCC-2: “immunomodulatory effects of new oligosaccharides”. • STW-Danone program: Specialized Nutrition. • Collaboration with TIFN: Gastro-Intestinal Health, Weight Management, Cardiovascular Health, Oral Health. • Collaboration with Ireland: Food for Health. • EU-program: Lipidiet. • EU-program: Early Nutrition. • RAAK PRO. • EU-project: IDEAL. • NCHA. • Celiac Disease Consortium. • Prevent CD. • KWF en AlpeduZes. • Alliantie Voeding Ziekenhuis Gelderse Vallei. In more detail the projects are: T1.103 CXC chemokine receptors: potential targets for chronic inflammatory diseases. Partners: Danone Research, MSD, Utrecht University, VU Amsterdam T1.201 COPD: Transition of systemic inflammation into multiorgan pathology. Partners: Maastricht University, UMC Utrecht, UMCG/RUG, GSK, Astra Zeneca, Nycomed, Danone Extra pulmonary manifestations and COPD T1.214 Immune modulation and tolerance induction, prevention and inhibition of inflammatory diseases. Partners: Danone Research, IQ Corporation, Pepscan Presto BV, UMC Utrecht, Utrecht University, Vaxinostics, VU Medical Center Amsterdam T1.213 Osteoarthritis: models, mechanisms and markers for patient stratification. Partners: Centocor, Erasmus MC (University Medical Center Rotterdam), Leiden University Medical Center, TNO T5.207 Parkinson and Alzheimer disease: from dysregulated human brain targets towards novel therapeutics. Partners: Abbott, DNage BV, EMC, LUMC, Netherlands Institute for Neuroscience, UMCU, UU, VU Amsterdam, VUMC D1.101 Exploitation of toll-like receptors in drug discovery.

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Partners: ISA Pharmaceuticals, Leiden University, Leiden University Medical Center, Maastricht University, Danone Research, MSD, Radboud University Medical Center, TNO, University Medical Center Utrecht University Utrecht Focus en Massa “Drug Innovation - The triangle immune system -neuroendocrine system – central nervous system. Partners: Danone, SHS Liverpool, UIPS-UU, Psychogenics ltd, Sepracor ltd. Utrecht Center of Food allergy. Partners: TNO, UMCU, UIPS, IRAS Carbohydrate Competence Center, CCC, WP 25. Partners: DGK-UU, UIPS-UU, Danone, Friesland-Campina STW-partner programma: 1. exosomes/breastmilk, Partners: DGK-UU, UIPS, Danone 2. biomarkers/metabolic and immune programming: Partners: UMCU,WKZ, UIPS, Danone Tolerantie en voedsel allergie (UIPS/UMCU/Danone). RAAK/PRO: screening/biomarkers for immunomodulation. Partners: HU, UMCU, Hubrecht lab,IRAS SLIM: Alternatives for animal experiments. Partners: HU, IRAS, GSK, Danone, Bioceros, UU Nutricia Research Foundation: Lipids and immunomodulation. Partners: Nutricia, UIPS Research project: Immunoregulation skin and gut. Partners: Danone, Munich University, UIPS Partnership Immune programming. Partners: Danone, Adelaide, Singapore, UIPS Partnership Metabolic programming. Partners: Danone, Singapore, UMCG, UIPS Program Microbiome and vaccination. Partners: Danone, Erasmus R'dam, UIPS, WKZ-Utrecht ILSI/HESI: allergy, safety, tolerance . Partners: Danone, ILSI, IRAS, UIPS UIPS-UU also participates in: Joint Programming Initiative: healthy diet for a healthy life Research area 3: Food and chronic diseases Preventing and suppressing chronic diseases and increasing the quality of life by delivering a healthier or therapeutic diet. ULS-Open Innovation for Food and Health. Partners: UU, UMCU, HU, Hubrecht Institute, TNO, Danone, Bilthoven Biologicals, Immuno Valley, GSK, MSD, Genmab, Artemis, Taskforce Innovatie Regio Utrecht, Gemeente Utrecht, Provincie Utrecht, Utrecht Science Park, Utrecht Valorization Center NUGO: European-funded Network of Excellence - The European Nutrigenomics Organisation: linking genomics, nutrition and health research (EU/FP6) Diogenes (EU/FP6): Diet, obesity and genes (UM coordinator- selected by EU as success story in the Framework Program) ECNIS (EU/FP6): Environmental cancer risk, nutrition and individual susceptibility HEALTHGRAIN (EU/FP6): Exploiting bioactivity of European cereal grains for improved nutrition and health benefits NEWGENERIS (EU/FP6): Newborns and Genotoxic exposure risks: Development and application of biomarkers of dietary exposure to genotoxic and immunotoxic chemicals and biomarkers of early effects, using mother-child birth cohorts and biobanks EFSD/Elli Lilly: Cardiac lipid content and energy status in type 2 diabetes mellitus. Carcinogenomics (EU/FP6): Development of a high throughput genomics-based test for assessing genotoxic and carcinogenic properties of chemical compounds in vitro EnviroGenomarkers (EU/FP6) - Genomocs biomarkers of environmental health

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EFSD- GSK: Fatty acid-induced uncoupeling in the prevention of mitochondrial lipotoxicity in type 2 diabetes mellitus Flaviola (EU/FP7): Targeted delivery of dietary flavanols for optimal human cell function: Effect on cardiovascular health Full4Health (EU/FP7): Understanding food-gut-brain mechanisms across the lifespan in the regulation of hunger and satiety for health Food4me (EU/FP7): personalized nutrition: An integradet analysis of opportunities and challenges IMI/JU (EU-IMI): An open, integrated and sustainable chemistry, biology and pharmacology knowledge resource for drug discovery (Open PHACTS) - Grant agreement No. 115191 DIaBat (EU/FP7): Recruitment and activation of brown adipocytes as preventive and curative therapy for type 2 diabetes CTMM: PreDICCT - Cardiac Lipotoxicity STW/NGI: development of high throughput toxicogenomics-based in vitro screens for rapid prediction of toxicity class TI Pharma- T1-20: Transition of systemic inflammation into multiorgan pathology Astmafonds/Danone: NUTRAIN study NGI: Integrated Centre for Nutrigenomics NGI- NTC: An applied systems toxicology approach in predicting chemical safety NGI-preseed XAir Diagnostics; a metabolomic approach in exhaled air for diagnosis and monitoring of inflammatory diseases NGI-NBIC: The Netherlands Bioinformatics Centre NGI: NCSB Netherlands Consortium for Systems Biology NANONext.NL:Molecular structure of Food

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2.2.8 Health technology assessment & quality of life

1. GOALS Healthcare innovation requires careful assessment of the impact it has on individuals and on society. Aim of this roadmap is to develop widely applicable methods and knowledge for such health technology assessments (HTA). New HTA approaches are needed to support the innovations in the LSH topsector and to rationalize dynamic decision making based on quality of life, cost-containment and productivity. More knowledge is needed about how technological, organizational and societal innovations actually improve healthcare processes and quality of life. Moreover, effective decision making and implementation requires support from many different parties, including patients, manufacturers, insurers, employers, municipalities, healthcare institutes, and professionals. New methods are needed to identify, measure and weigh the multifaceted impact that innovation has on each of these stakeholders. Private parties addressed in this roadmap are the health insurers, labor insurers, patient organizations, charities, and developers of innovations for which currently available HTA measures are insufficient (like, for example, eHealth, decision support systems and electronic patient files).

2. ACTIVITIES Methods for HTA have been predominantly developed for the evaluation of well-defined medical technologies in the curative sector, in controlled settings (like RCTs) and with a focus on the cost-per-QALY paradigm. However, more is needed to ensure a broad and timely evaluation of innovation in healthcare. Additional methods and knowledge are needed for the HTA research topics outlined below. Moreover, current definitions of quality of life may not be appropriate for the assessment of innovations among specific groups. Although this roadmap is not about the development of specific healthcare innovations, it should support those innovations by developing the required methodology. This mostly concerns fundamental research, but preferably with a direct link and application in the strategic, experimental and ‘proeftuinen’ research in the LSH topsector, to ensure general applicability and relevance. Use of routine and real-time monitoring data for cost containment and quality of care Increasingly, healthcare insurers are expected to have a prominent steering role in the provision of healthcare. How can this role be supported by information obtained from the variety of routine and real-time data insurers have at their disposal? How can these data be used and combined for different purposes, like to monitor and evaluate safety and other quality issues, to discover and interpret trends, to compare procurement options, to evaluate conditional reimbursem*nt, and for disinvestment decisions? What legal, social and ethical issues are at stake? What types of data and indicators are useful for which research questions and how can they be measured efficiently? What target values are attainable and when is quality good enough? What is needed to translate the data into relevant information to ultimately improve cost-containment and quality of care?

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Mechanisms by which innovation leads to savings Innovation of technology, organization or financing does not automatically lead to cost savings. In fact, innovation is seen as one of the main reasons for the increasing costs of healthcare. Nevertheless, there is a clear potential for healthcare innovations to reduce costs in several ways. New technology can be less expensive and less labor intensive than existing technologies. Better organization of care, shared decision making and self management can prevent unnecessary healthcare. More effective public health and healthcare lead to better quality of life, which may reduce future healthcare demand and improve productivity. However, little is known about the interaction between successful development, implementation, reimbursem*nt and costeffectiveness. Validated causal models of these mechanisms are needed to improve our understanding of how healthcare innovations actually lead to sustainable quality and savings. HTA and decision making during the development Early scanning and assessment of technological innovations can provide valuable information on their long term potential and can help to facilitate the societal and institutional innovations that are often necessary for successful implementation. However, at an early stage there are often uncertainties about what a technology in development will be like, in what context it will be used, and what its impact will be on healthcare processes and quality of life. New dynamic and pragmatic evaluation methods are needed alongside the development process, to support business case analyses and decisions on investment, admission, implementation, guideline development and reimbursem*nt. Which quantitative and qualitative tools for forecasting and early anticipation can be developed? How and by which stakeholders can decisions be made about (dis)continuation of a particular development and about market access? And on which of the many possible criteria should innovations be evaluated during their development, including return on investments, effectiveness, clinical relevance, budget impact, savings in different sectors, productivity, costeffectiveness, patient preference, equity considerations, or societal impact? Bio-statistical evaluation methods Routinely collected data, in patient registries or organizational databases, can provide very relevant information but the lack of clear a-priori research hypotheses necessitates careful statistical analysis. More knowledge is needed about how outcome can be predicted by diverse data collected for different purposes and with different biases. And how can the costs of more extensive routine data collection be justified when it is uncertain which research questions will be relevant in the future? Also the dynamic development process stretches the possibilities for statistical analysis. Timely evaluation is required, which is facilitated by efficient research designs with outcome parameters to match the phase of the development. Statistical methods should be developed to incorporate all information that is collected along the development process. Other statistical issues are the early identification of promising subgroups of patients, analysis of personalized care, analysis as part of the integrated care context, and analysis of performance indicators. The value of productivity and efficiency at work Healthcare has an important impact on society by improving productivity. Moreover, a future labor shortage may threaten the quality of healthcare. More methods need to be developed to quantify the consequences of medical products and other innovation on human resources and capacity planning. There is a need for validated instruments to measure the economic value of workers’ productivity while at work (‘presenteeism’) and for the value of unpaid labor (including domestic activities and informal care). Current

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methods to value job loss either overestimate productivity losses by including every hour that is lost until the retirement age (human capital approach) or underestimate productivity losses by including only the hours lost until the vacancy is filled (friction cost method). And more insight is needed into the economic value of (partial) reintegration and into productivity losses due to waiting time, inefficient collaboration between care providers and insufficient focus on functioning in the care process. Legal, organizational, social, and ethical aspects of innovation The legal and organizational context has a strong influence on the development, adoption, implementation and sustainability of innovations. Conversely, healthcare innovations may have unexpected and profound social and ethical implications (as illustrated by technologies like HPV vaccination, genetic testing, eHealth, domotics and electronic patient files). Although the focus of HTA has been on the cost-effectiveness of healthcare innovations, timely interdisciplinary research into other relevant aspects can be crucial to guide successful innovations. How can the legal, organizational and political infrastructure either frustrate or stimulate innovation in healthcare? How to anticipate and evaluate the ethical and social acceptability of specific innovations? What contribution can tools for early patient and other stakeholder engagement make? Quality of life – conceptual questions Current quality of life instruments (including the QALY) are based on the definition of health as a state of complete physical, mental and social well-being. In order to measure whether innovation really contributes to people’s quality of life it is important to enrich assessment methods with philosophical understandings about what quality of life is, empirical knowledge of how people perceive this, and how this may be different in specific groups. Which are the main dimensions of quality of life and how are these related? Which aspects of quality of life are already captured by current instruments and which are not? Can objective and subjective accounts of quality of life be brought together? How is quality of life related to concepts like expectations and adaptation, genetic susceptibility for disease, well being, social network, participation and sports, consumer experience, patient preference, and care dependency? Quality of life – concern for specific groups Improving health and quality of life is especially urgent in specific disadvantaged groups, such as those with relatively low levels of education. Can priority for disadvantaged groups be justified even if health promotion in well-off groups is more cost-effective in terms of cost per QALY? How should valuations of users, patients, or other target groups be related to the societal valuation which forms the basis for the QALY? More knowledge is needed on whether current quality of life instruments are appropriate to measure quality of life in a variety of contexts, including chronic conditions, multi-morbidity, the care sector, the public health sector, disadvantaged groups, children and the elderly.

3. CASE The major societal contribution of HTA is to facilitate sound and transparent decision making. HTA methodology should be used to prioritize research based on the expected societal impact on costs and benefits. By updating the estimates during the development process, important information is obtained to decide whether and how innovations should be implemented and become standard care. Early patient and other stakeholder involvement and ethical assessment can anticipate on whether emerging technologies are morally and socially acceptable. Moreover, HTA methodology

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supports in finding the appropriate and most sensitive measures of outcome such that the societal value of healthcare innovations can be fully captured. Traditionally, the Netherlands has a strong position in the fields of HTA, including health economics, ethics and social studies. Early initiatives to provide a sound basis for the basic insurance package have led to an emphasis on healthcare efficiency research, resulting in HTA departments at all university medical centers. HTA has a formal role especially in the reimbursem*nt of medication and in decisions on the content of the standard healthcare insurance package, for which the advice by the Healthcare Insurance Board (CVZ) explicitly includes the criteria of necessity, effectiveness, feasibility and cost-effectiveness. This evidence-based thinking has strengthened HTA research, but mostly for the economic evaluation of well-defined technologies ready to be implemented. The research topics in this roadmap extend the scope of HTA, by including more stakeholders earlier in the development process and by taking a broader interdisciplinary view on the societal value of healthcare innovations.

4. CONNECTIONS Tools developed in this roadmap should be applied and developed alongside innovations in the other roadmaps, both to prioritize proposals and to evaluate the societal impact of the resulting innovation. Moreover, application in other proposals ensures relevance and applicability of the developed HTA research. Priorities within this roadmap HTA and quality of life have been particularly aimed at HTA research relevant to healthcare insurers and at research to show the societal impact of innovations early in the development. Connection to research at universities Research departments on HTA research are funded at every University Medical Center and at the Technical Universities. This is both applied and fundamental research. Connection to HTA programs at ZonMw ZonMw program Healthcare Efficiency Research (Doelmatigheid) actively promotes research on the recognition, assessment and implementation of cost-effective interventions and fosters generalization of knowledge. In this program budget is reserved for HTA methodology. In 2010-2012 funding was available for HTA methodology research coupled to clinical empirical studies. Research is focused on development and evaluation of methods to support healthcare efficiency research. For example, research on ethical and legal aspects of cost-benefit research, methods to measure productivity costs and quality of life. For the period 2013-2015 the methodological focus will be on mechanisms that lead to healthcare and societal savings and alternative methods for RCTs. ZonMw Program Disease Prevention and Health Promotion. 1: cost-effectiveness of interventions in prevention and health promotion (lifestyle and behavior); 2: evidence of societal impact of prevention in relation to labor, social participation, and low socialeconomic class. ZonMw Program Efficiency studies: high cost medicines. The program funds 1: outcomes research on drugs that have been conditionally included in the policy

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regulations for inpatient expensive and orphan drugs; 2: development of HTAmethodology to be used as an instrument in outcomes research. ZonMw program KIKK (Koplopers in Kwaliteit en Kostenbesparing). Demonstration pilots in institutions to prove cost savings in practice using proven cost-effective interventions, development of tools for decision support for institutions, providers and insurers, i.e. cost-benefit tools, measurement instrument innovation, business case model for introduction and evaluation of health innovations in different environments, including long term return on investment. This program is also connected to TNO Programs on prevention, integrated care, health and productivity. Connection to NWO program Responsible Innovation The Responsible Innovation (MVI) program involves research into the ethical and societal aspects of new technologies and innovations (such as health technology, bio(medical) technology and neuro imaging). The objective is to help ensure that these innovations become properly embedded in society. The research within the MVI program is characterized by close ties between research in the fields of the science/technology, humanities and social sciences, and integration into the process of technological development. The program has an explicitly proactive dimension: right from the start, research, development and design must incorporate relevant ethical and societal aspects. As a consequence, the MVI program funds research that not only results in an analysis and understanding of a particular problem, but subsequently also leads to a 'design or create perspective'. The MVI research will deliver the ethical and societal contexts which are required to make innovations successful. Connection to CTMM The Center of Translational Molecular Medicine is a public-private partnership on translational medicine in which HTA is an integral part of the research portfolio. All consortia participating within CTMM assess cost-effectiveness of new technology and healthcare solutions that may result from their respective research programs. Connection to Europe European funding for HTA methodology is limited and not structural. In the Framework 7 program of DG research there is a subcall on HTA research (CP-STREP instrument). The funding should complement the activities undertaken by the EUnetHTA network. The EUnetHTA network is an EU funded cooperation of 34 governmental organizations in Europe by means of workpackages, but there are no research calls. The Netherlands is a member of EUnetHTA and therefore links national activities, data and policies to activities on a European level. The Quality of Life initiative has European connections with the Global Project on Measuring the Progress of Societies (OESO) en de Working Group on Statistics on Sustainable Development (UNECE/Eurostat/OESO). The Dutch Responsible Innovation program is a source of inspiration for comparable initiatives at the European level, like the Responsible Research & Innovation in Europe, an initiative of the European Commission Research & Innovation – Science in Society.

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2.2.9 Enabling technologies & infrastructure

Summary This roadmap introduces (i) the Dutch Biobanking Hub (DBH), (ii) the Dutch Techcentre for Life Sciences (DTL), and (iii) a framework of advanced facilities. Together, these roadmap components offer expertise and infrastructures in molecular life science technologies and biobanks, readily accessible for industry and academia. The expertise and infrastructures in enabling technologies and biobanking have a scope beyond LS&H by providing necessary technological infrastructure to other topsectors and cross-sector agendas, including Agro-food, Horticulture, Chemistry, and Biobased Economy, and with strong links to the innovation programs of High Tech Systems & Materials and the ICT agenda. Here, we focus on the contribution to topsector LS&H.

1. GOALS Cost-effective healthcare solutions & disseminated expertise to other research areas Life science strategies have proven very effective in tackling contemporary health issues. Their translational approaches provide deep understanding at the molecular level of the causes of disease and effects of therapies. LS&H research contributes to a more efficient, cost-effective and patient-centred healthcare system based on disease prevention, more accurate diagnostics, more focused treatments, and improved efficacy and safety of drug treatment in line with the 3R (Replace, Refine and Reduce) principles. In this research-intensive sector, technological advances in combination with a strong infrastructure are essential in accelerating innovations in each link of the LS&H chain: prevention, diagnosis, cure and care. To reduce costs and at the same time enable personalized treatment, progress depends on having access to well integrated molecular life science technologies. This roadmap aims to deliver top-level expertise and infrastructure in molecular technologies and biobanking. The cross-sector approach will enhance knowledge transfer between topsectors and will facilitate prioritization of investments in biobanking and technology research infrastructures on a national scale.

2. ACTIVITIES A. ET&I components The roadmap builds on three components: the Dutch Biobanking Hub (DBH), the Dutch Techcentre for Life Sciences (DTL), and a distributed facilities framework (DFF), responding to the requirements of the LS&H roadmap as well as those of other topsectors with a molecular bioscience component (Fig.1). Dutch Biobanking Hub (DBH) Three complementary large biobanking infrastructures (1, 2), i.e. (i) Biobanking and Biomolecular Research Infrastructure NL (BBMRI-NL), (ii) String of Pearls Initiative (PSI) and (iii) LifeLines (LL), will be integrated into one Dutch Biobanking Hub with high-quality clinical and molecular data, phenotypic information, and optimized

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accessibility. Combining PSI, LifeLines and most other Dutch biobanks under the aegis of BBMRI-NL integrates the Netherlands biobanking activities and greatly enhances the power for developing and validating clinical findings and translating these into programs for disease prevention and targeted drug discovery research in collaborations with industry and academia. This will further strengthen the frontline position of the Netherlands in biobanking and translational R&D in an international setting. BBMRI-NL currently includes approximately 150 Dutch biobanks that together contain different types of biological samples from over 500,000 individuals, including over 400,000 DNA samples.

Life Sciences & Health roadmaps Global health

HTA & quality of life

Specialized nutrition

One health

Pharmacotherapy

Regenerative medicine Homecare & selfmanagement Imaging & imageguided therapies Molecular diagnostics

Enabling Technologies & Infrastructure

ICT BioBased Economy

Dutch Techcentre For Life Sciences Molecular Life Sciences technology research infrastructure

DFF

Fig. 1 Enabling Technologies & Infrastructure components in the topsectors Dutch Techcentre for Life Sciences (DTL) The Dutch Techcentre for Life sciences (DTL) is founded by - and builds on - six national scientific centers with a strong technological basis in: (i) next generation sequencing (Centre for Genome Diagnostics), (ii) proteomics (Netherlands Proteomics Centre), (iii) metabolomics (Netherlands Metabolomics Centre), (iv) advanced microscopy (NL-BioImaging AM), (v) bioinformatics (Netherlands Bioinformatics Centre), and (vi) systems biology (Netherlands Consortium for Systems Biology). DTL builds on best practices and expertise developed in these centers of expertise. DTL makes widely available high-end enabling technologies (expertise, services, equipment and training) in the life sciences in general and in the field of health-related R&D of academia and industry in particular. DTL expertise and infrastructure is accessible for research institutes, hospitals and industry, with a specific proposition towards SMEs. DTL encompasses a broad network of expertise and facilities that is already involved in major public-private life science programs, and therein well-connected with over 70 SMEs and large companies. DTL combines its technology portfolio around the functional and structural molecular organization of living systems. It has the capacity to integrate the analysis at the DNA/RNA level with subsequent levels of molecular organization and regulation

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(proteins, metabolites, supra-molecular (and cellular) structures). DTL thus offers integrated technological approaches in next generation sequencing (NGS), proteomics, metabolomics and advanced microscopy, and includes bioinformatics and systems biology to streamline the analysis, integration and stewardship of life science data. DTL develops dedicated technology applications for industry and academia, responding to the needs of the healthcare system as detailed in the LS&H topsector roadmaps. Of course, novel technologies will emerge in the international fields to complement (or replace) the high-end technologies of today. DTL includes an active policy to continuously scout, develop and select emerging technologies that fit in the DTL portfolio. With a primary selection of the international (scientific) quality of the associated community, selected new technologies must have a strong potential within the LS&H and other topsectors, and be able to adopt the DTL strategy to set up enabling technology facilities. Importantly, DTL is a cross topsector ‘institute’ that, besides LS&H also has branches in the other topsectors and cross-sector agendas that have a molecular biosciences component: i.e. Agro-food, Horticulture, Chemistry, and Biobased Economy. Besides, it has a strong link to roadmaps of the topsector High Tech Systems & Materials and to the ICT-agenda. DTL offers the platform for national coordination as it comes to investments in life science technology research, in technological facilities and in the data handling and integration process associated with high-end bioscience experimentation. Aim is threefold: (i) to realize, cost-effective and efficient access to high-end life science technologies, (ii) to drive innovation by bridging technology fields and link comparable programs across topsectors, and (iii) to bundle the Dutch capacity in platforms that form national ‘nodes’ in international networks, programs and infrastructures (Fig 4). Distributed Facilities Framework (DFF) The Netherlands has a number of ultramodern research facilities that are accessible to third parties. Examples are the high-throughput screenings facility and compound data library in Oss. Combining these with libraries of TI Pharma, the Netherlands Toxicogenomics Centre (NTC) and the national infrastructure ‘NL-OPENSCREEN’ of small molecule libraries, will be important to find leads for the targeted disease areas. BioConnection, offers young and innovative biopharmaceutical companies access to state-of-the-art GMP facilities and a broad range of support services, and acts as an interface for expertise that is needed to successfully complete clinical trials and production to GMP standards. EATRIS-NL will provide access to distributed infrastructure for translational research in the area of (molecular) imaging, vaccine development, advanced medicinal therapeutic products (stem cells, tissue engineering) and biologics. The Central Veterinary Institute in Lelystad includes unique hBSL3 and aBSL4 facilities that will be part of the Emerging Disease Campus. (Transgenic) animal facilities, such as the new Center for Advanced Bioresource Services in Schaijk, might also be considered as part of the distributed facilities framework to bridge the gap between in vitro and human studies. The new initiative Mouse Clinic for Cancer and Aging research (MCCA) aims to house a transgenic facility for the derivation of genetically engineered mouse model, a mouse cancer clinic for preclinical intervention studies and cancer imaging in mice, and an ageing and phenotyping facility. Furthermore, close collaborations with the Advanced Medical Imaging infrastructure collectively represented by four IMDI core facilities will be initiated.

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B. ET&I Agenda Transition from the present fragmented situation to consolidated accessible expertise and infrastructures in high-end enabling technologies and biobanks creates exciting opportunities in healthcare as it helps to deepen our understanding of health and disease-related processes. Tangible deliverables for the next two years include the sustainability of the major ET&I roadmap components in an international (European) context. ET&I activities ensure application of enabling technologies and infrastructures across all topsectors, in LS&H and in diverse healthcare-adjacent areas such as toxicology/safety, nutrition, epidemiology or alternatives for animal testing. ET&I is working with the LS&H Regiegroep, universities, UMCs, NWO/ZonMW/STW/NGI, several TTI and industry representatives to bolster the development of a sustainability strategy for ET&I as a connecting national research infrastructure by putting forward the importance of: • coordinated (cross-sector) investments in accessible facilities • a specified budget for technology use and data stewardship in research proposals (&evaluation) DBH agenda • Integration of BBMRI-NL, PSI, and LifeLines into one Dutch Biobanking Hub (DBH; Fig. 2) with high-quality clinical and molecular data, phenotypic information, optimally accessible through a centralized, privacy-protected multilevel catalogue; • Linking biobanks to medical and socio-economic registries.

Fig. 2 Integration of biobanks in the Dutch Biobanking Hub (DBH) DTL agenda Development of DTL to an international expertise and enabling technology hub completes a process started in 2008 (Fig. 3).

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Fig. 3 Development of DTL from fragmented technology activities to a big technology research infrastructure Key to the development of DTL has been the establishment of national enabling technology centers: Netherlands Proteomics Centre, Netherlands Metabolomics Centre, Netherlands Bioinformatics Centre, Netherlands Consortium for Systems Biology, NL-BioImaging AM, and Centre for Genome Diagnostics, now together collated in DTL. The DTL agenda aims to deliver: 1) Research excellence DTL programmatic headlines target: a) Development of frontier technology applications in life science research. b) Research and innovation in individual DTL technology fields. c) Cross-technology research. d) Development of innovative technology for data analysis, integration and stewardship. 2) Research facilities & services a) Collection of Dutch nodes in international life science research infrastructures. b) High-end equipment and expertise for next generation molecular research. c) Bioinformatics expertise and tools for data handling and interpretation. d) Linking of the biobanking infrastructure with the enabling technologies. 3) Training & development a) Research ’hotels’ for hands-on training facilities for PhD’s and visiting research professionals. b) A human capital agenda with practical programs aiming at education, training and development of new professional job profiles. 4) Valorization & tech transfer

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a) Valorization policies aimed at developing an open market place for knowledge exchange, joint public/private research projects and targeted commercial development (spin out) of technologies and applications. b) Partner in open innovation networks with industry through R&D alliances programs. ET&I booster program DTL together with DBH will contribute strongly to sustain a strong and internationally visible biobanking and life sciences technology community in NL. Emerging programs of the DTL enabling technology hub and DBH biobanking hub contributing to this development include: • NL-BioImaging AM: Establishing an advanced light microscopy infrastructure in connection to the ESFRI EuroBioimaging infrastructure; • Proteins@work: Building out the DTL proteomics research facility; • DISC ELIXIR, Data Integration and Stewardship Centre: Forming a comprehensive life science infrastructure for data handling, integration and stewardship. DISC ELIXIR includes the CTMM Translational research IT infrastructure (TraIT) and represents the Dutch node in ELIXIR, the European ESFRI infrastructure for biological information; • Dutch Biobanking Hub/BBMRI-NL: Integration of the Netherlands biobanking activities. BBMRI-NL is the Dutch node in the European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI); • Next generation sequencing expertise network for genomics and epigenomics research; • Metabolomics analysis network. Summer 2011, the first four initiatives mentioned above have been submitted to the National Roadmap ‘Grootschalige Onderzoeksfaciliteiten’.

ET&I cooperation. Illustration of basic cooperation between DBH & DTL An example of an integrated ET&I approach is the ‘Genome of the Netherlands Project’ (GoNL), currently running as one of the BBMRI-NL flagship projects. GoNL is a national effort to sequence 1000 complete genomes from blood samples of Dutch individuals available to BBMRI-NL aiming to map genetic variation in the Netherlands. It combines high-quality biobanking with high-throughput sequencing and data analysis. GoNL provides insight into all genetic variation in the Dutch population, thereby serving as a strong selection basis for identification of diseaserelated genetic variation. The project has direct impact on the expertise and infrastructure for high-throughput sequencing analyses in The Netherlands, and will be an important asset for collaborative projects with private parties in life sciences. It offers unique opportunities for science and for the development of novel diagnostic approaches and therapeutic strategies.

C. ET&I Activities: Type of R&D The ET&I roadmap will provide enabling technologies and infrastructures for the other LS&H roadmaps and other topsectors (as depicted in Fig. 1). ET&I activities will range from fundamental research to concrete applications in healthcare. Patient and biobankbased studies and enabling technology-driven research will result in diagnostic and

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clinical applications. To this end, public-private partnerships between individual biobanks, enabling technology centers and industry already exist and will be extended. In addition, expert centers are being developed, establishing public-private partnerships in the pre-competitive, not-for-profit field. ET&I will share new developed methods and technologies with all other parties operating in the topsector programs as a service at cost price. There are strong links with activities of other LS&H roadmaps, including: • Molecular diagnostics. Integration of molecular diagnostic technologies and tools to provide straightforward diagnoses in a complex biological context facilitates the development of candidate biomarkers into validated molecular diagnostics in clinical use. • Imaging and Image guided therapy. Advanced Microscopy provides the resolution to reveal the molecular and cellular details necessary for understanding the biological mechanisms of human diseases, pre-clinical drug screening and optimization of treatment approaches. • Homecare, Self-management & ICT. The development, evaluation and implementation of technological solutions that will contribute to a sustainable healthcare system for people with chronic diseases or disabilities, is central to this roadmap. • Regenerative Medicine. Approaches presently under investigation employ the complete multidisciplinary toolbox of contemporary cell and molecular biology, materials science and bioengineering. • Pharmacotherapy. This roadmap, comprising therapy development for rare diseases, chronic and complex diseases, and infectious diseases, is the home base of the translation of life science discovery into future heath care. It is critically dependent on the technological and human resources and expertise available in the Enabling Technology Infrastructures. • One Health. Developments in vaccines, diagnostics and other interventions depend on a number of enabling technology platforms. Examples are -omics, molecular diagnostics and imaging. • Specialized Nutrition, Health and Disease. The management of these multifactorial diseases needs a new and integrated therapeutic approach based on appropriate phenotyping and by combining early diagnostics etc. The integrated ET&I research approach provides novel solutions in the ‘preventiondiagnosis-cure-care’ chain. Integrated data sets from key enabling technologies are essential to identify and measure personalized parameters that mark predisposition and onset of disease (prevention). Identifying and measuring critical disease-related parameters, using a broad range of technologies, allows personalized diagnostics, monitoring, and prognosis (diagnosis). Highly advanced technologies may be integrated in the care system improving the cost/benefit ratio (care). A convergent healthcare infrastructure, integrating biobanking with prospective treatment monitoring, allows optimizing therapeutic efficacy and reduces costs of ineffective treatment (cure). Current predictive models for human drug safety and efficacy are not sufficiently reliable. To narrow the translation gap, development and implementation of innovative technologies that better (i) predict the health developments, (ii) prevent adverse health effects, (iii) shorten the time to “first-into-human” phase, and (iv) are preferably nonanimal-based, are urgently needed. Such models would require data from innovative genomics technologies, life cell imaging and data analysis and integration to improve, in collaboration with the biobanking research infrastructure, translation to human diseases, therapeutic interventions and human drug-induced toxicities.

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Not only cryo-preserved human tissues, but preferably fresh human tissue and primary cells cultures should become available to the life sciences sector, preferably through dedicated, high quality bio-banking. These materials are needed to improve the predictability in the different phases of development; for screening of efficacy and for safety testing.

3. CASE: Societal benefits, strengths in industry and academia A. PRIORITIES: Benefits for society & effects on costs of healthcare The Netherlands has an acknowledged leading international position in life sciencesrelated R&D. The high quality ET&I technologies and infrastructures are essential to sustain and expand that position. • ET&I accelerates innovation in the life sciences. o It gives academia and industry easy access to high-end technologies, biobanks, expertise, materials and a distributed framework of facilities. o The cross-topsector focus of ET&I drives innovation by bridging fields. • ET&I accelerates development of key technologies and expertise. o Dedicated technology research and development accelerates talent development, boosts international lead position and attracts industrial involvement. • ET&I boosts commercialization of key technologies and expertise. o Supported by a dedicated Open Innovation structure, attracting top scientists and top commercial activities due to its excellence and international stature. o ET&I centers provide test/demo sites for novel equipment and technologies by creating a market place for vendors and applications. The combination of readily accessible key technologies, biobanks, expertise and materials will substantially contribute to more cost-efficient healthcare in the Netherlands. Below a few examples: • ET&I will enhance the rate of drug development, including regulatory acceptance, by giving Dutch academia and industry access to a high-end technology and expertise platform that is able to analyze and integrate multiple diverse data sets (genomics, proteomics, metabolomics, microscopy), giving detailed and patientspecific insight into the (mal)functioning of cells, tissues and complete human beings. • The integrated approach is strongly enhanced by combining ET&I technologies with ET&I biobanks and DFF facilities. Together, ET&I creates an accelerated translational road towards evidence-based and personalized health resulting in cost reduction by reducing trial & error in curative interventions, thereby decreasing the burden for patients. • Concentration of investments in high-end technologies, biobanks and expertise in a limited number of (distributed) national centers will result in cost reduction and enhanced accessibility of infrastructures and expertise. • Besides direct economic benefits, there are also major societal benefits due to the improvement of the quality of life by improved efficacy and safety predictions, diagnosis and treatment, and proper counseling. Although harder to quantify, improved diagnostics (often leading to the relief of concerns), proper counseling and well-targeted therapy all greatly improve the quality of life of patients, people at risk, their families and caretakers.

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B. STRENGTHS of the Netherlands Creating focus, critical mass, synergy and excellence in enabling technologies and biobanks in the Netherlands responds to the international trend of concentration of high-end expertise and infrastructure in the life sciences in a network of a limited number of national institutions. The ESFRI program is an exponent of this trend. The Netherlands has the opportunity – based on an excellent starting position – to harbor several of such hot-spots dedicated to the LS&H arena. This development strongly contributes to a Dutch open innovation environment with an ambition to compete with e.g. the Boston area. In the context of the ET&I roadmap this is underscored by the fact that BBMRI-NL and DTL are deeply involved in large-scale European research infrastructure initiatives (e.g. ESFRI): ELIXIR, Euro-BioImaging, BBMRI, ECRIN, EATRIS, ISBE, INSTRUCT and Prime-XS (Fig. 4). This development is a pay-off of sizeable investments of the Dutch government in life science research, biobanks and enabling technologies over the recent years (4).

Fig. 4 ET&I components in their national and international setting The Netherlands has a strong tradition of collecting clinical and population samples into biobanks and making them available to the LS&H communities. The high quality, diversity, quantity and accessibility of data and samples, combined with their level of organization and willingness to cooperate, the Dutch biobanking community has given the Netherlands a key position to create momentum in this field at the international level. Molecular diagnostics is one of the fastest growing segments in the healthcare industry. The value of ET&I expertise and infrastructures in technology and biobanks is increasingly acknowledged by industry. Given the steeply rising cost per successfully developed drug, the availability of an integrated resource in the Netherlands is essential. In this context ET&I facilitates research by making available a wealth of bio-

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samples and related clinical and molecular data for translational medical research. Technologies and expertise to analyze and integrate large and complex data sets, proper access to protocols and the development of computational models for predicting drug efficacy and safety, should attract large international funding to the Netherlands. These ET&I efforts will breed new synergies between the industry and academia, thus providing ample opportunity for IP development. In the above context, cooperation with industry, including large pharma, has already been initiated. Apart from investments from health-oriented industries and publicprivate consortia, ET&I particularly strengthens the Dutch biotech SMEs, not only in the field of diagnostics and drug development, but also in software, and data stewardship, analysis, sharing, and integration.

4. CONNECTIONS to other initiatives ET&I partners are already firmly embedded in several public private partnerships or other types of collaborations (Fig. 1 and Fig. 4). Currently the ET&I initiatives are affiliated with over 70 national and international companies in three different categories: technology providers, technology users and service providers (Fig.4). A. Connections to other roadmaps within Life Sciences & Health ET&I provides expertise and infrastructures in enabling technologies and biobanking for all other roadmaps within LS&H (Fig. 1). The ET&I components have many ongoing activities in molecular research endeavors that relate to disease areas exemplified in the LS&H proposition such as in rheumatism, in cancer, in coronary diseases/diabetes, in dementia or in infectious diseases. B. Connections to other topsectors ET&I offers technologies, infrastructure and expertise to understand life at the molecular level, regardless whether this is in human, in plant or in microbial technology. Thus, ET&I has natural links to several other topsectors and their research and innovation agendas (Fig. 1). In particular DTL is a cross topsector technology ‘institute’ that, next to LS&H, has branches in the other topsectors and cross-sector agendas that have a molecular biosciences component: i.e. Agro-food, Horticulture, Chemistry, and Biobased Economy. Besides, it has a strong link to roadmaps of the topsector High Tech Systems & Materials and to the ICT-agenda. DTL offers the platform for national coordination as it comes to investments in life science technology research, in technological facilities and in the data handling and integration process associated with high-end bioscience experimentation. C. Connections to existing programs & initiatives DBH • BBMRI-NL received initial funding from the NWO National Roadmap program in 2008. There is insufficient funding to achieve all goals, as initial start-up funding was granted for only 3 years, although with the intention of a follow-up. • PSI has been funded by a five-year FES grant of the Dutch government, which expires at the end of 2011. The NFU has decided to continue the support, but at a lower level which requires transition from the project phase to a more regular organization embedded in the UMCs. The sequel focuses on maintaining and

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•

consolidating the infrastructure and to embed the practices in all UMCs, with operation costs guaranteed by the UMCs. Additional funds are needed in the coming years to expand the scope with new disease pearls. LifeLines is funded partly by FES, partly by other sources and has funding until 2015. Given the scale of the project and its duration of a few decades in forthcoming infrastructure calls, additional funding is required.

DTL • DTL techcentres in part build on consortia in the NGI program (funding until 2012/2013): Netherlands Proteomics Centre (NPC), Netherlands Metabolomics Centre (NMC), Netherlands Bioinformatics Centre (NBIC) and Netherlands Consortium for Systems Biology (NCSB). DTL contains in addition expertise and technology of NL BioImaging AM and the Centre for Genome Diagnostics (CGD). • There are strong links to the Centre for Translational Molecular Medicine (CTMM) through the Translational Research IT (TraIT), a consortium setup between CTMM and NBIC. • The Netherlands Proteomics Centre (NPC) is coordinator of a FP7 funded European Large Scale facility for proteomics: PRIME-XS. • ET&I partners are well-embedded at the European level (Fig. 4), playing a leading role in multiple European initiatives such as: ELIXIR (bioinformatics), BBMRI (biobanks), EATRIS (translational research), Euro-BioImaging (imaging), PRIMEXS (proteomics), INSTRUCT (structural biology), and ISBE (systems biology) (3). Other programs relevant for ET&I roadmap • Other relevant programs include the NGI LifeSciences@work program for starters in the life sciences, the ZonMw program Translational Research, in which first inhuman studies are funded, the CSG Centre for Society and the Life Sciences that describes, analyses and improves the relationship between society and life science research, and the NWO Centres for Systems Biology Research. • Investment subsidies NWO-Groot and NWO-Middelgroot will often be relevant cross topsectors. • Many of the roadmaps focus on translational and applied research. Fundamental research drives new ideas and innovation. Relevant programs in this respect are the NWO and ZonMw Open Programs and the NGI Horizon program.

References (1) - Reardon S. ‘A world of chronic disease’, Science vol. 333, 558-559 (29 July 2011) - Royal Dutch Academy of Arts and Sciences, ‘Multifactorial Diseases in the Genomics Era’ (Amsterdam 2006). Foresight study in Dutch, with English summary. See http://www.knaw.nl - ‘European Biobanks and sample repositories – relevance to Personalized Medicine’, European Science Foundation, Position Paper http://www.esf.org/publications/science-position-papers.html - ‘Reflection paper on methodological issues associated with pharmacogenomic biomarkers in relation to clinical development and patient selection’, European Medicines Agency. Released for Public consultation 14 June 2011, www.ema.europa.eu, - Organization for Economic Co-operation and Development (2009). ‘Guidelines for Human Biobanks and Genetic Research Databases.’ Available at: www.oecd.org/sti/biotechnology/hbgrd

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- ‘European priorities in health research. The Dutch perspective.’ NFU position paper (2010) (2) - Brandsma M, van Ommen GJ, Wijmenga C Kiemeney LA. ‘Dutch government invests in existing biobanks.’ Ned Tijdschr Geneeskd. 2010;154: A2825. - Talmon JL, Ros MG, Legemate DA. ‘PSI: The Dutch Academic Infrastructure for shared biobanks for translational research’ Summit on Translat Bioinforma. 2008 Mar 1;2008:110-4. - Stolk RP, Rosmalen JG, Postma DS, de Boer RA, Navis G, Slaets JP, Ormel J, Wolffenbuttel BH. ‘Universal risk factors for multifactorial diseases: LifeLines: a threegeneration population-based study.’ Eur J Epidemiol. 2008;23(1):67-74. (3) - The Netherlands’ Roadmap for Large-Scale Research Facilities (Amsterdam 2008). See http://english.minocw.nl/documenten/Dutch%20Roadmap%20Eng.pdf - European Roadmap for Research Infrastructures Report 2006. See ftp://ftp.cordis.europa.eu/pub/esfri/docs/esfri-roadmap-report-26092006_en.pdf - ‘Meeting Europe’s challenges: the role and importance of Biological and Medical Sciences Research Infrastructures’ (2010) - The European Biobanking and Biomolecular Resources Research Infrastructure Business Plan (2011) - Memorandum of Understanding for the establishment of the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-ERIC). Signed by Dutch government (2011) - Memorandum of Understanding for the establishment of the DISC ELIXIR node in the European ELIXIR initiative (ESFRI). Signed by Dutch government (2011). - “Strategy Report on Research Infrastructures – Roadmap 2010” by ESFRI. http://ec.europa.eu/research/infrastructures/index_en.cfm?pg=esfri (4) Topsectorplan Life Sciences & Health, p. 37; Figuur 3.2 Gecommitteerde investeringen voor publiek private samenwerking. (5) WRR rapport ‘Innovatie Vernieuwd’, olv. prof Bart Nooteboom, mei 2008, pp. 55-63

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2.2.10 Global health, emerging diseases in emerging markets

1. GOALS The global health roadmap aims to provide solutions for poverty associated diseases that affect more than 2 billion people in the developing world. Some of these diseases are also present in or spreading to emerging markets, and the Western world. They can be classified into 3 sections: (a) The “Big- Three”: Malaria, HIV and Tuberculosis, (b) the 17 “most” neglected tropical diseases listed by the World Health Organization [1], (c) other diseases which cause a high burden on health and socioeconomic activities in emerging markets. These three sections collectively are referred to as emerging diseases. These diseases have an enormous economic impact as they affect young and working people. Various organizations such as World Bank and WHO have stressed that the lack of effective and affordable "tools" is the primary problem in disease control. This roadmap focuses on the formation of new public private partnerships (PPPs) and encourages to continue and/or expand existing PPPs and to use the know-how, infrastructure, products, etc. generated in those existing PPPs to provide new sustainable solutions for emerging diseases. The goal is to alleviate the health and socioeconomic burden of emerging diseases through better, simple, and cost effective detection, prevention, and treatment of these diseases and to improve the contribution of afflicted people to societal and economic activities. This also includes solutions for children’s and women’s health and safe, clean water, all which have a role in emerging disease management. Affordable solutions should be available for the (poor) populations living in the affected areas and individuals travelling and working in developing countries. Nevertheless, many of these diseases occur in emerging economies and are therefore becoming commercially more interesting. The Dutch private and public life science sector indicated significant interest in participation in emerging diseases and need clear incentives to do so, as many of the diseases do not generate a clear commercial incentive. It is believed that partnerships will be most successful when essential expertise from different partners complement each other and stakeholders jointly work towards a common solution. Incentives must be created for each stakeholder to be part of such a consortium.

2. ACTIVITIES In order to ensure adequate solutions being developed against emerging diseases, there are several key drivers: • Identification of specific unmet medical needs for emerging diseases • The strategy to develop powerful affordable solutions through partnerships between stakeholders within the Dutch life science sector with complementary expertise and technology including clear benefits for each stakeholder and clear paths to development across emerging diseases • The strategy to build networks with local research institutions and companies in countries of interest providing access to local infrastructure, to assess the local needs, to learn from these institutions and companies about causes of the diseases, and to exchange innovative knowledge • The ability for each consortium to tap into other areas in the sector to implement these solutions and effectively improve access to solutions • Generation of commercial incentives without jeopardizing access to those in need

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The Dutch life science sector is well positioned to provide solutions to emerging diseases. There are currently several partnerships in place that are sharing expertise or technology to develop solutions such as diagnostics, drugs and vaccines to these diseases. There are several partnerships with local companies who contribute information on local needs, know-how, and infrastructure, valuable to the design of each global health solution. Moreover there is a continued willingness from both private and public players to contribute their expertise in the name of corporate social responsibility (CSR). Networks, infrastructure and products have already been developed for solutions in the area of “The Big- Three” which affect both the developing world and the developed world (dual market), based on both the fact that a profitable market is present, and clear achievable benefit can convince stakeholders to participate in this area. These benefits include complementary partners, opportunities to enhance human capital, validation of technologies in different diseases, financial aid and reduced risks. The following steps will be taken: Addressing unmet needs For all emerging diseases, the unmet medical needs are as follows [2]: drug discovery and development towards new targets, chemical entities, improvement of existing drugs, monitoring and treating resistance, and increasing access to drugs. Vaccine solutions include improvement or development of high quality prophylactic vaccines and improving vaccination coverage. Diagnostics development includes making new or existing diagnostics affordable (for companies and patients), simple, accurate, sensitive and specific and applicable to drug-resistant variants and co-infections. Methods and technologies that support cost effective solutions are therefore needed as well. Various emerging diseases are water born and sustainable solutions need to be combined with providing safe, clean water. Some emerging diseases are also associated with zoonotic transmission and food production. Women and children are largely affected by emerging diseases, and play a strong role in the socioeconomic structure and future workforce of countries. Current drugs are ill suited for these populations, and diagnostics often misdiagnose symptoms in these populations. Solutions for emerging diseases will help in sustaining technical solutions through stabilization of communities, education, etc. New partnerships based on existing networks In the area of “The Big- Three” partnerships between public and private players already exist and are managed by entities in part (4) including TI Pharma, NGOs, private and public institutions. For example, in malaria vaccine development there is a unique network of organizations where development from animal models, cellular models and human challenge studies are established present in the Netherlands. Such partnerships can also be tapped for spearheading initiatives for other (most neglected) diseases (e.g. Leishmaniasis). Important to note is that with the emerging diseases as a whole, co-infections and co-morbidity and the development of drug resistance force the group of emerging diseases to share challenges and solutions. Expertise exist in improved diagnostics (or use thereof for appropriate treatments), vaccine centers, and new drug and delivery development. In the coming 2 years, we expect several preclinical and clinical R&D for solutions that need continued support. Creation of incentives for companies to participate In the area of the 17 “most” neglected diseases”, lessons, partners and infrastructure and technologies can be shared with the Big- Three, albeit there are fewer partnerships. An even greater incentive is necessary to develop solutions to these

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diseases. Diseases where a dual market is available (e.g. Dengue, Leishmania, Chikungunya, and drug resistant forms of the Big-Three) pose the best incentives for private driven solutions. These diseases affect both the poor in developing countries and the middle to high income people of emerging economies and are emerging in the developed world. As a result a new market is developing that is commercially interesting and this would be the right moment to step into these opportunities. The Dutch project euSEND has shown that partnerships in dual market diseases need lower subsidies to fuel development of these solutions than those with a single nonpaying market alone [3]. Where no paying populations exist in the majority of the most neglected diseases, development is still possible. This is demonstrated by partnerships with private partners, Dutch, international and local (e.g. the Phosphodiesterase consortium - see section 4), albeit larger subsidies are needed in combination with incentives in the areas of CSR, and leverage of human and technology potential. Encouragingly, Dutch SMEs are willing, able and already participating in these areas. In this area the most impact can be made through development of better (cost effective) ways to manage these diseases, through improved drugs, cheaper formulations, better diagnostics, streamlining of mass administration of costly drugs, and prophylactic vaccines. Priorities here that can assist in more private involvement include the setup of enabling technologies to improve discovery and valorization of new solutions, such as the development of assays, knowledge, data and biobanks to support fundamental, clinical and translational research in various diseases, and technologies that create affordable products while at the same time generating a commercial incentive for SME, pharma, CROs, and diagnostics companies. Access to and collaborations with companies and institutions present in the target countries enable early and easier access to emerging markets providing a competitive head start. Mechanisms to further strengthen the interest of SMEs The Dutch ATM index has provided incentives for global pharma companies to improve access to medicines for emerging diseases through R&D [4]. The few SMEs participating in these disease areas are strongly motivated by Corporate Social Responsibilities (CSR), the entry of these SMEs into emerging markets, partnerships with local stakeholders, access to wide networks both in the Netherlands/Europe and the target markets, and access to specific training (of medicinal chemists for example) in developing drugs for countries where heat sensitivity, stability, and other factors pose a challenge for the development of drugs. Strong partnerships will emerge in these disease areas in the Netherlands in upcoming years, with clear benefits to individual stakeholders, if there are more subsidies in place.

3. CASE Unlike other roadmaps, the global health roadmap cannot gain by tax breaks, credit loans and similar instruments, as investments yield limited financial return. Market failure leads the many private players away from participation in the development of such solutions. Activities need a fair amount of subsidy to get parties to cooperate and remain profitable to cooperate. This roadmap is an ideal case to be stimulated by various ministries and especially the Ministry of Foreign Affairs with budgets for the top sector. Priorities for the global health roadmap include the detection, prevention, treatment and control of specific emerging diseases in developing and emerging countries. Significant

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reduction in morbidity, mortality and socioeconomic burdens of these societies through these solutions is sought. The use of rational diagnostic, drug, and vaccine discovery approaches allows an efficient translation of knowledge obtained from The Big- 3 towards commercially less viable targets. This area is clearly a market with currently little commercial incentive, but significantly developing interest, especially from companies, as it provides an entry into emerging markets (BRIC Countries, etc). In addition, some of the emerging diseases are now also threatening the richer parts of the worlds (TB, Malaria, Dengue, West Nile) and an early entry in this market may therefore increase the commercial interests in these areas. Possible solutions (more than other life science sectors) demand partnerships to share costs and risks involved, with some financial aid. This is strengthened by strong benefits of securing knowledge base in emerging infections, CSR, stimulating innovation and skilled workforce and addressing government, private and public priorities. Private sector priorities include adequate commercial incentives, new validated technologies (especially for SMEs) in various diseases systems, cost reduction, creation of patents, sustainable projects and partnerships, with minimized risks shared among stakeholders, and access to emerging markets and growing economies. Other priorities include quality assurance of these solutions, along with adequate returns on investments in terms of CSR and highly skilled expert workforce for the Netherlands with experience in developing countries. Public sector priorities include fundamental disease know how, valorization of knowhow, creation of spin-outs, the capacity strengthening of staff in the Netherlands to get first firsthand experience in development of sustainable projects, and solutions in harsh climates, where stability, heat tolerance and other stress conditions apply. Other priorities include innovation to combat drug and vaccine resistance and capacity strengthening of collaborations. Donor, procurer and regulators priorities include cost effectiveness of solutions, adequate access to solutions, adequate quality control and sustainable programs associated with each solution. Policy maker priorities include the adequate use of resources across many disciplines, and could work well with partnerships and solutions that connect themes of emerging diseases with energy, water, sanitation and reproductive / maternal health, and align appropriate roadmap strengths, with appropriate public support. The current Ministry of Foreign Affairs priorities already address several of these themes, and provide a big stimulus for the knowledge consortia addressing emerging diseases. Highest priority will be given to areas in which no other players are active or for which solutions are currently not available. This includes solutions for the most neglected diseases, such as Buruli ulcer, the availability of medicines, and correct diagnosis methods for children and pregnant women. Since it is better to prevent than cure, highest priority also includes the development of sustainable solutions (including clean water and energy for running technology-based solutions) that target long-term eradication or control of these diseases. The strengths within the Dutch life science and health sector have largely been underestimated for emerging diseases. Historical relationships with developing countries and emerging economies date far back, and infrastructure to monitor, treat

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and care in these countries are available for future solutions. Dutch organizations have tight links with local institutions, manufacturers and producers of current and future solutions and access to field sites for clinical testing, validation and easy implementation of solutions. SMEs have specific expertise and technologies to ensure innovative solution development and express willingness to share this with a returned shared risk. Strong public sector involvement and cooperation through partnerships has been going on for several years and have led to solutions being developed or already developed for several emerging diseases. A strong business mindset and strategic management of projects is imperative in partnerships, where no single player can develop a solution alone. This influences also the ability to make solutions affordable, simple and of high quality for use in various settings. An unpolished diamond of the sector is the ability to adapt formulations of various drugs for specific populations or enhance drug delivery, improve vaccine activity in populations and make diagnostics cheap, more sensitive and selective. Moreover a strong incentive for pharmaceutical and generic companies to participate in global health solutions is developed solely by the Dutch ATM index. The benefits of working towards emerging diseases are immense and give health, societal and economic benefits that must not be overlooked. The sector is ready and willing to share and contribute to this world cause improving Dutch and global health and wealth.

4. CONNECTIONS The stakeholders, expertise and technology that are brought by different public and private stakeholders are valid for a variety of diseases. Companies active in one disease can validate their technology in other diseases, making the use of their technology more versatile and creating a stronger diversified portfolio that also allows entry into emerging economies. For example, SMEs active in oncology diagnostics can use their technology for the detection of emerging diseases. Unlike the other top sector life science roadmaps, more creative risk sharing strategies and incentives are needed for the stakeholders to remain strong in this roadmap. Small subsidies reduce risk in such partnerships, and can stimulate research in dual market diseases more than single unpaying markets, which need higher subsidies and grants. Stimuli for stakeholders to develop solutions for emerging diseases cannot use many current instruments from the Dutch government that need strong returns on investment, such as credit loans and tax breaks. Subsidies are necessary from the government to create greater incentives. This may be sufficient to gather more private participation in the global fight against emerging diseases. Advocacy provided by the UN Global Health Goals and the Gates foundation among others, has done much to highlight the case of investing into research on neglected diseases, not only from a perspective of global responsibility but also from a commercial standpoint. The global health roadmap has connects to roadmaps “Molecular diagnostics”, where the framework can offer technologies that could be implemented in emerging diseases in developing countries. New ways to use existing diagnostics and drugs for the management of diseases such as TB can be augmented through strategic alliances with stakeholders in the roadmap ICT and clinical support. Development of drugs and vaccines and improving the efficiency of such development and ensuring quality of these are necessary in emerging diseases, and thus provide an alignment with stakeholders and results of the roadmap “Pharmacology and Pharmacotherapy”. “Nutrition and health” is a crucial roadmap in the fight against any disease, and links well to any global health solution developed for use in malnourished populations

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(especially children and pregnant women). “One health” offers untapped unique (private) expertise in veterinary fields that can be used for developing solutions against zoonotic emerging diseases. There is for example direct link to malaria and Leishmaniasis vaccine development. Technologies, expertise and players can be shared between these roadmaps. Future funding calls should include sharing expertise between roadmaps, while allowing space for emerging diseases with more public support than in other roadmaps Existing policies offer also sharing of resources of both emerging diseases and its control, through improved water and sanitation to reduce transmission, and nutritional supplementation that can aid the immunity to emerging diseases or food production and emerging diseases caused by zoonosis. These areas when combined with efforts and stakeholders in emerging diseases can fit into already existing policy areas such as those presented by the Dutch Ministry of Foreign Affairs. Several partnerships in the big three and most neglected diseases have been started and stimulated by the FES funded TTIs (TI Pharma runs ~7 global health projects -total budget of > €20 million), leading to several SMEs, pharma and public institutes partnering for new drugs and diagnostics and vaccines in emerging diseases. These include not only solutions for HIV, Malaria and TB, but also most neglected diseases such as leishmaniasis and trypanosomiasis, and trachoma. A thorough analysis (by project euSEND) showed the motivations, stimulus and incentives needed for further supporting such partnerships [3]. Positioning of these partnerships through key leaders in global health, private and public players and product development partnerships, major donors and procurers has also ensured that the Dutch sector is visible towards strong players in global health solutions. The consortia are: • Phosphodiesterase consortium • Trypanosomiasis and Leishmaniasis drug discovery consortium • HIV detection and metabolites consortium • emerging disease diagnostics consortium (Leishmania, Trachoma and TB) • Malaria vaccine consortium • Heat stable medicines consortium • Chikungunya vaccine consortium • Schistovacconsortium • Respiratory virusconsortium • (parts of) Nanonext consortium-TB • IDEAL initiative-Leprosy • CLIMB TB • IDEA-coinfections The Dutch public sector is made up of several NGOs and research institutes that have largely been funded to perform research and discovery through donors and NWO (WOTRO) programs. These have led to several academic driven inventions and improvements in technology that has strengthened the participation of these institutions in partnering for emerging diseases. These mechanisms were responsible for the strong network of vaccine development (BPRC, RUNMC, LeidenUMC to name a few). The Dutch Ministry of Foreign Affairs has also been a prime donor of global health, through financing of local institutions such as KIT, leading to the development of several cheap, effective and useful diagnostics and contributing model systems and technologies for drug development. This ministry has funded through the PDP grant scheme (70 mln Euro, 2011-2014) 7 PDPs for product development (including IAVI, FIND, DNDI and AERAS), and partnerships with these PDPs with Dutch organizations have benefited from this.

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Several global health solutions have been included through the FP7 initiatives, which connect Dutch players to the European arena. One of them is SchistoVac, a public institution driven global consortium focusing on schistosomiasis, a most neglected disease affecting children. The continued stimulus to include emerging diseases in the FP7 programs is crucial for the maintenance of such consortia. Parts of larger consortia also target emerging diseases, such as the Nanonext and Smartmix consortia, which have TB sections, while some are unique to single diseases such as the IDEAL consortium for leprosy. The Dutch life science sector also includes NGO support like KNCV tuberculosefonds and various HIV organizations like IAVI (EU headquartered Amsterdam) substantially performing outsourced R&D in the Netherlands. These include development of diagnostic methods, roll-out of new ways to manage TB and HIV and active field participation in developing countries through capacity building, education, advocacy and support. Clinical trials capacity could be strengthened by EDCTP and certain CROs. These networks can be tapped for the other emerging diseases as needed.

References [1]http://www.who.int/neglected_diseases/2010report/WHO_NTD_report_update_2011. pdf [2] A needs-based Pharmaceutical R&D agenda for Neglected Diseases Chapter 6.9 Priority medicines for Europe and the World October 2004. [3] euSEND (European Solutions Enterprise for Neglected Diseases) unpublished data. [4] Access to Medicines Index 2010

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2.3 Six disease examples detailed This section details the six disease examples. These demonstrate: • How roadmaps connect to form integrated solutions for priority health challenges • The impact of public-private partnerships in the topsector Life Sciences & Health on society and the economy in terms of quality of life, affordability of healthcare, productivity and business activity Each example is organized into five sections: the health challenge; the health solution; details on the value created by the solution; how the solution is developed; and the principals behind the public-private partnership(s) required. Two distinct forms The examples come in two different forms: • Illustrations of disease oriented connections between roadmaps: examples focusing on breast cancer (2.3.1), infectious diseases (2.3.2) and rheumatic disorders (2.3.3) • Illustrations of existing disease oriented programs that connect to roadmaps: examples on dementia (2.3.4), diabetes (2.3.5) and Parkinson's disease (2.3.6) Intended only as examples The examples have been developed for illustrative purposes only. They do not represent areas, programs, activities or partnerships that have been earmarked in any way.

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2.3.1 Breast cancer

SUMMARY Cancer is the #1 disease in the Netherlands. In 2010, there were 95,500 new cancer patients and 44,000 people died of cancer (33% of all deaths). In 2020, 123,000 individuals will present with cancer, and 4.2% of the Dutch population will be a cancer survivor. Worldwide, 16 million new cancer cases are reported per year, 70% of them in developing countries. The aim of future research is to improve early detection and treatment by making them highly patient tailored. Cancer is not a single disease, but consists of numerous tumor types and subtypes, each requiring a specific approach. For breast cancer, which is the #1 cancer in women, major contributions can be expected from recent insights into the biology of tumor cells. These insights can be translated into improved technologies for early detection that will support patienttailored therapy, healthy survivorship and optimal palliative care. Major benefits can be expected based on emerging technologies from various LSH Roadmaps. This will reshape healthcare and thus lead to more effective and affordable healthcare. Moreover, it will lead to major commercial enterprises for a huge market.

Global health

Global health Global health

Global health

1. THE HEALTH CHALLENGE Globally, breast cancer is the most common cause of cancer-related death in women, with some 327,000 deaths each year. There are 1.35 million new cases every year, and about 4.4 million women are living with breast cancer. In 2020, around 1.7 million women will be diagnosed with breast cancer – a 26% increase from current levels. Most of these cases will be in the developing world. In 2010, about 13,250 Dutch women were diagnosed with breast cancer, and 3,215 died of this disease. For improved outcome, early detection, optimal treatment, healthy survivorship and optimal palliative care are crucial. Early detection should clearly be optimized, as the current approach of mammographic screening detects only part of new breast cancer cases, while false positives frequently occur. Moreover, in young women at high risk for developing breast cancer, none of the present imaging modalities allow optimal early tumor-specific detection.

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Optimal treatment should be obtained for the 3 treatment pillars. More precise and less burdensome surgical and radiotherapeutic strategies are needed. Also, development of new drugs and personalized therapy, based on tumor characteristics, is necessary for more effective, less toxic and less costly treatment. Healthy survivorship is a major future challenge given the rapidly expanding number of cancer survivors. Strikingly little is known about how to guarantee their healthy survivorship, and limited scientific evidence is available. Cancer survivors face an increased risk of second malignancies and other chronic diseases such as cardiovascular diseases. Sedentary lifestyles and overweight are highly prevalent in cancer survivors. Recent evidence indicates that breast cancer patients develop changes in body composition (like weight gain) during and after systemic treatment, with striking and adverse effects on overall prognosis. Until recently, these effects have been neglected. Optimal palliative care still requires major attention to enable optimal care at home. Findings will have to be translated to clinical applications in an affordable way, not only in the Western world but also in the developing countries, where cancer is still a neglected disease. This is illustrated by the situation in Africa, where breast cancer is the second most common cancer after cervical cancer, while 32 of the 53 countries in Africa have no radiotherapy services, or screening programs. 2. THE HEALTH SOLUTION For breast cancer, major improvements are now within reach. Early detection will benefit from novel biomarkers, including new imaging strategies such as optical imaging with fluorescent tracers. Optimal treatment is more effective, less toxic and less costly, and can be greatly supported by imaging and biomarkers. Molecular imaging of tumor characteristics by means of novel techniques such as central sensing technology (i.e. fluorescence and optoacoustic imaging), can likely aid tumor specific early detection/screening and optimal surgery. Surgical and non-surgical local strategies (such as radiotherapy including proton therapy and high intensity focused ultrasound) are increasingly tailored to patient and tumor characteristics, focusing on sparing healthy tissue. The wealth of insights into cell behavior emerging from the laboratory is supporting the development of new drugs, which can be used in personalized treatment based on biomarkers. Healthy survivorship can be achieved by characterizing individuals at risk by using biomarkers and imaging, which can lead to intervention strategies – including nutritional and drug interventions. Optimal palliative care can improve by developing appropriate technology for home care and the use of effective drugs with fewer side effects for individual patients. HTA research will support clinical translation of these findings in an affordable way, not only in the Western world, but also in developing countries.

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3. VALUE CREATED Innovation in breast cancer screening and treatment will address all areas that can affect value creation. Quality of life of breast cancer patients: Obviously, earlier tumor detection leads to less intense treatments being required to cure the patients, and therefore to reduced short-term and long-term toxicity and a better health related quality of life. Drug discovery efforts are aimed at reducing side effects, for example of hormonal treatment. Better patient selection will limit unnecessary therapy, and personalized treatment will avoid unnecessary toxicity and mutilation. Improved efforts to achieve healthy survivorship will greatly benefit the high numbers of cancer survivors. Affordability of care for breast cancer patients: Numerous examples can be given. Mammography is less reliable in dense breasts only, making optical imaging a particularly beneficial alternative for women with dense breasts. Dense breasts occur in over half of women aged 40-50, so mammography currently is not offered routinely to this subgroup. With biannual optical imaging, 0.5 million additional women per year could become eligible for population-based screening. Considerable health benefits could be expected for these women. Moreover, during current screening many women over 50 years of age turn out to have also dense breasts. Optical imaging is likely cheaper than MRI, leading to major savings. Optical imaging can also guide surgeons, who currently lack any intraoperative feedback to obtain tumor-free margins. This can avoid repeated surgeries for up to 23% patients for positive resection margins. Clearly, proper characterization of tumor lesions using biomarker and omics strategies and molecular imaging will limit unnecessary treatment. Moreover, it can increasingly guide treatment with existing and novel drugs at the right time for individual patients, with the fewest possible side effects and at the lowest cost. Productivity of healthcare and productivity of breast cancer survivors: Replacing current screening, imaging and stratification strategies with novel, superior blood tests and in vitro diagnostic device technology will require fewer healthcare workers. Breast cancer occurs at all ages. Therefore, a higher cure rate and healthier survivors will greatly contribute to their participation in the labor force. Commercial enterprise: There is strong commercial enterprise in the Netherlands in biomarker and imaging technologies as well as involvement in drug development and healthy lifestyle. This means that breast cancer research will benefit commercial activities in medical technology (imaging), drug development in local SMEs and big pharma, and the food industry. The potential market for optical imaging for early detection is enormous: all women in screening programs – up to 1 million women per year in the Netherlands and 100 million women per year worldwide. Within the Netherlands, 3,250 women per year are diagnosed with metastases, and since they will have to be imaged repeatedly, this amounts to a potential market of about 10,000 scans per year (worldwide up to 1 million). This underscores the economic potential of these newly developed techniques and therapies, as highlighted below. An increasing number of SMEs are working on new oncology treatments. Some of them are highly relevant for breast cancer.

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These novel tools can be optimally explored and implemented by collaborations between science and industry, structured in public private partnerships (PPPs). In the Netherlands several PPPs are joining the efforts of academia and companies, and some SMEs are already developing novel markers and targeted therapies. Current and new PPPs active in this field are discussed below.

4. DEVELOPMENT OF THE HEALTH SOLUTION For breast cancer, we are focusing on the roadmaps for biomarkers, imaging and pharmacotherapy. The logical steps in all 3 roadmaps are preclinical research followed by early, small and smart clinical trials. When preclinical data are mature enough, clinical trials can start immediately. Academia, several big companies (Dutch and foreign) and SMEs are well equipped to be strong partners in this research. The opportunities for carefully executed clinical breast cancer trials in the Netherlands are numerous, given the excellent infrastructure, prominent clinical researchers and strong willingness to collaborate. Roadmap 1: Biomarkers: The use of new diagnostics for screening and patient selection for therapy deserves rapid analyses. Preliminary data indicate a high potential for this approach. Much is expected from the omics approach, which includes genomics, proteomics and metabolomics. For this roadmap in breast cancer, a strong relationship with roadmap 9 on infrastructure is crucial. Roadmap 2: Imaging & image-guided therapies: Major progress is to be expected in the area of imaging in breast cancer. Optically targeted fluorescent molecular imaging is an interesting method for screening and for guiding decision of the surgeon during surgery. High precision radiation techniques require new image-guided strategies to ensure adequate target coverage. Advances in MRI instrumentation will increase sensitivity (spatial resolution) and specificity (metabolism) for better tumor characterization. For metastatic disease staging, PET/SPECT with novel molecular targeted tracers is the preferred imaging method, due to its high sensitivity and specificity. Moreover, whole body visualization can be achieved with acceptable radiation exposure. Roadmap 5: Pharmacotherapy: Cancer drug development is ongoing in the Netherlands and will be pursued especially by SMEs. Moreover, several big pharmaceutical companies see the Netherlands as a preferred location for their clinical trials with novel drugs. Major efforts should be invested into combining future clinical trials with biomarkers and imaging modalities. The Netherlands is especially suited for this and has a strong track record in this respect. Other critical Roadmaps: • Roadmap 7: Nutrition: Nutritional aspects in cancer survivors deserve clinical trials in combination with the analyses of the value of novel biomarkers and imaging. • Roadmap 8: Health technology assessment & quality of life: These aspects must be part of all the clinical trials. Moreover, clinical trials should also take into account the significance of their findings for implementation in neglected cancer populations in undeveloped countries. • Roadmap 10: Global health: Affordable technology (biomarkers tests, optical) will be essential to address the immediate needs of breast cancer patients in the developing world.

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5. PUBLIC-PRIVATE PARTNERSHIP Several PPPs have been initiated in the Netherlands that focus on developing novel tools for early detection and treating breast cancer. In the Center for Translational Molecular Medicine, 3 large public-private consortia are targeting breast cancer: Breast Care, MamMoTh and Volta. Within TI Pharma, PPPs have targeted the understanding of kinases in breast cancer. Follow-up is required to identify new molecular entities that target specific kinases. Initiatives are underway to identify such molecules and test their relevance for patients. Diagnostics to personalize treatment (matching the right patient to the right drug) are required. Moreover, initiatives are underway to identify whole new classes of drug targets, e.g. in epigenetics. This is largely done in academia, but follow-up will require collaboration with industry. Companion diagnostics must be developed to identify patients who will benefit from these drugs. Another novel approach is to apply specific monoclonal antibodies to boost the ability of breast cancer patients' immune systems to kill tumor cells. Immunology in the Netherlands is advanced, and SMEs that follow this approach have worked closely with academia in PPPs. Within TI Food and Nutrition, there is ongoing research on cancer patients together with the Dutch food industry. This deserves further expansion. Other examples of successful PPPs include the Dutch Imaging Hub and the four imaging CORES in the 'IMDI initiative', collaborations between universities and industry. Sustaining these programs is essential for the development and implementation of novel imaging techniques, markers for diagnosis and more effective drugs. Recently, concerted actions have been initiated between universities, insurance companies, patient organizations and industry targeting the well being of the patient. To speed up the implementation of new care solutions addressing the health of cancer survivors, we envisage an important role for PPPs that consists of hospitals (academic and otherwise), patient organizations, insurance companies and the food and nutrition industry. Patient organizations with patient advocates and charities (KWFKankerbestrijding, Alpe d’HuZes, Pink Ribbon, Borstkankervereniging Nederland, etc.) will play an increasingly important role in organizing and sponsoring these efforts, meanwhile ensuring the active participation of the patients themselves in these PPPs.

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2.3.2 Infectious diseases

SUMMARY The introduction of antibiotics revolutionized modern medicine and agricultural industry, yet the current pandemic of antibiotic resistance now represents one of the major threats for human healthcare. An estimated 25,000 people die each year from an infection with antibiotic-resistant bacteria in the European Union and such infections create extra healthcare costs and productivity losses of at least €1.5 billion each year. Antibiotic use (and misuse) in humans and animals and transmission of resistant bacteria and their genes fuel this rapidly emerging healthcare problem. The complexity of antibiotic resistance requires a multi-disciplinary approach for solutions, which should include better use of antibiotics, new antibiotics, earlier detection of resistance, more effective control of spread and better prevention (for instance through vaccination), all for humans and animals. As the Netherlands are considered a worldwide leader in controlling antibiotic resistance and in agricultural production, our solutions will generate global interest. There is a strong commercial enterprise in the Netherlands in diagnostic technologies, vaccine development and involvement in drug development. Antibiotic resistance research will continue to stimulate these developments.

Roadmap

Prevention

Detection

Treatment

1. Molecular Diagnostics 5. Pharmacotherapy 6. One Health 7. Specialized Nutrition, Health & Disease 8. Health Technology Assessment & Quality of Life 10. Global Health

Prevention in animals and humans

Education, housing, sanitation, vaccination, biomaterials

Detection in animals and humans

Optimal use of existing and development of novel rapid diagnostic methods to be used at point-of-care, in the Netherlands and at the origin of antibiotic resistance development

Treatment in animals and humans

Optimal use of existing and development of new treatment options, including antibiotics, protective antibodies and therapeutic vaccines

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1. THE HEALTH CHALLENGE Antibiotics are used to treat and prevent bacterial infections in humans and animals. Their introduction revolutionized human medicine and agricultural industry, but their success has now created a public health threat caused by antibiotic-resistance, both in developed and in developing countries. Infections caused by Klebsiella pneumoniae resistant to carbapenem, one of the most powerful antibiotics, are emerging worldwide and extensively drug resistant Mycobacterium tuberculosis, causing tuberculosis, is knocking on the Eastern borders of Europe. The direct consequences include loss of healthy life years because of treatment failures and increased costs for healthcare due to longer hospitalizations. In the Netherlands these infections currently mainly affect hospitalized patients, where resistance now seriously threatens successful treatment of patients with cancer or in intensive care units. Furthermore, antibiotic use in food animals – for treatment, disease prevention or growth promotion – selects resistant bacteria, which may spread to humans through the food-chain. In addition, changes in biodiversity and increased migration of animals and people across countries, increases the potential of rapid global dissemination of bacteria with new resistance mechanisms. Although the Netherlands are internationally recognized for their successful control of antibioticresistant bacteria and for rational prescription of antibiotics by physicians, these recent developments seriously challenge this position in the near future. The prospect of untreatable infections caused by pathogens that rapidly cross species and country borders is no longer hypothetical.

2. THE HEALTH SOLUTION The complexity of antibiotic resistance requires a multi-disciplinary approach for solutions, which should include improved surveillance, better diagnostics, optimal use of antibiotics, prevention of resistance transmission (of bacteria and their resistance genes) and infections and the development of new classes of antibiotics, all for humans and animals. Diagnostic tools are needed to identify patients that need antibiotics and to determine drug sensitivity for guiding treatment choices, also in low- and middle income countries, which often are the sources of new resistance variants. These innovative tools should be rapid and preferably to be used at the point-of-care. Optimal treatment must be realized by development of new antibiotics and optimizing usage of available antibiotics. Apart from antibiotics, pathogen-specific antibodies may serve as alternative treatment options for infections caused by highly resistant bacteria. Infection prevention strategies can significantly alleviate the threat of antibiotic resistance and several approaches should be considered, such as innovation in biomaterial development (including antibacterial coatings) and optimizing adherence to basic infection prevention measures in healthcare settings. Furthermore, the composition of the human microbiota seems a crucial factor in resistance to disease, including infectious diseases, offering innovative ways to improve immune competence, for instance through modulating bacterial flora.

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Vaccination is the most cost-effective infection prevention measure, but vaccines for infections caused by major antibiotic-resistant bacteria in humans and agricultural industry are lacking.

3. VALUE CREATED Solutions to the antibiotic-resistance problem will directly benefit patients in Dutch hospitals, and will open a global market for diagnostic, therapeutic and preventive products in human healthcare and agricultural industry. Life years gained: The direct value created for human healthcare includes life years gained, because of better treatment of infections and infections prevented, as well as quality-adjusted life years through reductions in length of stay in hospitals and rehabilitation centers. In the European Union each year at least 25,000 people die from an infection with antibiotic-resistant bacteria and such infections create extra healthcare costs and productivity losses of at least €1.5 billion each year. Affordability of healthcare: Emergence of resistance increases the need of intravenous treatment of infections (frequently necessitating admission in healthcare settings) that were usually treated with oral antibiotics in the ambulatory setting. Furthermore, the immediate threat of antibiotic resistance in the Netherlands is for hospitalized patients at increased risk for opportunistic infections, because of underlying diseases or immune modulating treatment. Antibiotic resistance will increasingly complicate treatment of such patients, which will considerably increase the healthcare costs per patient. Increased sustainability: In agricultural industry more selective use of antibiotics and better control of antibiotic resistance will increase sustainability and, thereby, improve the international market position, as well as the acceptance of the industry by the general public. Commercial enterprise: As the Netherlands are considered worldwide leaders in controlling antibiotic resistance and in agricultural production, our solutions will generate global interest, and will be applicable in other developed countries, including emerging industrial countries such as India, China, Brazil and Russia. The latter countries are facing enormous problems with antibiotic resistant bacteria, which is fuelled by over-the-counter prescription practices and unregulated production of antibiotics. There is a strong commercial enterprise in the Netherlands in diagnostic technologies, vaccine development and involvement in drug development. Antibiotic resistance research will (and has) stimulated these developments in local SMEs and large pharmaceutical and medical technological industry.

4. DEVELOPMENT OF THE HEALTH SOLUTION For antibiotic resistance at least 6 of the 10 roadmaps are connected to the proposed solutions; molecular diagnostics; pharmacotherapy; one health; specialized nutrition, health & disease; health technology assessment & quality of life; global health. The logical first step in most of these roadmaps is preclinical research, followed by clinical trials. Other roadmaps will focus on applied research which can start with largescale cost-effectiveness studies. The presence of excellent research groups in Dutch

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academia, high-quality SMEs and large pharmaceutical and medical technological industry together with existing research collaborations creates a unique environment for antibiotic resistance research. Roadmap 1 Molecular diagnostics: Novel diagnostic approaches are needed to better identify those patients that need antibiotics and to guide choices for those that prescribe antibiotics. These tools should be developed for application in human and animal healthcare, and should be readily available (at low costs) in low-income countries to curb resistance development at the source. Although (inter-)national research consortia are pursuing similar research goals, these attempts have not yet sufficiently improved diagnostic capacities. Roadmap 5 Pharmacotherapy: Novel classes of antibiotics are the ultimate solution to antibiotic resistance. The European Union has invested 300 million euro’s in the last ten years in antibiotic development research, without any products currently evaluated for clinical use. Better coordination of research activities is desperately needed and Dutch academic research groups, together with private partners and big pharma possess the capacities and experience to be successful in this area. The same holds for the development of effective and innovative antibody therapies. Roadmap 6 One Health: It has become increasingly clear that antibiotic resistant bacteria cross species borders and that human and animal reservoirs share multiple connections. In the Netherlands research activities from both disciplines already have successfully connected, but further integration of these activities, together with entrepreneurial activities will create a unique environment to develop, evaluate and implement solutions to this problem. Roadmap 7 Specialized nutrition, health & disease: Recent developments in science now allow detailed investigation of the composition of the human microbiota, which seems a crucial factor in resistance to disease, including infectious diseases. This offers innovative ways to improve immune competence, for instance through modulating bacterial flora. Dutch academia, together with private partners, act at the cutting edge of this research area. Roadmap 8 Health technology assessment & quality of life: Each newly developed product (antibiotic, vaccine, intervention to change human behavior, etc) must be assessed to quantify its effectiveness and costs in real life. Developments in public perceptions of scientific experiments with humans and regulations for new products have a huge impact on how such assessments need to be designed and executed. Innovation in this research area is needed, through close collaboration between academic leaders and industry. Roadmap 10 Global health: Diseases that were until recently contained in tropical countries now represent a global threat, and this includes antibiotic resistance. This roadmap promotes early recognition and education at the site of origin to contain spread as early as possible. Various initiatives between public and private parties have already been set up in the Netherlands to provide solutions.

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5. PUBLIC-PRIVATE PARTNERSHIP Examples of public-private partnerships include collaboration between academic research groups and industry for developing diagnostic tools, pathogen-specific antibodies and vaccines: The ALTANT(ALTernatives for ANTibiotics) program that is coordinated by Immuno Valley, a public-private research consortium with 27 partners funded by the Dutch Ministry of Economic Affairs, Agriculture & Innovation as well as by academic and industrial partners with the aim to generate knowledge and alternative tools that complement the available treatments to control infectious diseases in farm animals. One of the projects (“Evasion Molecules in Bovine Mastitis Vaccines”) aims to develop a series of vaccines against difficult to treat infections with certain bacteria known to cause bovine mastitis, such as Staphylococcus aureus, Streptococcus uberis and Escherichia coli. This is a collaboration between Merck Animal Health (known as MSD Animal Health outside the USA and Canada) and Department of Medical Microbiology of the UMC Utrecht and the Faculty of Veterinary Medicine of Utrecht University. The MARS (Molecular Diagnosis and Risk Stratification of Sepsis) project is a collaboration between 3 academic partners, 6 industrial partners and CTMM. The goal is to develop and evaluate biomarkers for risk stratification and rapid diagnosis of infections, including antibiotic resistant bacteria, in patients in intensive care units. A databank is developed containing clinical data of 7500 patients in intensive care units together with a biobank containing daily obtained blood samples, which will be used to assess the innovative diagnostic tools for biomarkers and pathogen detection. The CAPiTA (Community-Acquired Pneumonia immunization Trial in Adults) study is a collaboration between the UMC Utrecht, Julius Clinical Research and Pfizer. This is a randomized double-blind placebo-controlled trial with 84.496 elderly to determine the effectiveness of a 13-valent conjugate pneumococcal vaccine. The primary endpoint is community-acquired pneumonia caused by one of the 13 pneumococcal serotypes of the vaccine. With the help of 2100 general practitioners >500,000 candidates (all >65 years of age) have been contacted and with the help of 58 hospitals endpoints are detected. Inclusion ended in January 2010 and final results are expected in 2013. This is one of the largest randomized double-blind placebo-controlled trials executed ever. Within the MLPA project funded by ZonMW and WOTRO, a consortium of KIT Biomedical Research, RIVM, AMC, MRC Holland B.V. and tuberculosis reference laboratories in Bulgaria and Georgia develops a test that allows simultaneous detection of multiple DNA mutations in Mycobacterium tuberculosis. These mutations provide information on antibiotic resistance, allowing more appropriate selection of therapy. These 4 examples of public-private partnerships exemplify the opportunities present in the Netherlands to embark in large-scale cutting edge science of Dutch research to combat the threat of antibiotic resistance.

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2.3.3 Rheumatic disorders

SUMMARY Over two million Dutch citizens suffer from rheumatic disorders. Rheumatic disorders consist of many different (sub)types, each requiring a specific approach. Most roadmaps will contribute to better treatment of these patients in the (near) future. Diseases will be diagnosed up to 10 years earlier, enabling optimal personalized treatment before disabilities develop. Optimal treatment of rheumatoid arthritis means that medicines will be given earlier, but only to the responsive patients and self measurement of disease activity will enable reduction of medicine administration to patients where possible. Treatment of osteoarthritis will be aimed to reduce damage to joints so that implantations of artificial joints can be postponed or prevented. These improvements in disease control will enable citizens to live better and more productive lives. The societal value of increased productivity is expected to more than compensate for the treatment costs. Moreover, new therapeutics, diagnostics and home care products will be commercialized by innovative spin off and larger companies. The excellent position of the Netherlands in rheumatology and associated areas enables the increasing number of patients to benefit from better treatment strategies while healthcare costs are contained at the same time.

1. THE HEALTH CHALLENGE Rheumatic disorder is a non-specific term for medical problems affecting joints and connective tissue. These disorders are characterized by chronic (though often intermittent) pain and functional impairment. They are very common: 2,3 million Dutch citizens suffer from rheumatic disorders. 50% of the patients is under the age of 65 and also children may be affected. Rheumatoid arthritis (RA: 150.000 affected in the Netherlands) is characterized by inflammation that causes irreversible damage to joints. Osteoarthritis (OA: 1.200.000 affected in the Netherlands and rising due to ageing and increased obesity) is characterized by more degenerative changes in joints. Currently both diseases cannot be cured. Therapies aim at controlling disease activity and progression. Ten years ago, in people diagnosed with RA, 75% of the ability to

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work was lost within 2 years. Since then, the Netherlands have played a pivotal role in testing and implementing innovative new therapies based on biologicals. The effects on quality of life are enormous, as is the rise in treatment costs. In a few years time three biological RA-treatments ranked among the 10 most expensive treatments. Finding a true solution for these diseases is obviously most relevant. There is an imminent need for better treatment strategies for both RA and OA to benefit the increasing number of patients and contain the associated healthcare costs at the same time.

2. THE HEALTH SOLUTION RA patients will 1] be diagnosed earlier, 2] get the right medication and 3] in the optimal amount. The ultimate goal remains to cure RA. Early stage biomarkers (molecular diagnostics and imaging, companion diagnostics !) and new medicines need to be developed. Envisioned medicines may be small molecules, new or smarter (like half life enhanced) biologicals or new innovative therapies based on (stem)cells or genes. Companion diagnostics will allow prediction of patient response to medicines, and will thereby shorten the time needed to find out the right medicine for the individual patient. Frequent interaction between patient and physician allows precise administration of medicines (tight control). The availability of home tests to measure disease severity in combination with online communication with the physician will facilitate this. Participation in the treatment process (self management) makes it more acceptable for patients to diminish medicine when disease activity has become low. Recent research suggests that OA is not one disease. It is a final common pathway, triggered by different routes, like cartilage damage, increased bone turnover or synovitis, weak muscles or mechanical stress. These new insights in patient subgroups will provide realistic leads for treatment. Specific clinical research may prove existing (and rejected) products valuable for specific patients. Probably earlier research on new medicines was carried out on too large and diverse patient groups. On shorter notice, the most important gain is to postpone implantation of an artificial joint. Strategies include evaluation of protocol adherence and stop disease progression earlier.

3. VALUE CREATED Quality of life Early diagnosis and treatment before disabilities develop will enable citizens to live better and more productive lives. The costs per treatment may still be high, but its effectiveness may substantially be improved by targeting the responsive patients. These patients will contribute and participate in society without relying on care givers too much. Healthcare costs At present 30% of RA- patients on biologicals do not respond to the treatment, indicating that expensive medicines are, in fact, wasted. It now takes 6 months to ascertain if the medicine is the right one or not. Prediction of success within 6 weeks spares wasting 4500 Euros on a biological that the patient does not benefit from. Since personalized treatment of patients might change the management of patients completely it is difficult to predict the value in terms of money. It certainly increases value for money.

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Reduction of medicine administration to patients with low disease activity. Patients generally receive not only medicines against the initial disease, but also medicines to prevent or counteract adverse reactions. Reduction of the administration of the initial medicine may also enable the reduction of other prescribed drugs. In the Netherlands, every year nearly 100.000 artificial joints are implanted. Generally, an artificial joint lasts for 15 years. Postponing or preventing the need for implantation for only a few years would reduce cost, since most therapies are less expensive than surgery, and improve patient outcome. Productivity Earlier diagnosis and better treatment not only prevents damage to joints but it can also prevent that people lose their jobs. Evidence has shown that early effective treatment can preserve productivity for many years and that the societal value of that productivity can more than compensate for the treatment costs. Valorization The Netherlands have an excellent knowledge base in the basic sciences related to rheumatology. In rheumatologic research the Netherlands is in absolute numbers nr 3 (1 USA, 2 UK); relatively the Netherlands is number one. This is underscored by the fact that the Netherlands was the first country to implement biologicals in RA treatment on a large scale. Many initial clinical biological trials were performed in the Netherlands. Now biologicals form a 70 trillion euro worldwide market. Still, in this field Dutch and foreign companies are interested to enter public-private partnerships. Commercialization of new therapeutics, diagnostics and home care products. In these fields innovative spin off companies are started. 4. DEVELOPMENT OF THE HEALTH SOLUTION Molecular Diagnostics

Imaging & Imageguided Therapies

Home Care and Self Management

Regenerative Medicine

2-5 years Development of companion diagnostics. Development of imaging techniques for early detection and therapy monitoring. Development of a self test to measure disease activity score. Further development of a portal for patientphysician interaction. Development of material based methods for targeted drug delivery.

5-10 years Development and Implementation of companion diagnostics. Imaging to guide and monitor gene and (stem) cell based therapies.

10-20 years

Imaging to guide and monitor gene and (stem) cell based therapies on an individual basis.

Development of domotics.

Development of new innovative gene and (stem) cell based therapies using instructive biomaterials that support endogenous repair.

Implementation of new innovative (stem) cell and gene based therapies.

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Pharmacotherapy

Health Technology Assessment & Quality of Life

Personalized clinical testing of existing (rejected) leads. Development of products and companion diagnostics. Implementation of conditional approval of new products. Assessment of the impact on patients and society of the developed solutions.

Implementation of material based targeted drug delivery therapies. Development of new innovative biological, gene and (stem)cell based therapies.

Implementation of new innovative gene and (stem)cell based therapies.

5. PUBLIC-PRIVATE PARTNERSHIP The CTMM-TRACER consortium aims to develop diagnostic and stratifying tools to identify patients with very early, early and established rheumatoid arthritis with different characteristics of progression of the disease and different responses to treatment modalities. By use of a combination of these tools prediction rules for cost effective treatment should improve individualized treatment preventing unnecessary delay of treatment, side effects, and costs. The TRACER consortium consists of 6 academic centers and 12 SMEs. TI Pharma currently funds a project on development of markers for patient stratification in OA and several projects on innovative therapies for inflammatory diseases, including RA. Within BMM the OA-control project is funded on the controlled spatial and temporal delivery of OA medicines using biomaterials. The objective is to curb arthritis as early as possible and to recover cartilage using new synthetic drug delivery biomaterials. The OA-control consortium consists of 4 SMEs and 3 academic centers. On a smaller scale SMEs and research groups cooperate to develop innovative therapies for rheumatic disorders. For instance, Arthrogen BV, the AMC and the Dubai Bone and Joint Center cooperate on the development of local gene therapy for rheumatic diseases. Novirun and the VUmc cooperate on a targeted drug delivery system in RA. Synthon is developing (antirheumatic) biopharmaceuticals. Pontes Medical and the UMCU combine mechanical distraction with growth factors to stimulate endogenous repair of cartilage in osteoarthritis. Dutch rheumatology is unique in the world because of the high standard of basic and clinical research, of the cooperation of Dutch academic rheumatologists as a group, and also the cooperation with rheumatologists outside the University Medical Centers, enabling the Netherlands to gather large cohorts of well defined patients. This forms an important basis for possible international R & D investments in the Netherlands in the field of rheumatology and immunology.

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2.3.4 Dementia

SUMMARY Dementia is a fast growing societal problem, often called the epidemic of the 21st century. In the Netherlands, the number of people suffering from dementia will double up to half a million by 2040. Medical and societal costs for dementia already reach 7.2 billion euro yearly. Research into the aetiology and treatment of dementia is urgently needed. There is ‘a world to be won.’ For example research leading to the delay of disease by 5 years would reduce prevalence by 50%! Therefore the European Parliament made dementia an EU public health priority and calls for member states to take action. The Netherlands’ Deltaplan Dementia is expected to be launched in September 2012. The plan builds on two pillars: scientific research and healthcare delivery. The research agenda is aligned with the European Strategic Research Agenda of the Joint Programming Neurodegenerative Diseases (JPND) and includes the establishment of a National Dementia Registry. People with dementia become increasingly dependent on the support and care of others. Deltaplan Dementia aims to postpone inpatient care by supporting patients and their caregivers in the home situation (e-health solutions, self management). Such support improves quality of life for patients, but also relieves the burden for caregivers, reduces costs and contributes labor market constraints. Selected LSH roadmaps contribute to and reinforce the Deltaplan Dementia as a public private initiative. Developing and implementing solutions for dementia as a worldwide phenomenon, provide substantial economic opportunities.

1. THE HEALTH CHALLENGE At present, an estimated 250,000 people in the Netherlands suffer from dementia. The prevalence of dementia doubles every 5 years as of the age of 65 and the total number is expected to double to more than 500,000 by 2040. Within the same time frame, the working population will decrease by 9%. Consequently, fewer professionals will have to care for twice as many patients. In view of these numbers, dementia can be defined as the fastest growing societal problem and is often called the epidemic of the 21st century.

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The risk to develop dementia is one in five in a lifetime, Alzheimer’s disease being the most common cause. Patients become increasingly dependent on the support of others and eventually institutionalization is inevitable. Current drug treatments are not designed to slow down the disease process significantly. Moreover, many patients receive medical intervention too late for effective intervention. To optimize both pharmaceutical and psychosocial care delivery, early detection is essential. The majority of people with dementia live in the community and care is mainly provided by (family) caregivers. This trend illustrates the need to develop interventions that support caregivers. Finally, the development of successful therapeutic and preventive strategies will be derived from studies involving individuals in the earliest stages of illness. Patient’s children provide more than half of the informal care! They combine their role as caregiver with work, childcare and other daily tasks. They are under pressure, at risk for burn out or depression and often have to decrease their working hours or even leave the work force, leading to significant loss of productivity on a macro-economic level. In summary, the expected rise in number of patients, the shortage of long-term care facilities and professionals, the lack of effective therapy as well as cost-control measures in the healthcare sector reconfirm the need to find solutions for dementia rapidly.

2. THE HEALTH SOLUTION The European Parliament made dementia an EU public health priority and calls for member states to take action. Several countries have already launched and started national dementia plans that include care and scientific research. The ‘Deltaplan Dementia’ ensures the Netherlands will catch up by presenting a research agenda and action plan that reinforces its strengths particular in clinical research, cohort studies, phenotyping, biobanking, neuro-imaging, functional genomics, social and healthcare delivery. The Deltaplan Dementia is set up as a public-private partnership and builds on two pillars: scientific research and healthcare delivery. It is expected to be launched in September 2012. The proposed research agenda of the Deltaplan Dementia includes: • Improving early diagnostics • Unraveling the origins of disease • Developing therapy & prevention, including a unique and extensive focus on nutrition • Improving participation, functioning and quality of life of patients • Supporting the complete patient system aiming at self management in the home environment • Improving cost-effectiveness of care. The national research agenda is aligned with the European Strategic Research Agenda of the Joint Programming Neurodegenerative Diseases (JPND). The proposed innovative improvements in care include: • To establish a National Dementia Registry, that o Includes data on the prevalence, characteristics of memory clinics, patients and visits, and quality indicators o Facilitates knowledge sharing (development, maintenance and application of diagnostic and treatment protocols)

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o Facilitates clinical and therapeutic research (sub-registry clinical trials). Development of an online e-health patient portal for dementia patients and caregivers, enabling: o Information and psycho-education: about the disease, progression, coping advices, nutrition, practical issues, new developments, preventive role o Self management tool (e-health, domotica, peer support, community) o Peer support: national community to contact peers, exchange experiences, forum discussion etc. o Improvement of quality and coordination of care: facilitating and accommodating local communities, overview of available healthcare and services, collaborative care, accommodating personal health records.

3. VALUE CREATED Quality of life Compared to other chronic diseases such as cardiovascular disease and cancer, dementia has the highest burden on disability and as such a deep impact on quality of life of both patients and caregivers. Dementia is in the top 10 of diseases with the highest burden in terms of disability adjusted life years. Research leading to the delay of disease by 5 years would reduce prevalence by 50%! Slowing of progression and delay of institutionalization will greatly benefit future patients and their caregivers. Caregiver support and remote assistance is needed to improve quality of life and reduce caregiver burden and morbidity. Healthcare costs reduction Current healthcare costs associated with dementia amount to 3.6 billion euro per year. These costs mainly relate to long-term care for institutionalized patients. Deltaplan solutions aim to reduce costs by 1) scientific breakthroughs in early detection, diagnosis and treatment, 2) preventing and postponing inpatient care, 3) e-health solutions and 4) reduction of hospital admissions. Economic productivity Especially in their final years, patients need intensive surveillance and care, which substantially affects the healthcare labor market and jeopardizes the economic productivity of caregivers. Providing support to caregivers can prevent this to a certain extent. Combined with increased morbidity in caregivers (depression, burn out, CVD), the indirect societal costs of dementia are estimated to be another 3.6 billion euro yearly. The Deltaplan Dementia aims to reduce loss of productivity 1) by slowing down the progression of disease and reducing symptoms (especially for early onset dementias) allowing patients to work longer, 2) by enabling patients to stay at home as long as possible, hence reducing the need for inpatient care and 3) by reducing the time dedicated to care giving, enabling caregivers to provide care in a more efficient way through e-health and other kind of innovations. Valorization The Deltaplan Dementia foresees an increase in economic activity as a result of: 1) developing innovative care solutions (online portal, valorization of care products, domotica, GPS equipment), 2) boosting scientific research as well as research and development (start up companies biotech, pharma, clinical trial services), 3) seeking new economic opportunities 4) exploiting international markets as dementia is a worldwide phenomenon and 5) building on proven strengths.

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“The economic argument for investing in science and research in order to promote growth and jobs, even under severe budgetary constraints, has already been won. If we invest wisely and strategically in dementia now, we can ensure better, more costeffective healthcare for the future.” [Prof. Philippe Amouyel, Chair JPND]

4. DEVELOPMENT OF THE HEALTH SOLUTION Deltaplan

Research agenda (2013-

National Registry (2012-

Portal (2012-2014)

Dementia

2020)

2013)

1. e-health solution for

1. diagnostics

1. register key data

patient/caregiver 2. community of professionals

2. aetiology

2. knowledge sharing

Roadmaps

3. therapy and prevention

3. facilitating research

Molecular

biomarkers for detection of

4. cost-effective care Diagnostics

pathology identifying patients for trials measuring drug efficacy prognostic markers personalized medicine

Imaging

enabling earliest diagnosis tracking disease progression tracking effect of treatment prognostic markers

Specialized Nutrition

fundamental research into mode of action prevention of dementia

screening patients for interventions and follow up registered nutritional status

symptomatic treatment

treatment of nutritional deficiencies education in nutritional benefits

delay progression metabolic imprinting Homecare and Selfmanagement

Health Technology Assessment implementation of novel care products home care and safety technology care organization for sustainable productivity social innovation

quality indicators performance of memory clinic services evaluation of interventions

prevention and early diagnosis monitoring remote treatment remote assistance support of daily activities informal care support peer group and mutual support group

5. PUBLIC-PRIVATE PARTNERSHIP ‘Deltaplan Dementia’ is an initiative by Alzheimer Nederland, VUmc Alzheimer Centre, NFU and ZonMw aiming to find solutions for dementia as one of the great challenges of the first half of this century. Successful implementation of the Deltaplan requires expertise in the fields of: • The disease and related scientific and R&D issues • The establishment and maintenance of a National Registry. • The building and maintenance of the digital portal.

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• •

The creation of innovative financial models that allow public – private stakeholders’ investments Healthcare finance and reimbursem*nt for care delivery related innovations.

Partners Public private partnerships will play a key role in the design and implementation of the proposed solutions. Partners that already pronounced their commitment are: banks, pension funds, health insurance companies, relevant branch organizations, government, etc. Approach An integrated national plan that − Aligns with the international agenda, covering both research and care innovations with short and mid term horizons 2012-2020 (€200 million) − Creates high quality and efficiency gains − Delivers short and mid term benefits − Aligns and creates synergies among government, science, social venturing en entrepreneurship.

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2.3.5 Diabetes

SUMMARY In Europe, approximately 60 million people live with diabetes. As a result of sedentary lifestyles and unhealthy diets, the number of patients with diabetes is increasing rapidly. Halting this exponential increase and reducing the medical, social and economic burdens of diabetes and its complications is imperative but unfeasible, as we do not have a cure and too few healthcare providers are available. We urgently require innovative solutions based on the roadmaps of the topsector LSH. For instance, reliable detection of the susceptibility to diabetes based on molecular and biomarker methods and cell therapy to treat insulin deficient patients are promising approaches. ICT, telecom and progressive guidelines can create a virtual outpatient clinic that strongly facilitates self-management. The roadmaps offer opportunities for more effective, accessible and affordable care and it stimulates out of the box businesses.

Global health

1. THE HEALTH CHALLENGE In the Netherlands, about 800,000 people suffer from diabetes. This number increases by 10% yearly and the onset of type 2 diabetes occurs at ever-younger age. At the time of diagnosis, 50% of the patients have chronic complications. Notably, specific ethnic groups are young and less obese when type 2 diabetes occurs and they suffer from a larger burden. Patients with type 1 diabetes are insulin deficient, have large morbidity, and they contribute substantially to direct and indirect costs for diabetes. In spite of the nearly 2 billion euro direct health expenditure for diabetes, our economy will be heavily damaged by this disorder in the near future, as it will significantly affect the work force in an ageing Dutch population. Clearly, innovative solutions are required to prevent or cure the disease and to provide high quality care at low costs. 1. We do not reliably predict type 2 diabetes and fail to prevent diabetes and its complications; 2. We do not have a cure for type 1 diabetes;

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3. An increasing mismatch occurs between the number of patients and care providers and self-management is hardly implemented as the required monitoring is lacking; 4. In our intercultural society, language barriers and cultural differences stand in the way of good quality care for those who need it most.

2. THE HEALTH SOLUTION Promising molecular and biochemical methods to predict type 2 diabetes are available that can be translated into high throughput methods. Early detection is needed to prevent diabetes. Novel cell therapies can replace insulin treatment and cure insulin deficiency. Approximately 70% of all patients, who have developed diabetes, can be treated fully in a virtual reality setting. Preliminary data of the DiabetesStation project show that this enhances the effects of self-management. In this project, patients are interactively guided in their own language (the current version speaks 10 languages) and cultural background: they answer questions about their medical history and the current clinical situation; they take their own physical examination and perform their laboratory tests, and they receive links at home via internet with personalized advice about lifestyle, medication, compliance training, coping with diabetes and complications, and advises to enhance labor participation. Early detection, restoring physiology by cell replacement therapy and well-monitored follow-up by the virtual physician of very large populations will improve cure and care.

3. VALUE CREATED Quality of life Prevention is optimal, but a more physiological approach provided by cell therapy in patients with type 1 diabetes and strong self-management by the patients with type 2 diabetes certainly reduce morbidity and improve the quality of life as well. Cell therapy potentially cures type 1 diabetes. Automatic performance monitoring can be part of the communication and measuring processes facilitating data mining as well to improve the quality of care of chronic patients: learning systems and algorithms during real time monitoring. This will lead to optimized evidence based follow-up of patients and it will enable quick assessment of the impact on the quality of life and the cost-effectiveness of new treatment approaches. Affordability The novel diagnostic methods require development into rapid and easy methods to reduce the cost per test. Widely applied cell therapy should replace the expensive and the suboptimal insulin therapy in type 1 diabetes. An approach as exemplified in the DiabetesStation reduces the number of required healthcare workers. The multilingual system is better accessible than the current care providers. Productivity Removing the mismatch between the number of patients and healthcare workers directly restores capacity of healthcare providers. The physician will have more time to focus on the treatment of patients with co-morbidities. Moreover, the overall efficiency of operational management is improved by integrative systems like the DiabetesStation.

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Working resumption by the patients will be enhanced. The rapidly increasing number of patients under 65 years will get monitoring of their work life. Recently, in the Netherlands a national, evidence based guideline has been developed for diabetes with a number of ‘return to work’ recommendations. This will impact the overall cost effectiveness of ‘Diabetologist 2.0’. Business case A reliable and rapid test to predict the risk of diabetes has a hungry worldwide market. A high yield of cells for therapy can replace the expensive insulin treatment. One DiabetesStation can offer the full care to 4000 persons with diabetes. Such an approach will reduce the unemployment among patients with diabetes, improve the insurability of patients, and is excellently suited for export based on its multilingual properties. Worldwide 346 million people have diabetes mellitus.

4. DEVELOPMENT OF THE HEALTH SOLUTION All roadmaps of the topsector LSH are of interest to diabetes. The examples describe three specific problems: the lack of reliable prediction of diabetes, no cure for type 1 diabetes, and the mismatch between the number of patients and care providers. For our examples the following roadmaps are important: Reliable prediction to prevent diabetes: • Roadmap 1 (Molecular diagnostics): Early identification of the persons, who will develop diabetes, is required to better prevent the disorder. Our genetic findings do not easily translate into accurate prediction of type 2 diabetes, but our preliminary data strongly suggest that a number of biochemical analyses predict more accurate. We need to translate these findings into rapid and easy tests. • Roadmap 5 (Pharmacotherapy): We need drugs that are able to prevent type 2 diabetes. The Dutch universities have a large tradition of collaboration with pharmaceutical companies in clinical trials to test novel drugs. • Roadmap 7 (Specialized nutrition, health & disease): The Dutch industry is one of the most important developers of specialized nutrition of the world. We need to develop food that reduces the risk of diabetes and preferably to make it personalized based on the individual molecular/biochemical backgrounds. In The Netherlands, we have the structure to perform large-scale clinical trials to test such smart food. • Roadmap 8 (Health technology assessment & quality of life): Information about efficacy, cost-effectiveness and the influence on the quality of life are required for all diagnostic tests and therapies that are investigated and implemented in clinical practice. • Roadmap 9 (Enabling technologies & infrastructure): Making databases and biobanks are of interest of each clinical trail and also during the follow-up of patients. Without this approach the innovation of diagnostics, safety monitoring and therapies is going too slow. We should be able to go back in time and test, using the database and stored samples, if new inventions have large potential. Cell therapy for type 1 diabetes: • Roadmap 4 (Regenerative medicine): We urgently need a cure for type 1 diabetes and the novel cell replacement therapies are very promising. • Roadmap 5 (Pharmacotherapy): It might be that the cell therapy is optimized by interaction with specific drugs. Moreover, we need pharmacologic methods to proof and understand all mechanisms involved.

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Roadmap 8 (Health technology assessment & quality of life): Information about efficacy, cost-effectiveness and the influence on the quality of life are required for all diagnostic tests and therapies that are investigated and implemented in clinical practice. Roadmap 9 (Enabling technologies & infrastructure): Continuous monitoring of patients in clinical trails and during follow-up of patients is required. Without this approach the innovation of safety monitoring and therapies is too expensive and too slow. We should be able to go back in time and test, using the database and stored samples, if new inventions have large potential.

The DiabetesStation approach: • Roadmap 3 (Homecare & self-management): The Dutch industry is one of the most important developers of homecare and self-management devices. In the current example, the close collaboration between clinicians and designers, ICT-ers, communication experts and especially experts in logistics of the processes accelerated this applied technology project, resulting in a high quality out of the box solution. • Roadmap 8 (Health technology assessment & quality of life): Information about efficacy, cost-effectiveness and the influence on the quality of life are required for all diagnostic tests and therapies that are investigated and implemented in clinical practice. • Roadmap 10 (Global health): The virtual physician is an excellent solution for healthcare in the developing world. In addition to the DiabetesStation we are developing - among other diseases - modules to treat and follow up HIV patients. This example also has links to the roadmap ICT of the topsector High Tech Systems and Materials (HTSM).

5. PUBLIC-PRIVATE PARTNERSHIP The String of Pearls Initiative links all 8 Dutch university hospitals with nationwide disease related databases and biobanks. This means that we have an excellent infrastructure to test novel molecular and biochemical diagnostics and therapies. Moreover, large follow-up studies (Rotterdam Study, Hoorn Study and LifeLines) and multiple case-control studies are available as well. All Dutch universities have offspring companies in the field of diagnostics. There are numerous public-private partnerships in this field and given the large market of the current example great propositions are ahead of us. For example, the Prediction and early Diagnosis of Diabetes and Diabetes-related Cardiovascular Complications (PREDICCT) is a biomarker project including deep phenotyping (for instance with an AGE reader), which is performed within CTMM. All Dutch university medical centers, a number of universities, a broad spectrum of small en medium-sized enterprises, major industry leaders including Philips and the Dutch government are involved. A unique cell therapy project is funded by ‘Fonds Economische Structuurversterking’ (FES) in Top Institute Healthy Ageing (Ti-GO) and by the ‘Diabetes Fonds’ (DFN). It is performed by the consortium Diabetes Cell replacement Therapy Initiatives (DCTI). This consortium is a strong collaboration of LUMC, university of Twente, UMCG, and biotechnology companies (Biofocus, Polyganics BV, Xpand Biotechnology BV). In the Netherlands, we have the so-called ‘diabetes chain care’ program in which the first and second line collaborate. The DiabetesStation is a public-private partnership between the Erasmus MC and IPT Medical Services of KPN. It enables physicians to take care of more patients; therefore, production pays the investment of this innovation.

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The organization of healthcare differs strongly between countries. For export optimal collaborators per country are chosen: primarily care providers, insurance companies or governments, depending on the specific organization of care, make the investments. Piloting ‘Diabetologist 2.0’ will give us insight in an optimal effective business model for the private development of ‘DiseaseStations’.

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2.3.6 Parkinson's disease

SUMMARY Demographic, societal and technological developments call for a fundamentally new approach to healthcare. Public‐private partnerships (PPPs) are needed to ascertain a high‐quality, affordable healthcare for future generations. This particularly includes neurodegenerative diseases, which will become the second most common cause of death by the year 2040. Parkinson’s disease is a prime example of a common, disabling and costly neurodegenerative disorder. The availability of the national ParkinsonNet infrastructure offers unique opportunities to shape new collaborative PPPs, with concrete plans within various LSH roadmaps. A crucial step is creation of a new infrastructure that involves the entire healthcare chain, from primary prevention to chronic disease management. This infrastructure can be exploited as ‘test bed’ for scientific evaluation of healthcare innovations and new technologies, with emphasis on personalized medicine, self‐management and lifestyle changes. New knowledge can be rapidly implemented into clinical practice, with two aims: improving the quality of care, at substantially reduced costs; and allowing private partners to create business propositions for a growing international market. Importantly, the experience obtained with Parkinson’s disease can serve as a model to develop comparable networks and PPPs around other common chronic conditions.

1. THE HEALTH CHALLENGE Parkinson’s disease is an excellent ‘model’ to illustrate the health challenges that lie ahead of us. A. Neurodegenerative diseases like Parkinson’s disease become the second most common cause of death by the year 2040, surpassing cancer and coming second only to vascular causes. There are 50.000 Parkinson patients in the Netherlands alone, with an expected doubling by the year 2030. However, fewer professionals become available to care for this growing number of patients. B. Parkinson’s disease is severely disabling; it is ranked second among chronic disorders with a negative impact on quality of life. Parkinson is also very complex, with frequent misdiagnoses and complicated treatments. This calls for specialized personnel and improved diagnostics. C. Parkinson is costly (annual costs €180 million), because patients survive long despite accumulating disability. Important cost drivers are medication, hip fractures and nursing home admission. Indirect costs from lost productivity and caregiver burden are also high: up to 85% of Parkinson patients are forced to retire early, and many immediate caregivers are on the brink of collapse. Development of effective solutions to contain healthcare costs is hampered by: (a) the current ‘zero sum competition’ between healthcare organizations; and (b) lack of emphasis on preventive strategies. D. Modern patients increasingly demand a personalized approach to their own health and disease.

2. THE HEALTH SOLUTION A. Fewer professionals The solution is increased self‐management of health and disease, which also helps to improve quality of care. Tools to enable self‐management can be developed through

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PPPs, with abundant opportunities: e.g. shared‐decision making tools; technology to enhance independence at home; or high end (group) video communication and community software. B. Need for specialized personnel and improved diagnostics The solution is specialized networks like ParkinsonNet, where professionals specialize and collaborate around specific conditions. Improved diagnostics and biomarkers will be developed though PPPs. C. Rising healthcare costs • Alternative for ‘zero sum competition’. The solution is true ‘value‐based care’. This necessitates a focus on regional networks that collaborate to offer integral care across traditional echelons, from primary prevention to chronic care. This calls for new integral financing of all network participants within a specific region, who will be jointly paid for outcome, instead of performance. • Emphasis on disease prevention. The solution is implementation of lifestyle changes for primary & secondary prevention. Preventive strategies and tools can be developed through PPPs, with abundant opportunities: development of specialized/personalized nutrition to support a healthy lifestyle; promotion of physical activities, using e.g. ambulatory monitoring as motivational tools; and serous gaming to support these lifestyle changes. D. Request for personalized medicine One example of an important solution here is creation of a personalized electronic medical record, to coordinate and bundle all medical activities within the entire healthcare network. We envision the use of personal health communities in a safe, web‐based and user‐friendly environment that is fully owned by the patient (PPP virtual health, cyber security). Here, patients can build their individualized virtual hospital, store their medical information in one central place, and communicate with their medical team.

3. VALUE CREATED Quality of life • Our approach offers many opportunities for patients to be actively involved in their own health and disease management, which is a consistent wish of modern patients. • Promoting physical activities creates greater mobility and independence. • Specifically trained occupational therapists can postpone or prevent job loss, for both patients and caregivers. Being able to make a meaningful contribution to society improves quality of life. Cost reductions • Converging evidence shows that ParkinsonNet reduces healthcare costs, by as much as €20 million annually. This equals a 10% reduction of total healthcare expenses for Parkinson’s disease. Further cost reductions can be achieved via improved efficiency, by enhancing professional expertise and by informing clients. Better quality of care within integral networks also reduces costly disease complications. For example, the number hip fractures is reduced by 50% in ParkinsonNet regions. • Development of networks for other conditions could substantially reduce costs further, assuming that a comparable 10% reduction of healthcare expenses can be achieved.

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• • •

•

Self‐management leads to substitution of care, patients taking over simple duties from professionals. Introduction of ‘value‐based care’ will further reduce healthcare costs, because this introduces strong incentives for network participants to contain their joint overall costs. Development of neuromarker detection and new imaging equipment will support an earlier diagnosis. This opens avenues for a dedicated approach to prevent and possibly delay disease complications of Parkinson’s disease, using lifestyle interventions or dedicated nutrition. Dedicated support for caregivers reduces their time spent on caring. The long‐term aim is prolonged independence for patients, with less demand for expensive domestic care or institutionalized care.

Productivity • Professional productivity is boosted by application of web‐based communities to facilitate interdisciplinary collaboration, co‐creation of new knowledge and exchange of information. • Efficiency is promoted by participation in specialized networks where professionals work closely together to treat large numbers of patients. • Even small reductions in the number of unemployed Parkinson patients would substantially boost productivity. Economic activity • This proposal holds many promises for private partners to increase their economic activity and to create added value business propositions for an international market. We will develop a variety of evidence‐based healthcare innovations, including e‐health solutions, domotics, serious gaming, ambulatory monitoring devices, virtual health communities, etc. • Specialized/personalized nutrition and lifestyle supporting methods will generate an evidence‐based proposition in specialized foods, ICT and manufacturing industry. • Collaboration with pharmaceutical companies helps create an attractive infrastructure for bio‐and neuromarker discovery, personalized molecular diagnostics, future drug development and business investments by pharma in the Netherlands. • Partnership with healthcare insurers in developing innovative financial solutions for regional care creates a unique export product in the global healthcare market.

4. DEVELOPMENT OF THE HEALTH SOLUTION The proposed healthcare solutions link to a number of LSH Roadmaps. In each Roadmap area, a consortium of public, research and private partners cooperates to expand their expertise, scientific knowledge and international position. 1. Upgrading the existing ParkinsonNet infrastructure. This will be developed in Year 1, while implementation will start in Year 2, alongside with a scientific evaluation. Cost savings for health insurance companies can be expected from Year 2 onwards. 2. Exploiting the national ParkinsonNet infrastructure as test bed for healthcare innovations. We will capitalize on our broad experience with large‐scale clinical studies to evaluate cost‐effectiveness. Several studies are ongoing, others are in the development phase (Year 1‐5).

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3. Implementing new knowledge. From Year 2 onwards, innovations with proven cost‐effectiveness can be implemented into Dutch clinical practice, generating new business for private partners. 4. Extending the ParkinsonNet infrastructure to other disorders. Development of a network for dementia patients will be prioritized as part of ongoing collaborations within the LSH framework (Dementia Deltaplan). Several parties have committed or expressed serious interest to develop comparable networks for other conditions (Year 1‐5). 5. Exporting the existing knowledge to other countries. Concrete negotiations with EURegio are in full swing. Analysis of barriers and facilitators of a German ParkinsonNet (region of Duisburg) can start in Year 1, and actual implementation can start from Year 2 onwards. If successful, we will extend our activities to different parts of Germany and other countries from Year 3 onwards. This can place the Netherlands at the international forefront of healthcare innovation. Roadmap Molecular diagnostics

Imaging & imageguided therapies

Specialized nutrition

Pharmacotherapy

Homecare & selfmanagement

Enabling technologies & infrastructure

Goals • Patient‐driven research • Genome wide association studies • Early disease detection and monitoring • Prognostic information • New neuromarkers • Identifying adaptive plasticity in parkinsonism, as target for innovative treatment (DBS, TCDS, rTMS) • Identifying adaptive plasticity in preclinical parkinsonism, as target for presymptomatic treatment • Brain‐computer interfacing • Development of evidence‐based guideline to reduce malnutrition and food‐drug interactions • Specialised nutrition to increase compliance to diets • Specialized nutrition to delay progression in overt parkinsonism • Specialized nutrition to prevent parkinsonism in preclinical mutation carriers • Specialized nutrition supporting healthy eating behaviour, reward mechanisms, habit support • Development & implementation of shared decision making tools in de novo untreated Parkinson’s disease, and in late‐stage Parkinson’s disease • Personalized medicine through individual healthcare communities • Development & implementation of partner consultation • Equipment and integrated software for behavioural support, screening, self‐management, machine-man interface • Self‐management, supply chain management, serious gaming, decision support, home care – institutionalized care • Neural networks in diagnostic and self‐management support • User friendly, web‐based, safe virtual health environment: the virtual hospital • Development & implementation of integrated regional healthcare financing

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• •

Implementation of ambulatory monitoring to promote lifestyle changes Equipment / integrated software for behavioural support, self‐management, machine‐man interface

5. PUBLIC-PRIVATE PARTNERSHIP This proposal addresses the entire healthcare chain involved in Parkinson’s disease, including early disease stages (improved diagnostics, home care), advanced disease stages (hospitalization, institutionalized care) and preclinical disease stages. To speed up implementation of new healthcare solutions, we propose PPPs that consist of specialized professionals working in regional collaborative networks (e.g. ParkinsonNet), insurance companies, pharmaceutical companies, universities and industry (food & nutrition; ICT; serious gaming). Patient organizations and modern communication media will play an important role in organizing and disseminating these efforts, and to ensure active participation of patients in these PPPs. Specifically, our initiative bundles the following expertise: • Several health insurance companies have committed to support development of value‐based care for Parkinson’s disease. The department of VWS has expressed support to alleviate barriers (NZA, NMA) to facilitate regional collaboration. Additionally, VWS will collaborate on integrating healthcare services currently financed separately (AWBZ, ZVW). This way, we can build integral care across traditional echelons, with joint financial incentives for efficient collaboration and cost‐containment. • Various partners have committed to develop behavioral change strategies to promote a healthy lifestyle: partners within Food & Health industry will develop personalized/specialized nutrition to support a healthy lifestyle; partners from creative industry will develop ambulatory monitoring tools to promote physical activity and enhance independence; partners from social and neurosciences will develop strategies to promote behavior/choice mechanisms; and ICT partners will develop modern applications that enable self‐management, e.g. web‐based health communities, serious gaming. • Partners from universities, pharma and technology have committed to develop new technology to promote early diagnoses, opening avenues for preventive strategies. Several PPPs are already operational, others are starting their cooperative program in the coming months. Our perspective is that these PPPs offer unique opportunities: for Dutch companies, to create new business around innovative healthcare solutions in a fast growing market; and for Dutch scientists, to build a distinctive international research profile through scientific evaluation of these innovations.

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3. Structure and governance – a proactive topsector The topsector Life Sciences & Health has implemented the proactive governance structure proposed in the topsector plan. This structure consists of a Regiegroep and a core team which are responsible for the continuity of the topsector and the implementation of the topsector plan. The Regiegroep works with (temporary) taskforces to implement the plan. The topsector aims to bundle different public stimulus funds and instruments to act together. The topsector is currently designing a light organization for the public-private innovation infrastructure that will guide the distribution of resources in open competition in order to create focus and mass and to support the most promising public-private partnerships that contribute to the topsector's goals. Three main sets of selection criteria for resource distribution refer to social, economic and scientific merits. The administrative function should be responsive to different types of partnerships and stimulate SME participation. It should be set up to support partnerships in the long term, requiring the ability to include different types of funding from different sources. 3.1 Organization of the topsector Life Sciences & Health The organization of the topsector Life Sciences & Health as proposed in the topsector plan has been implemented and shared via the publication Cahier no. IV, Introducing the Regiegroep Life Sciences & Health. The topsector has a proactive governance that offers long-term continuity and facilitation of the topsector plan's implementation. Regiegroep Life Sciences & Health The Regiegroep (or steering group) brings the various perspectives of the topsector together. The Regiegroep facilitates the topsector and takes the lead in the implementation of the topsector plan and activities associated with the IC. A "golden triangle" team leads from within the Regiegroep (figure 6). This core team consists of chair Rob van Leen (big industry), Roland Lageveen (SMEs), Eduard Klasen (academia) and Paul Huijts (government). TOPSECTOR GOVERNANCE REGIEGROEP with members from all corners of the sector, guides the sector and gives substance to the dialogue and cooperation between stakeholder groups CORE TEAM of four Regiegroep members takes lead and makes decisions

TOPSECTOR Temporary TASKFORCES with one or more organizations/experts from the sector give advice and support implementation Request Report

TASKFORCE that advises …

TASKFORCE that investigates … Small, professional SECRETARIAT supports the Regiegroep and the core team

TASKFORCE that implements …

Figure 6. Governance structure of the topsector Life Sciences & Health (figure from Cahier no. IV, Introducing the Regiegroep Life Sciences & Health) Taskforces support the Regiegroep The Regiegroep mobilizes the field's strengths via taskforces. These taskforces are asked to specify issues and report back their findings. This document has been developed by the Taskforce Roadmaps. There are a few other taskforces active:

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•

The Taskforce Finance aims to support the government in designing the generic instruments SME+ innovation funds and tax incentives. It also provides information about these instruments to the sector. The taskforce discusses several issues with the government, including the difficulty SMEs face in tax incentives on income taxes when most are not yet profitable and in WBSO ceilings. This IC does not include detailed information on these generic instruments, as the awarding does not depend on the roadmaps. Should the awarding become dependent on the roadmaps and IC, the topsector will appropriately embed the instruments in future ICs – good access to these instruments (especially for SMEs) is crucial for the topsector The Taskforce Legal and Regulatory is a sounding board for the government and regulatory bodies on legislation and regulation related to the Life Sciences & Health sector. This includes the trajectories of (pre-)clinical research procedures, market access and reimbursem*nt, which are essential for accelerating the development and uptake of health innovations in (clinical) practice. A supportive and encouraging legal and regulatory environment is a boundary condition for effective proving grounds. Several challenges in this area were identified during the formulation of the roadmaps. These challenges were communicated to this taskforce, which will include these in its implementation. The Taskforce Human Capital has developed a human capital agenda for the Life Sciences & Health sector in close cooperation with the other topsectors. The implementation of the IC will be directly related to the availability of enough good people. The success of the human capital agenda is therefore fundamental to the long-term success of the IC The Taskforce International Positioning supports the positioning of the topsector at international events to attract business and talent to the Dutch Life Sciences & Health sector. This taskforce's activities are also therefore instrumental to the implementation of the IC. At the same time, the IC is a tool for positioning the Netherlands and for attracting business and talent

3.2 Organization of the public-private innovation infrastructure of the topsector The topsector aims to evolve towards a consolidated public-private innovation infrastructure that bundles different public stimulus funds and instruments of the topsector policy to accelerate development and delivery of health innovations through public-private partnerships. The topsector is currently designing an administrative organization within this consolidated infrastructure to support public-private partnerships and guide resource distribution. It will incorporate the model of Topconsortium of Knowledge and Innovation (TKI) as well as other instruments and stimulus funds of the topsector policy. Several guidelines taken into account in designing this administrative function are mentioned below. Building on experience The experience and functional building blocks for developing this administrative function already exist in the topsector's well organized public-private innovation infrastructure. Its organizational nuclei, NWO/ZonMw/STW, NGI and the three TTIs (see chapter 6), have gained a wealth of experience in setting up and managing publicprivate partnerships, including: • Distribution of resources on the basis of open competition • Assessment of individual partnerships, portfolios and programs • Agreements on knowledge sharing and intellectual property rights in partnerships • Monitoring and evaluation of projects, portfolios and programs, and the development and measurement of associated indicators

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Open competition Resources will be distributed on the basis of open competition also within thematic programs. Objective, transparent processes will be set up in which consortiums of private and public partners can submit proposals to compete for public resources. Selection criteria and the creation of focus and mass The administrative organization needs to be equipped to distribute resources to only the most promising partnerships in their contribution to the goals of the topsector and create focus and mass within the roadmaps. Selection can be made on the basis of sets of criteria referring to: • Economic relevance: the economic value of the expected research results for (future) industry • Social relevance: excellence of clinical objectives (connected to form integrated health solutions) and contribution to quality of life and affordable, labor-efficient healthcare (in terms of economic and user perspectives, see chapter 2) • Scientific quality: combined scientific strengths of the private and public partners in the project The contribution of proposed partnerships to maintaining the affordability of healthcare is a selection criterion of particular importance. SME participation The administrative function should be designed to stimulate the participation of SMEs in public-private partnerships. SMEs, for example, have indicated that they prefer smaller and focused projects over large consortia: in terms of amount of investments or number of partners. Types of partnerships should be tailored towards full participation of and benefit for SMEs. Types of partnerships The public-private innovation infrastructure should account for different types of partnerships in different fields and in different phases of the innovation cycle in order to accelerate progress from innovative idea to (clinical) implementation and reimbursem*nt. The administrative organization should therefore become responsive to a variety of partnerships in terms of: • The size of partnerships, stimulating large and small partnerships (e.g. for SMEs) and/or entire programs in terms of focus, investment and participants • The type of investment, supporting in cash and in kind contributions • The sharing of results, in terms of flexibility in intellectual property arrangements • The distribution of activities and investments between private and public partners and for different types of activities; for example, the topsector plan describes three generic types of partnerships: o Public-driven public-private partnerships as in the incubator ("kweekvijver") model from the topsector plan, which often operate in early stages of the innovation process and/or build enabling technologies and infrastructure, both of which require relatively large public investment o Private-driven, pre-competitive public-private partnerships as in the TTI model from the topsector plan, which often execute applied research and development and in which significant private investment exists o Private-driven public-private partnerships that implement clinical use of a health innovation as in the proving ground model from the topsector plan, in which private parties are the major investors and public parties are among those creating the right conditions for testing, use and reimbursem*nt

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Proving grounds Most experience in public stimulus funds and instruments for public-private partnerships has been made in pre-competitive research. Accelerating actual clinical implementation and reimbursem*nt of health innovations in proving grounds will often involve competitive R&D activities. The model of proving grounds and how the innovation infrastructure can best incorporate this model is yet to be discussed. Long-term perspective The administrative function should be designed for the long term. The budgets of public stimulus funds within the topsector policy that can be distributed in open competition are limited at present. The sector plans to mobilize other sources of funding (public and private) and will seek to incorporate and align with private sources of funding like health foundations and insurers' innovation funds. Furthermore, the topsector expects that the availability of public resources increases in the future. 3.3 Value creation This IC aims to create social and economic value. Roadmaps connect private and public parties, creating a knowledge interplay between companies, research institutes, users, payers, regulators and other organizations. This interplay will result in the (joint) development and implementation of cost-efficient health solutions. Sector specific instruments Public-private partnerships and generic instruments, like the SME+ innovation fund and WBSO/RDA which support in-house R&D, accelerate value creation in established companies. Another route to value creation is the spin-out of results of organizations/partnerships into new companies. In recent years, the topsector Life Sciences & Health has developed a set of sector-specific instruments that target the first steps in the spin-out of a company. An important one is NGI's Life Sciences @ Work program that helps entrepreneurs develop a business plan, trains them in business skills, provides coaching, introduces them into networks and assists them in securing financing. A major part of the program is the successful Pre-Seed Grant that provides starting entrepreneurs with resources to make their very first steps before applying to a seed fund or other investors. In line with the topsector plan, this IC supports the continuation of these sector-specific instruments. For 2012, there is funding for this within NGI; for the period thereafter, additional public investments are required. Technology transfer offices Knowledge and IP transfer between research institutes and companies is a basis for value creation. Instrumental to this are the technology transfer offices at research institutes. The topsector, as outlined in the topsector plan, calls upon these organizations to continue to professionalize and to bundle their efforts. Enabling participation The topsector aims to bring different organizations together to innovate and create value. Participation from every corner of the sector is necessary to strengthen the public-private innovation infrastructure. Many Dutch stakeholders are already involved, having participated in drafting the roadmaps, and these and others will continue to develop and implement this IC. Foreign organizations (e.g. companies, research institutes) investing/partnering in the Netherlands are also important value co-creators, especially in a topsector like Life Sciences & Health which made the transition to open innovation and which addresses global markets. The Dutch topsector offers many opportunities for foreign

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organizations, which are communicated with the support of the Taskforce International Positioning. For example, Roche recently made a strategic alliance with the UMCs at Groningen, Nijmegen and Amsterdam (VUmc), investing significantly in the area of imaging for pre-clinical and clinical research. The topsector invites foreign organizations to participate/invest in public-private partnership in the Netherlands, and in the set-up of the administrative function and in the execution of the roadmaps aims to secure access and support for such participation. Europe offers many opportunities for participation in international research and innovation programs, and through such programs Dutch stakeholders can benefit from EC funding arrangements. The national knowledge and public-private innovation infrastructure will connect to international programs as much as possible and aims to support Dutch stakeholders' own participation. A two-track approach has proven fruitful. One track is to influence European programming right from its design making it compatible to Dutch strengths. The other is to adapt national programming in order to enable Dutch stakeholders to participate in international consortiums.

3.4 Monitoring progress The topsector Life Sciences & Health wants to monitor its progress towards meeting its objectives and to measure the impact of its activities. Such systematic monitoring is not yet in place, and thus needs to be developed in the coming period. This will be done in close cooperation with the government, building on experience gained in the past. First attempt in the topsector plan A first attempt to develop a systematic approach to monitor the topsector's progress was made in section 4.2 of the topsector plan. There, two types of indicators were proposed: 1. Macro-indicators that measure the sector's economic development (e.g. turnover, growth, employment, R&D investments, pipeline development) and impact on healthcare (e.g. affordability of healthcare, productivity, quality of life) 2. Micro-indicators that measure the progress of specific actions (e.g. speed of partnership formation) and their results (e.g. midterm/final results of partnerships in terms of patents, papers, people, health solutions, healthcare cost/labor savings) Experience Much experience in monitoring progress and results of investments in public-private partnerships can be harnessed. Many public-private partnerships have been subjected to midterm and final reviews, and the TTIs, NGI and ZonMw closely monitor progress and results of the partnerships they manage. The topsector can build on this experience, and steer systematic monitoring to more strongly incorporate the measurement of effects of partnerships on healthcare cost and productivity – objectives that have gained importance within the topsector. A similar reasoning holds for macro-indicators. The innovation program Life Sciences & Health and Nyenrode University, for example, have set up an annual Life Sciences monitor to measure the sector's economic development. Future systematic monitoring of macro-indicators also needs to better include the sector's impact on the affordability and productivity of healthcare.

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4. Commitment – a strongly committed topsector ready to invest In this innovation contract, the topsector Life Sciences & Health demonstrates its strong commitment to public-private partnerships. As of the closure date, February 15, 2012, 408 letters of intent or support were received from organizations in the topsector, corresponding to an intended investment of EUR 293 million, EUR 130 million of which from private parties. An inventory of public-private partnerships resulted in the identification of 263 initiatives that involve about 800 organizations. The topsector already invests substantially in ongoing public-private partnerships, and several partnerships have recently been developed and are ready to start. Based on the commitment of organizations in the topsector, an indicative financial plan has been developed for investments in public-private partnerships in the coming years. The financial plan describes the potential to grow to new investments of EUR ~350 million per year by 2015/2016, 40% of which are from private resources.

4.1 Commitment of the topsector Private and public organizations in the topsector Life Sciences & Health are strongly committed to public-private partnerships. Results of a mapping exercise in the past months demonstrate this commitment. The exercise was performed through a call for letters of intent and support (demonstrating new commitment), and an inventory of new and ongoing public-private partnerships (demonstrating ongoing and ready to start initiatives). New commitment: letters of intent and support Between mid-December 2011 and mid-February 2012, 408 organizations in the topsector signed a letter of intent (which includes an actual amount of intended investment) or a letter of support: 334 private parties (including Life Sciences & Health companies, health insurers, healthcare providers, health foundations, patient organizations, associations and other NGOs), 56 public research institutes (including universities, UMCs, TUs, higher vocational institutes) and 18 other parties (including public-private partnerships, regional and local governments). An overview of the organizations that signed letters of intent and support, as well as the typical text of these letters, are provided in Appendix B. The letters of intent add up to EUR 293 million spread over multiple years, EUR 130 million of which from private parties (see table 2).7 These figures are only a snapshot, and the letters of support show promise for even more intended investments. # letters of Intended investments [EUR million] # letters of intent and intent Total 2012 2013 2014 2015 2016 2017-2020 support Private parties

334

115

130

Public research institutes

118

Other parties

Total

408

145

293

Table 2. Summary of the results from the request for letters of intent and support8; investments exclude those of public organizations that are part of the topsector policy

It cannot be excluded that there is minor overlap between the letters of intent for the roadmaps and investments in existing, ongoing partnerships. 8 All calculations shown in the tables in this chapter have been made with unrounded numbers. Tables give rounded numbers after calculations.

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Inventory of new and ongoing public-private partnerships The results of an inventory of new and ongoing public-private partnerships in the topsector reveal 263 public-private consortia. These partnerships bring about 800 organizations together: about 580 Life Sciences & Health companies (including subdivisions of large companies), 85 research institutes, 36 (health) foundations and patient organizations, 8 health insurers and many other organizations. No competitive selection has been applied to the outcome of the inventory; that becomes relevant as funding for calls for proposals is available. Such funding will be distributed through the administrative organization described in section 3.2. Nevertheless, these figures indicate a huge interest in public-private partnerships in this topsector. Appendix C lists the partnerships and the roadmaps to which they will contribute. Appendix D lists all organizations that participate in these partnerships. New partnerships ready to start The commitment of the topsector to new partnerships is illustrated by two newly proposed initiatives on a national scale that are ready to start: Innovative Medical Device Initiative (IMDI) and a new call for proposals in the area of pharmacotherapy. These initiatives have already been assessed by international review. Their detailed business plans and financial plans have been published, and letters of commitment of all its partners signed. They also illustrate the aim of the sector to move towards 40% private contribution to public-private partnerships: • In the Innovative Medical Device Initiative, a funding arrangement is projected in which the private contribution is expected to grow to 50% in year 10 of the program, while at the same time the government's contribution will decrease to 0%; the other 50% in year 10 will be provided by research institutes • The newly proposed call for proposals targeting primarily the pharmacotherapy roadmap includes a private commitment of EUR 40 million over the period of four years which is planned to be invested on the basis of 40% private investment. TI Pharma has already been able to increase the private investment from 25% to 40% in its most recent 2011 call for proposals Ongoing partnerships Several public-private partnerships are ongoing in the topsector Life Sciences & Health (see chapter 6), a large part of which has been identified by the inventory of new and existing public-private partnerships. Table 3 illustrates the significant investments in ongoing partnerships by the topsector by showing the consolidated financial figures of NGI, CTMM, TI Pharma, BMM, FES 2009 consortia and the Life Sciences Park in Oss. Committed investments in ongoing partnerships [EUR million]

2012

2013

2014

2015

2016

Private organizations

Public research institutes

Public stimuli

133

Totaal

263

170

Table 3. Investments in several large ongoing public-private partnerships Enthusiasm The sector's participation in the process of designing the roadmaps illustrates its enthusiasm. • Over 100 people from about 70 organizations in the sector participated in the Taskforce Roadmaps and/or in one of the teams that detailed the roadmaps: 18 companies (11 large companies and 7 SME(+)), all relevant industry associations were represented, 12 health foundation/patient organizations, the major publicprivate initiatives (TTIs, NGI, and others) in the field, all UMCs and several other

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•

research institutes, NWO/ZonMw/CW/ALW/STW/WOTRO, RIVM, TNO, and four Ministries (see Appendix A for the composition of the roadmap teams) A sector meeting was held to obtain input on the roadmaps: over 500 people from the topsector came to this meeting, ~32% from companies, ~43% from research institutes, ~4% from health foundations and patient organizations, and the remaining from intermediary organizations, government and other relevant organizations. Pictures of this successful event are shown in figure 7

Figure 7. Pictures of the sector meeting held on December 19 in Nieuwegein

4.2 Indicative financial plan based on the sector's commitment Based on new commitment and the topsector's ambition, an indicative financial plan for private and public investments in public-private partnerships has been outlined. The plan describes new investments on top of investments in ongoing partnerships. The plan shows the public investments that can be accommodated based on the private commitment obtained. The realization of the plan and the materialization of the new private commitment will depend on the government's investment. Three components The topsector aims to shape new public-private partnerships with three components: 1. Private organizations: in cash and/or in kind contributions to partnerships 2. Public research institutes: primarily in kind contributions to partnerships 3. Public stimuli: resources to be distributed in open competition to the most promising partnerships to make the largest contribution to the topsector's goals (social, economic and scientific benefit, see section 3.2) Indicative financial plan for new investments The topsector Life Sciences & Health aims to increase new investments in publicprivate partnership to EUR ~350 million per year by 2015/2016 (see table 4). Of these new investments, 40% (EUR ~140 million) will be private (component 1, see above), and 60% (EUR ~210 million) will be public (components 2 and 3). These amounts are on top of commitments for ongoing public-private partnerships (table 3).

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New investments in public-private partnerships [EUR million]

2012

2013

2014

2015

2016

Private organizations

109

121

137

141

Public research institutes

108

102

104

Public stimuli

107

Total

252

306

318

343

352

% private

31%

35%

38%

40%

% pub lic (pub lic research institutes + public stimuli)

69%

65%

62%

60%

Table 4. Indicative financial plan for new investments in public-private partnerships in the topsector Life Sciences & Health Explanation of the financial plan The financial plan as described in table 4 is based on: 1. Newly obtained private commitment for public-private partnerships 2. The ambition to maintain the 2012 level of private commitment in the coming years (sum of new commitment and commitment in ongoing partnerships) For 2012, new public and private investments (table 4) are based on newly obtained private commitment. For 2013 onwards, the figures are also based on the ambition. Ad 1. New commitment is shown in terms of the letters of intent and the new partnerships ready to start (see section 4.1). Table 5 describes this new commitment over time and the required public stimuli associated with this commitment. Note that the additional public commitment required for a 40/60% private/public distribution of funds has been shown as public stimuli (component 3). There is, however, some degree of freedom in the distribution of public investments over components 2 and 3. New commitment for public-private partnerships [EUR million]

2012

2013

2014

2015

2016

Letters of intent

New partnerships ready to start

Public research institutes (committed)

Letters of intent

New partnerships ready to start

Investment that can be accomodated b ased on letters of intent assuming 40% private contribution

Investment that can be accomodated b ased on two new partnerships ready to start according to their financial plan

Private organizations (committed)

Public stimuli (required)

Table 5. Newly obtained commitment and associated public stimuli required9 Ad 2. The newly obtained commitment and the commitment in ongoing public-private partnerships decrease over time. This is due to the limited format by which organizations were asked to express their new commitment and the limited period that ongoing partnerships will be active. For 2012, we have a reliable estimate for the total private commitment. For 2013 onwards, additional commitment must be accounted for. 9

The financial plan of IMDI (one of the new initiatives ready to start) has been adopted in table 5 in an adjusted form: the in kind contribution of public research institutes between 2013 and 2016 has been lowered with respect to the original plan. This has been done to achieve a private contribution of 40% of the total investment in 2015. In the original plan, 40% private contribution is achieved several years after 2015.

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Therefore, it has been assumed that the level of private commitment in 2012 (sum of new commitment and commitment in ongoing partnerships) can also be achieved for 2013 onwards. This leads to additional private and public investments from 2013 (table 6). The calculation in table 6 assumes 40% private contribution, 25% contribution of public research institutes and 35% public stimuli. Note that there is some degree of freedom in choosing a different distribution of public investments over components 2 and 3. Commitment required to maintain 2012 level [EUR million]

2012

2013

2014

2015

2016

Private organizations: total commitment (ongoing and new)

143

Commitment in ongoing partnerships (see table 3)

New commitment given (see table 5)

Private organizations: additional commitment required to maintain 2012 levels = ambition

Public research institutes: additional commitment required for ambition

Public stimuli: additional commitment required for ambition

Table 6. Newly required private and public commitment in 2013-2016 to maintain 2012 private commitment level

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5. Request to the government – invest with us in health and the economy The government is asked to support this IC, to continue to invest in public-private partnerships, and to create a more sustainable funding base to support public-private partnerships in the future. The topsector asks the government to make new investments growing to EUR ~100 million public stimuli that can be distributed by the topsector in open competition and EUR ~100 million in kind participation in partnerships by public research institutes by 2015/2016. The topsector understands the present budgetary constraints that make it difficult to fully cover the governmental part of the financial plan on a short notice. Therefore, the topsector Life Sciences & Health urges the government to provide at least EUR 20 million in public stimuli in 2012 as soon as possible; this will enable the topsector to invest freely available resources in open competition in new public-private partnerships in 2012, thus giving the topsector the opportunity to materialize part of the new private commitment and to start implementing the IC. Public organizations that are part of the topsector policy are addressed individually for their contributions. TNO, RIVM, KNAW and DLO are asked to maintain or increase current levels of investments in the topsector Life Sciences & Health and to keep contributing in kind to public-private partnerships. The ministries and the intermediary organizations NWO, ZonMw and STW are requested to carry the investment for public stimuli. The government is also asked to maintain current levels of competitive funding for research and innovation in Life Sciences & Health at research institutes through the "tweede geldstroom". The government is asked to participate in partnerships as a cooperative regulatory authority and launching customer of new products in their first phases of deployment, and enable investments of others through e.g. fiscal support for health foundations and incentives for foreign organizations investing here and Dutch organizations participating in international programs. Finally, the government is asked to design dedicated policies and financial instruments for supporting Life Sciences & Health SMEs.

5.1 Request to the government to invest in public-private partnerships In line with the topsector plan, the government is asked to continue its support of public-private partnerships. Invest with us in our country's economic strengths, quality of life, and affordable and labor-efficient healthcare. Towards a sustainable funding base in the long term In recent years, much has been invested by sector and government in public-private partnerships in the topsector Life Sciences & Health. There are ongoing public-private partnerships, often co-financed with FES funding. Investments are committed and these partnerships will be active in the coming years. Committed investments, however, decrease in the lead up to 2015/2016 (see table 3). The topsector expects it can close this investment gap with new private and public investments in new publicprivate partnerships. In that, the topsector will increase private participation, and asks the government for additional public investments based on the large private commitment. Public organizations are asked to make new investments in public-private partnerships, growing to (see table 4): • EUR ~100 million per year in public stimuli that can be distributed through open competition in 2015/2016 (see also the topsector plan)

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•

EUR ~100 million per year in in kind contributions from public research institutes in 2015/2016 This will be accompanied by new private investment growing to EUR ~140 million per year in 2015/2016. The government is asked to create a more sustainable funding base to support publicprivate partnerships in the future. A minimal horizon of 4-5 years for public commitment to a specific public-private partnership is required in order to formulate meaningful research and innovation projects. Invest at least EUR ~20 million in public stimuli in the very short term For 2012, the financial plan (table 4) suggests new investments of EUR ~96 million in in kind contributions by public research institutes (already committed, see section 4.1) and EUR ~78 million in public stimuli. This is based on newly obtained private commitment of EUR ~78 million. The topsector understands the present budgetary constraints that prevent such large governmental investments through public stimuli in the short term. Therefore, the topsector urges the government to make AT LEAST EUR ~20 MILLION in public stimuli available as quickly as possible; this will enable the topsector to materialize part of the new commitment from private organizations and public research institutes, thus giving the topsector the opportunity to start implementing the IC as quickly as possible. This immediate response is necessary in order to maintain the momentum that has been created in the development of the innovation contract. The conditions for which these resources become available are crucial. The topsector prefers to invest freely available resources in open competition to support the best proposals for public-private partnerships and to steer them towards the topsector's goals. After this start-up funding, it is essential to grow as fast as possible towards the projections made for 2013 and beyond in the financial plan, as shown in table 4. With these new investments, the topsector will redesign the public-private innovation infrastructure as discussed in chapter 3. 5.2 Request to individual organizations that are part of the topsector policy to invest in public-private partnerships The governmental topsector policy binds several public organizations. The public organizations that are part of the topsector policy and are relevant to the topsector Life Sciences & Health are: TNO, RIVM, KNAW, DLO, NWO, ZonMw, STW, and various ministries. These organizations are requested to contribute to the public investment described in the financial plan (table 4).

Public research institutes are requested for in kind contribution Part of the in kind contribution from public research institutes as proposed in the financial plan (table 4) must be carried by the topsector policy. The public research institutes TNO, RIVM, KNAW and DLO are requested to maintain or increase current levels of investments in the topsector Life Sciences & Health and to keep contributing to public-private partnerships. Ministries and funding organizations are requested to carry the full budget for public stimuli The public stimuli proposed in the financial plan (table 4) should be fully covered by the topsector policy as FES funding is coming to an end. The following organizations are requested to carry the investment in public stimuli together:

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• •

• • •

The intermediary organizations NWO, ZonMw and STW are requested to carry a considerable part of the requested budget for public stimuli The Ministry of Economic Affairs, Agriculture and Innovation is requested to reserve a large part of the RDA+ (or better, WBSO+ as this would have a more direct effect on knowledge workers) for the topsector Life Sciences & Health. As the initiator of the topsector policy, this ministry is furthermore requested to find additional resources to realize the requested budget for public stimuli The Ministry of Health, Welfare and Sport is requested to reserve its total budget for the topsector policy for the topsector Life Sciences & Health The Ministry of Education, Culture and Science is requested to contribute to the requested budget for public stimuli through NWO The Ministry of Foreign Affairs is requested to reserve EUR ~5-10 million per year for contributing to the requested budget for public stimuli, to be invested in public-private partnerships in Life Sciences & Health that respond to health priorities in developing countries (see the global health roadmap)

5.3 Other requests to the government and public organizations Next to direct investments in public-private partnerships, the topsector requests the government to support public-private partnerships in several other ways. Participate in partnerships Regulatory authorities are invited to participate in public-private partnerships, e.g. in proving grounds. In such public-private partnerships, the sector and government can together accelerate innovation by creating a favorable legal and regulatory landscape for (pre-)clinical research, market access, reimbursem*nt, etc. For some areas, like homecare and self-management, effective delivery of innovations even requires fundamental changes in the healthcare delivery/business model; a public-private challenge. The Taskforce Legal and Regulatory is currently discussing several hurdles in this area. Much acceleration of innovation can be achieved through public purchasing policies. So-called pre-commercial procurement would be an example here, where the government acts as the first buyer and shares the risks and benefits of new product R&D with the suppliers in the earliest phases of deployment – this creates good conditions for wide commercialization and take-up of R&D results. Stimulate investments of others Furthermore, the government is asked to enable other stakeholders to invest and participate in public-private partnership, e.g.: • Health foundations invest about EUR 160 million per year in research and development in the topsector Life Sciences & Health, including in public-private partnerships. They strongly believe in the importance of the topsector Life Sciences & Health: to meet the major health challenges that society faces through the development of much needed, innovative health solutions. Health foundations have taken their responsibility in the past in investing in Life Sciences & Health and have been instrumental to building the successful public-private innovation infrastructure that exists today. They are committed to keep investing and seek opportunities to even increase investments and/or make their investments even more efficient in close collaboration with the government and public and private parties in the topsector. Health foundations are currently developing plans for joint investments. The government is requested to support health foundations by co-designing and participating in their plans, for example through a stimulating tax environment for scientific investments

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•

European research and innovation programs must be easily accessible to Dutch stakeholders. Participation in such programs requires matching investments of national funds. This is particularly in the case of the Horizon 2020 program (see chapter 6), even more so than in the current 7th Framework Program. Government budgets and national innovation policies must allow for and encourage such public investment (e.g. an EU matching fund; see topsector plan and Cahier no. III, 2010) Foreign companies must be enabled and encouraged to invest in R&D in the Netherlands and to participate in public-private partnership. Tax support, for example, is not an effective instrument for these companies. Stimulus funds and instruments must be designed to support "onshoring"

Invest in science-driven research Science-driven research at research institutes is a crucial foundation on which this topsector builds. NWO and partners (ZonMw, STW, FOM, etc) are expected to dedicate a substantial part of their budgets to topsectors from 2012 onwards, to a total of at least EUR 275 million annually by 2015, EUR 100 million of which directly invested in public-private partnerships for all topsectors. Thus part of the budget that was dedicated to science-driven research at research institutes will be redirected to research in public-private partnerships (to partly compensate for the withdrawal of FES calls). Although the funding of public-private partnerships does not necessarily harm the scientific drive of academic researchers, the topsector wishes to emphasize that the above mentioned redirection of resources on its own does not provide a sustainable solution in the long term. We are already behind in investments in sciencedriven research with respect other countries. Current levels of competitive funding for science-driven research in Life Sciences & Health at research institutes through the "tweede geldstroom" should be maintained. The topsector Life Sciences & Health thus asks the intermediary organizations NWO, ZonMw and STW to keep investing in science-driven research at research institutes at the 2011 level. This implies that the total budget for Life Sciences & Health (sciencedriven research and public-private partnerships) of these organizations needs to increase. Support Life Sciences & Health SMEs SMEs play a crucial role in Life Sciences & Health innovation. They generate and pick up promising ideas and deliver proof of concept, after which large companies often become involved. The typical Life Sciences & Health SME is of a special kind, differing from the typical SME in many other topsectors: they require large investments, take large risks and need many years before generating a profit. The government is asked to design dedicated policies and financial instruments for supporting SMEs in the topsector Life Sciences & Health that take these characteristics into account. Invitation to other public organizations Next to investments from public organizations which are part of the topsector policy, other public organizations are invited to invest, such as local and regional governments. Many such organizations already invest in Life Sciences & Health and public-private partnerships, and they are asked to continue and intensify investments. Good examples can be found in the south of the Netherlands. For example, the Province of Limburg is accelerating the development of the Chemelot Campus in Sittard-Geleen. Together with DSM and Maastricht University and its UMC, the Province of Limburg contributes to an additional investment of EUR 180 million in research facilities, an investment fund, an education program and real estate. And in February 2012, the Province of North Brabant, the North Brabant Development Agency, the municipality of Oss and the national government matched EUR 33 million investment of MSD to invest a total of EUR 66 million in the Life Sciences Park in Oss.

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6. The starting point – unique foundations for partnership The topsector Life Sciences & Health is in a good position to take this next step in public-private partnerships. Through its TTIs and NGI, the topsector has already initiated many successful public-private partnerships. Funding organizations like NWO, ZonMw and STW play an important role in stimulating academic research and its transfer into industry and healthcare. UMCs have been expressly designed to translate research findings into medical and technical practice, in most cases in collaboration with TUs and WUR, and in some cases in collaboration with general hospitals. Strong regional clusters, in which public and private players work together, have been built with clear focus. Dutch industry and academia are heavily involved in European/international research and innovation programs, and organizations like health foundations invest profoundly in research and innovation. This chapter details the current public-private innovation infrastructure: the solid foundations on which the topsector will build as it looks to the future.

6.1 National research and innovation programs National programs have supported the build-up of a unique research and public-private innovation infrastructure in the topsector Life Sciences & Health. Several of the programs and key organizations are described below. Innovation programs In cooperation with the Ministry of Economic Affairs, Agriculture and Innovation, the Life Sciences & Health innovation program was established in 2008. Its aims include improving the conditions for SMEs and the sector's international position, monitoring progress in the sector, and supporting education and training. The program ends in 2012. The Ministry of Economic Affairs, Agriculture and Innovation has also supported publicprivate partnerships for research. An example is Castellum, in which companies and research institutes develop vaccines against zoonoses. Technological top institutes The "technological top institutes" (TTIs) are main bodies of the public-private innovation infrastructure in the topsector Life Sciences & Health, and internationally acknowledged as good practices. Calls for proposals from the TTIs attract consortiums of private and public parties. The Life Sciences & Health sector currently has three TTIs: • Center for Translational Molecular Medicine (CTMM) – focuses on medical technologies that enable new and personalized treatments for the main causes of mortality and reduced quality of life; term: 2008-2014, total budget of EUR 300 m (50% government, 25% companies, 25% research institutes) • Top Institute Pharma (TI Pharma) – focuses on improving the development of socially relevant medicines; term: 2007-2013, total budget of EUR 275-280 m (45% government, 30% companies, 25% research institutes) • BioMedical Materials Program (BMM) – focuses on the development of new biomedical materials and their applications; term 2008-2014, total budget of EUR 90 m (50% government, 25% companies, 25% research institutes) The TTIs have accomplished major public-private partnerships in the sector. Large companies like Philips, DSM and MSD Oss and a large number of SMEs have invested millions of Euros via these TTIs. The TTIs bring together about 40 large companies, more than 100 SMEs, all Dutch university medical centers and technical universities, health-related charities and many international research institutes. An independent

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mid-term review of one of these TTIs, TI Pharma, confirms its "excellent project portfolio that addresses societal needs", that the TTI "attracts international investment to the Netherlands", and that "the Netherlands has an international best practice of public-private partnership in house". Ongoing projects are still underway at these TTIs, funded by budgets that will end between 2012 and 2014. Netherlands Genomics Initiative The Netherlands Genomics Initiative (NGI) is a public-private program that focuses on genomics research/technology and applications in healthcare, chemistry, agro-food and elsewhere. The NGI is currently in phase two (2008-2013), which was rated as excellent in an independent mid-term review. About EUR 500 m has been invested in this phase, about 50% of which is from the government, 10% from companies and 40% from research institutes. These funds have been invested in, among other areas, eighteen genomics centers: publically driven public-private partnerships targeting "omics" technologies or genomics applications in several topsectors. Of the total budget, about 60% is dedicated to the topsector Life Sciences & Health. FES consortiums The public-private programs mentioned above are in part financed by the FES funds. Other public-private programs that have recently been financed by FES include: Virgo/NeuroBSIK, Cyttron II, NIRM, TeRM, Parelsnoer, TI Gezond Ouder Worden, Hersenen en Cognitie. In the 2009 FES round, a number of these programs were linked to the TTIs in the sector, leading to consolidation and alignment. The government plans to withdraw from executing FES calls in the future. Most of the governmental commitment in ongoing partnerships shown in table 3 results from previous FES calls. NWO The Netherlands Organization for Scientific Research (NWO) is a major public funder of academic research through its competitive procedures based on peer review. As the independent intermediary organization for the Ministry of Education, Culture and Science, the NWO plays a key role in the development of science, technology and culture in the Netherlands (budget EUR ~640 million for 2012). Responsive mode funding aims to encourage scientific talent, ideas and infrastructure and is organized through nine main scientific fields, at least three of which are (partly) devoted to Life Sciences & Health. Managed mode funding is organized in nine thematic cross-cutting programs, one of them devoted to Living in Health. NWO houses temporary taskforces like NGI, ACTS and NIBC. NGI, STW, ZonMw and the Earth and Life Sciences, Chemical Sciences and Physical Sciences divisions of NWO are members of the NWO Taskforce Life Sciences (TFLS). ZonMw The Netherlands Organization for Health Research and Development (ZonMw) is the independent intermediary organization that promotes quality and innovation in health research and healthcare. ZonMw manages the division of medical sciences of NWO (budget EUR ~40 million for 2012) and is an intermediary for the research and innovation resources of the Ministry of Health, Welfare and Sport (VWS; budget EUR ~100 million for 2012). By combining the interests of both main commissioners, ZonMw serves the whole innovation cycle with its funding, from the early phases of exploration to the final phases of exploitation. Overall, the programs of ZonMw are driven by the demands of patients/users. ZonMw also participates in international research programs within the Life Sciences & Health sector, such as EU Joint Programming Initiatives for Neurodegenerative Diseases, More Years Better Lives, Healthy Diet for a Healthy Life, Antimicrobial

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Resistance and the European Innovation Partnership Active and Healthy Ageing. For these transnational programs, primary funding is supposed to come from the participating member states, and the EU matches the successful ones. STW The Technology Foundation STW funds scientific research at Dutch universities and institutes. Its working methods bring together researchers and potential (private) users of the results of that research. The users provide input and also financial or other contributions to the project. Besides scientific excellence, STW strongly considers utilization in its funding decisions. STW receives its resources from the Ministry of Education, Culture & Science (through NWO) and from the Ministry of Economic Affairs, Agriculture and Innovation. STW has invested in a number of innovation programs within the topsector Life Sciences & Health, including NeuroSipe, H-Haptics, On-time and Genbiotics. IMDI The Innovative Medical Device Initiative (IMDI) is endorsed by intermediary organizations for health (ZonMw), physics (FOM), technology (STW) and informatics (former ICTRegie) and consists of eight Centers of Research Excellence (CoREs). The CoREs were selected based on R&D quality and focus, as well as on the potential to achieve international recognition as a leading R&D center in the area of medical devices. The EU 2020 Health Priorities align perfectly with the science and technology as well as the HTA and innovation of the IMDI program. IMDI will increase the efficiency of cure and decrease the length of hospital admissions and will contribute to the desired shift away from expensive inpatient care towards less expensive forms of outpatient care. Overall, the eight IMDI CoREs focus on medical devices intended for homecare, self-care and rehabilitation, on medical imaging and image processing, and on new instrumental techniques for minimally invasive procedures. In these CoREs, nearly 50 research groups from the 3 technical universities, 8 UMCs and a number of companies and healthcare institutions in the Netherlands are involved in a unique structure of cooperation between healthcare partners in the public and private sectors. The research groups that make up the CoREs now generate combined annual research proceeds of more than EUR 80 million. IMDI aims to double the proceeds and outcomes of the research conducted by the eight CoREs. The structure of the CoREs emphasizes the importance of both engineering and medical sciences in the development of medical devices. The CoREs are therefore active in the topsectors HTSM/Health and Life Sciences & Health, and symbolize the inseparable bond between these topsectors in the development of new medical devices. TNO TNO is the organization for applied research in the Netherlands. TNO invests in research and innovation in the topsector Life Sciences & Health via its Healthy Living Theme. The ambition of TNO for Life Sciences & Health is to generate innovative healthcare solutions that strengthen the competitiveness of the Dutch industry and increase the (cost-)effectiveness of the sector. For 2012, an amount of EUR 4.7 million has been earmarked for this topsector. From 2012 on, TNO has the ambition to increase investments in the topsector Life Sciences & Health. TNO leverages these investments by generating additional funds from the EU and other international organizations in high ranked consortia of academia and industry. In total, an investment of at least EUR 7-9 million is anticipated for the coming years. On top of this, TNO

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generates approximately EUR 10 million in innovative applied research with the (inter)national life sciences industry. UMCs and TUs Over the last 15 years, eight university medical centers (UMCs) were created in the Netherlands. In a UMC the Faculty of Medicine is merged with the Academic Hospital. Each UMC is a private non-profit enterprise. The finances come from the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sport, as well as from health insurance companies and contract research activities. Although UMCs are legally private entities, they have a distinct public mission that integrates its three core functions: patient care, (bio)medical research and (bio)medical education. The UMCs fulfill their public functions in a new, more market oriented healthcare system. Together the UMCs have an annual budget of EUR 740 million for research and innovation. According to the scientific ranking of Times Higher Education, five Dutch UMCs are among the top 20 European institutions in clinical medicine, and one of them is in first place. About one-third of all Dutch scientific publication comes out of UMCs. In addition to the UMCs, the Netherlands houses general hospitals that support the Dutch clinical research infrastructure and often cooperate in clinical research with UMCs. The three technical universities (TUs) in the Netherlands work together in the 3TU Federation. The TUs and UMCs also work together in common areas of technology and care, via the three TTIs and in IMDI. The two most promising areas of cooperation are biotechnology and ageing populations, subjects that connect roadmaps in this document. Both are expected to be priorities of the European Knowledge and Innovation Community (KIC) to be established in 2013. Other priorities for cooperation are devices for self-care and prevention and information systems for healthcare. KNAW The Royal Academy of Arts and Sciences (KNAW) was founded in 1808 as an advisory board to the Dutch government, a role that it continues to play today. KNAW derives its authority from the quality of its members who represent the full spectrum of scientific and scholarly endeavor and are selected on the basis of their achievements. It is also responsible for 18 internationally renowned institutes whose research and collections put them in the vanguard of Dutch science and scholarship. The Academy encourages these institutes to cooperate with one another and with university research groups. RIVM The National Institute for Public Health and the Environment (RIVM) is a recognized and leading center of expertise in the fields of health, nutrition and environmental protection. RIVM works mainly for the Dutch government. RIVM also shares its knowledge with governments and supranational bodies around the world. The results of its research, monitoring, modeling and risk assessment are used to underpin policy on public health, food, safety and the environment. RIVM is the central coordination hub for the national vaccination program governed by the Ministry of Health, Welfare and Sport, and is responsible for the underlying vaccine research and development. 6.2 Regional innovation programs Within the Life Sciences & Health sector, strong regional focus has been developed around research institutes and large companies. Regional innovation programs have been created in various ways, including through partial financing from cities, provinces, and programs like Pieken in de Delta and the European Regional Development Fund (EFRO).

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Clusters The Netherlands has a range of regional Life Sciences & Health clusters. Each cluster is a concentration of companies, (applied/academic) research institutes (such as UMCs, TNO and research centers of higher vocational institutes) in specific areas of Life Sciences & Health, and many public-private partnerships have arisen. For example, Brainport in the southeast part of the Netherlands, which comprises North Brabant and Limburg, includes one of the most knowledge intensive regions in Europe. Utrecht University and its medical center form a strong life sciences cluster, particularly in imaging, with the Eindhoven University of Technology. Another example is Medical Delta in South Holland. The Medical Delta initiative is based on the synergy of the universities of Leiden, Rotterdam and Delft, including their science parks, in order to realize breakthroughs in medical sciences and healthcare, to develop novel technologies and to fuel related economic opportunities. Science parks Science parks are important physical infrastructures where public and private players incubate and innovate together. The Netherlands has a number of these local infrastructures in Life Sciences & Health, mostly established around a large company or university. Parks of particular national importance include Leiden Bio Science Park, the High Tech Campus in Eindhoven and Chemelot in Sittard-Geleen. There are also science parks in Amsterdam, Nijmegen, Utrecht, Twente, Groningen and Maastricht, which provide facilities for open innovation in the Life Sciences & Health sector. MSD Oss, the national government, the North Brabant province, the city of Oss and the North Brabant Development Agency (BOM) are collaborating in the development of the Life Sciences Park in Oss. Academic and vocational institutes are involved, including Radboud University Nijmegen. Total investment in this public-private partnership to make (high-end) research infrastructure available is about EUR 66 m, half of which is contributed by MSD Oss. Regional public-private partnerships The Netherlands has a range of public-private programs at the regional level, established in some cases with the Pieken in de Delta stimulus funds, EFRO (European Funds for Regional Development) and investments from regional governments. In the northern region of the Netherlands, for example, there is the Healthy Ageing Network (HANNN), the population based biobank LifeLines, and a forthcoming proton facility for particle treatment of tumors. Public-private initiatives with a physical nucleus in a certain region (often built on virtual collaboration with national and international partners) are found in other regions as well. 6.3 International innovation programs European policy in the area of research and innovation is in a transition phase. Financial instruments are increasingly applied to major social issues (the so-called grand challenges) and to the global competitiveness of the European knowledge economy. On the one hand, the European Commission will design its eighth Framework Program (Horizon 2020) into a more thematic mode, breaking away from the traditional responsive mode instruments of its seven predecessors. On the other hand, the Commission seeks alignment between national research and innovation programs themselves and with Horizon 2020, aiming at a so-called Common Strategic Framework of the Commission and Member States. The Joint Programming Initiatives (JPIs) and the joint infrastructure initiatives initiated by the European Strategy Forum on Research Infrastructures (ESFRI) are important tools to support this endeavor.

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In order to speed up "time to market", the European Innovation Partnerships (EIPs) have been launched as part of the Innovation Union 2020. In these partnerships, European Commissioners work together on platforms around policy, science and industry. The EIPs show similarities to our topsectors. The first EIP that is launched is on "Active and Healthy Ageing". The Netherlands does well in Europe The Netherlands is doing well in Europe because it has excellent national knowledge and public-private innovation infrastructures. With EUR 283 million from the seventh Framework Program allocated to Dutch participants (from the total of EUR 3.2 billion in the health theme allocated between 2007 and 2010), the Netherlands ranks fourth in the mobilization of European funds for life sciences research and has the highest perproject success rate. Dutch public and private parties participate heavily in the Innovative Medicines Initiative, a European platform for public-private partnership in pharma. The Netherlands hosts the European and Developing Countries Clinical Trials Partnership, a European Economic Interest Group that works on global health. Furthermore, the Netherlands is prominently involved in JPIs, ESFRI and in the first EIP that is closely linked to the Life Sciences & Health sector. Participation in Joint Programming Initiatives • JPND: Neurodegenerative diseases, in particular Alzheimer's, to advance progress on the scientific, medical and social levels • HDHL: A Healthy Diet for a Healthy Life, aimed at health and nutrition • MYBL: More Years Better Lives, focused on healthy ageing, increases in healthy life years through attention to health and performance, social systems and welfare, work and productivity, education and learning, and urban development and mobility • JPAMR: AntiMicrobial Resistance, focused on (re)emerging infectious diseases • AAL: an art 185 program in the field of Ambient Assisted Living "to enhance the quality of life of older adults through the use of ICT, whilst strengthening the European industrial base for products and services in this domain" Participation in ESFRI Roadmaps • BBMRI: biobanks • EATRIS: translational research (led by the Netherlands) • EuroBioImaging: medical/population imaging and advanced biological imaging • ECRIN: organization of RCTs (European Clinical Research Infrastructures Network) • ELIXIR: ICT/bioinformatics, biological information storage, management and processing • ISBE: Infrastructure for Systems Biology Europe • INSTRUCT: An Integrated Structural Biology Infrastructure for Europe • EU-OPENSCREEN: European Infrastructure of Open Screening Platforms for Chemical Biology Participation in European Innovation Partnership The EIP Active and Healthy Ageing (AHA) aims to speed up innovation. It is an umbrella for various JPIs and ESFRI initiatives involving European government and industry. Strategic and operational plans have been recently launched. NFU and ZonMw presented a joint position paper on AHA in Brussels, confirming our frontrunner position in this broad area. 6.4 Other innovation programs In addition to innovation programs in which the government has invested through a variety of grants, there are also public-private partnerships that are entirely financed by non-governmental partners. Examples can be found in health foundations and global

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health organizations. The Dutch Kidney Foundation (Nierstichting), for example, finances a public-private partnership, iNephron, for the development of an artificial kidney. Dutch health foundations invest a total of about EUR 160 million a year in research and innovation, and are crucial participants in the topsector's research and innovation infrastructure.

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Appendix A: Composition of the Regiegroep, taskforce and roadmap teams Composition of the Regiegroep • Rob van Leen – large industry, chair of the Regiegroep • Geert Blijham – university medical centers, medical practice • Clemens van Blitterswijk – scientist and entrepreneur • Jeroen van Breda Vriesman – health insurance • Fred Dom – small industry, entrepreneur • Henk van Houten – large industry • Paul Huijts – government • Len de Jong – small industry, entrepreneur • Eduard Klasen – university medical centers • René Kuijten – venture capital • Colja Laane – public-private partnership • Roland Lageveen – small industry, entrepreneur • Marcel Levi – public-private partnership, practitioner • Sijbolt Noorda – academia • Tom Oostrom – health foundation • Anton Pijpers – academia, veterinary • Joep Pluymen – large industry Composition of the Taskforce Roadmaps • Hans Stoof and Geert Blijham, chairs of the taskforce • Hans Hofstraat (Philips, medtech) • Rene Aerts (MSD Animal Health, human/veterinary) • Wim van Gelder (Danone, nutrition and health) • Richard Janssen (Galapagos, SME) • Ada Kruisbeek (DCPrime, SME) • Peter Bertens (Nefarma, industry associations) • Barry Egberts (Achmea, health insurance) • Peter van Dijken (TNO, biomedical innovations) • Peter Luijten (CTMM, imaging/diagnostics) • Matthijs Oudkerk (UMCG, imaging/healthcare) • Ton Rijnders (TI Pharma, (bio-)pharma) • Frank Baaijens (BMM, regenerative medicine) • Colja Laane (NGI, technology) • Hans Clevers (KNAW, biomedical research) • Edvard Beem (ZonMw, health research) • Wilbert van den Hout (LUMC, health economics) • Tom Oostrom (Nierstichting, health foundations) • Wilna Wind (NPCF, patient organizations) Disease area experts • Liesbeth de Vries (UMCG; breast cancer example) • Marc Bonten (UMCU; infectious diseases example) • Hans Bijlsma (UMCU; rheumatic disorders example) • Philip Scheltens (VUMC; dementia example) • Eric Sijbrands (Erasmus MC; diabetes example) • Bas Bloem (UMC St Radboud; Parkinson's disease example)

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The following government representatives have worked with this taskforce: • Pieter van Verloren van Themaat (Ministry of Economic Affairs, Agriculture and Innovation) • Roel Meeuwesse (Ministry of Economic Affairs, Agriculture and Innovation) • Menno Horning (Ministry of Economic Affairs, Agriculture and Innovation) • Frank Flier (Ministry of Health, Welfare and Sport) • Veronica van Nederveen (Ministry of Health, Welfare and Sport) • Jeannette Ridder-Numan (Ministry of Education, Culture and Science)

Composition of the roadmap teams Molecular diagnostics • Peter Luijten (CTMM) • Henk Vietor (Skyline Diagnostics) • Bastiaan de Leeuw (Noviogendix) • Youssef Khayali (Roche diagnostics) • Gerrit Meijer (VUmc/KWF) • Mat Daemen (AMC) • Pauline Evers (NKF) • Marcella Hallemeesch (ZonMw) • Anke Stekelenburg (STW) • Alain van Gool (TNO)

Imaging & image-guided therapies • Peter Luijten (CCTM) • Frank de Jong (FEI) • Hans Aerts (Philips) • John Lapre (Nucletron) • Frederik Barkhof (VUMC) • Matthijs Oudkerk (UMC Groningen) • Nick Guldemond (TU Delft) • Hans Stam (Hartstichting) • Piet Lommerse (STW) • Wouter Vaes (TNO) • Denijs Guijt (ZonMw)

Homecare & self-management • Hans Hofstraat (Philips) • Tom Oostrom (Nierstichting) • Andrea Nijhuis (Nierstichting) • Luc de Witte (CCTR) • Haske van Veenendaal (CBO) • Ronald Mooij (TNO) • Denijs Guijt (ZonMw) • Christiane Kloditz (NWO) In addition, a team of 22 persons from companies, research institutes, patient organizations, health insurers, health foundations and practitioners has contributed.

Regenerative medicine • Frank Baaijens (BMM) • Marc Hendriks (DSM) • Anja van de Stolpe (Philips) • Hans Clevers (Hubrecht) • Wouter Dhert (UMCU) • Ruud Bank (UMCG/NIRM) • Christine Mummery (CVON/LUMC) • Hans Stam (Hartstichting) • Jasper Boomker (Nierstichting) • Carine Stevens (Diabetes) • Marcella Hallemeesch (ZonMw) • Anke Stekelenburg (STW) • Roeland Hanemaajer (TNO)

Pharmacotherapy • Ton Rijnders (TI Pharma) • Mirjam Mol-Arts (MSD Oss) • Yvo Graus (GenMab) • Rudy Mareel (Synthon) • Ada Kruisbeek (DCPrime) • Aletta Kraneveld (Univ. Utrecht, chair FIGON) • Rob Leurs (VU A’dam) • Erik Frijlink (RuG) • Pieter Stolk/Bert Leufkens (CBGMEB, tbc)

One health • René Aerts (Merck Animal Health) • Johan Hanstede (Dutch Vaccin Group) • Theo Lam (GD – DGK) • Andre Bianchi (CVI) • Claire Boog (RIVM) • Dick Heederik (DGK) • Peter Hermans (Radboud) • Freek van Muiswinkel (DGK) • Anton Pijpers (Faculty of Veterinary Medicine)

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• • • • •

Lodewijk Ridderbos/mw Lether (Reumafonds) Pim de Boer (Astmafonds) Saco de Visser (ZonMw) Arlette Werner (CW) Peter van Dijken (TNO)

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Vincent Rijsman (Animal Sciences Group WUR) Martin Scholten (Animal Sciences Group WUR) Frank Schuren (TNO) Jaap Wagenaar (DGK) Eussen (Fidin) Herman Heuver (ZLTO) Toon van Hoof (ZLTO) Arno Vermeulen (Immunovalley) Miriam L’Herminez (ZonMw) Kirsten de Bruijn (NWO)

Specialized nutrition, health & disease • Wim van Gelder (Danone) • Wim Saris (DSM) • Hanno Cappon (Nutricia Medical Nutrition) • Aletta Kraneveld (UU) • Annemie Schols (NUTRIM, Maastricht UMC) • Jan Sikkema (Groningen UMC) • Lubbert Dijkhuizen (RUG) • Philip Scheltens (alzheimercentrum VU) • Bas Bloem (UMC St Radboud) • Aletta Kraneveld (FIGON) • Valesca Kuling (ZonMw) • Annemieke van der Kooij (ALW) • Ben van Ommen (TNO)

Health technology assessment & quality of life • Wilbert van den Hout (LUMC) • Barry Egberts(Achmea) • Marcel Verweij (Universiteit Utrecht) • Marianne Boenink (Universiteit Twente) • Carmen Dirksen (MUMC) • Ardine de Wit (RIVM/UMCU) • Kees van Bezooijen (patiënt) • Mechteld van den Beld (Revalidatiefonds) • Marco Blom (Alzheimer Nederland) • Lissy Terhell (ZonMw) • Marlies van de Meent (GW) • Paulien Bongers (TNO)

Enabling technologies & infrastructure • Colja Laane (NGI) • Jan Raaijmakers (GSK) • Hans Schikan (Prosensa) • Marcel van Tilborg (DSM) • Ruben Kok/Onno Bieleman (DTL) • Gert-Jan van Ommen (BBMRI) • Philip Scheltens/Ronald Stolk (Parelsnoer) • Ton Rijnders (TI Pharma) • Peter Luijten (CTMM) • Frank Baaijens (BMM) • Martien Groenen (WUR) • Marcella Hallemeesch (ZonMw) • Kirsten de Bruijn (ALW) • Jasper Diderich (NGI) • Cyrille Krul (TNO)

Global health • Richard Janssen (Galapagos) • Jay Iyer (TI Pharma/project euSEND) • Paul Klatser (Royal Tropical Institute/VU/UvA) • Marja Esveld (Ministry of Foreign Affairs) • Margreet Bloemers (ZonMw) • Eva Rijkers (Wotro) • Peter van Dijken (TNO)

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Appendix B: Letters of intent and support The table below summarizes the letters of intent and support that have been received from private and public organizations in the topsector Life Sciences & Health. Organization

Roadmaps of interest

PRIVATE PARTIES

Global health Enabling technologies & infrastructure (ET&I) Health technology assessment & quality of life (HTA&QoL) Specialized nutrition, health & disease (Spec Nutr, H&D) One health Pharmacotherapy (Pharma) Regenerative medicine (RM) Homecare & self-management (HomeC&SM) Imaging & image-guided therapies(Imaging&IT) Molecular diagnostics (MolDiag)

2M Engineering Limited AB SCIEX Netherlands BV Abbott BV Accenda BV Achmea Achmea - Zorg & Gezondheid Achmea - Zorg & Gezondheid AgendD AIMM Therapeutics BV Almende BV Amdix BV Amgen BV Andarr Technology Services BV Angita BV Arcadis Nederland BV ArjoHuntleigh Netherlands Arthrogen BV Artinis Medical Systems BV A-Skin Asolutions BV Astmafonds AstraZeneca

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Organization

Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

ATOS Avantor aXtion BV Biocomputing Platforms Ltd Oy BioFarmind BiOrion Technologies BV Biosenz BV BioVisible BV Bonstato BV Brevidius Brink& Bruker Nederland BV Cancer Clinic International Foundation Capgemini Nederland BV CardioGenx BV Care Visual Carintreggeland CellCoTec CheckTB MANGO Consult Chiralix BV ChiralVision Cinsol BV Consument en Veiligheid Coöperatie Integratie Huisartsenzorg Nijmegen e.o. (CIHN) Coöperatie VGZ UA CSI Service Curavista BV CURIT BV CyTuVax CZ Danone Research BV DC4U BV De Hart&Vaatgroep De ondernemende huisarts Deerns Raadgevende Ingenieurs BV Delft Prosthetics DELMIC BV Delta Phenomics BV Diabetes Fonds

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Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Diabetesvereniging Nederland DIGIFiT BV Digitalis Rx BV DIVA Delft Dolphys Medical BV Dr Jen BV Dr Oscar Schoots MBA Driehoek Research Support Drug Discovery Factory DSV Innovatie Dutch Association of Dietitians Dutch eHealth Foundation Dutch Gynaecological Oncology Group (DGOG) Dutch Society for the Replacement of Animal Testing, Proefdiervrij Dutch Society of Cardiovascular Nursing (NVHVV) Dutch Vaccines Group Dynomics BV Echo Pharmaceuticals BV EFARAM I Elsinga beleidsplanning en innovatie Ericsson ERIKS Aandrijftechniek Schoonhoven Eurofins Medinet EuroProxima BV Eurovet Animal Health Euvadis Evean Zorg Evident EvoCare BV ExpertDoc BV Federatie Textielbeheer Nederland FEI Company FIGON (The Netherlands Federation for Innovative Drug Research) Focus Cura Healthcare Innovation BV Foundation Zorg Binnen Bereik Fujifilm Manufacturing Europe BV Furore BV Future Diagnostics Fytagoras BV

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Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Galapagos Gameship GenDx Genmab BV Genos Ltd Gezondheidsdienst voor Dieren BV Gino Software BV GlaxoSmithKline BV GlycoCheck BV Glycostem Therapeutics Griffin discovieries BV HAL Allergy BV Hans Mak Instituut Hanzekliniek BV Harbour Antibodies BV Health Initiatives BV Health Management Research BV HealthNet Pro TPO Herrie.nu Het Roessingh - centrum voor revalidatie Huisartsenzorg Drenthe BV ICIT Solutions BV Immunaffect BV Immunoblock BV iMTA BV INAD Medical Software BV Indes Holding BV Innoser BV Innospense Innovative Medical Solutions Integraal Kankercentrum Nederland Integrex BV Intermax Managed Hosting IOTA Pharmaceuticals I-PADD BV IPPZ BV Ipse de Bruggen IQ Products BV IQ Therapeutics BV IS Diagnostics Ltd

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Organization

Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Janssen Research and Development Janssen-Cilag BV Jonker Verweij Instituut Julius Clinical Research BV Kenniscentrum voor Ketenzorg Chronische Ziekten KNCV Tuberculosis Foundation Kreatech Diagnostics KSYSOS TeleMedical Centre BV KWIC Healthcare BV Lavoisier BV LEAS, bureau voor zorgvernieuwing Life Clinic Europe LifetecZONe LIMIS-Institute LioniX BV Lysiac Macawi BV Masterplan Zorg voor de Toekomst (onderdeel van het Zorg Innovatie Forum) Maxima Medical Center McRoberts BV Mead Johnson & Co LLC Mead Johnson Nutrition Medical Center Leeuwarden Medicinfo Meditas BV Menzis Mercachem Merck BV Merck Serono Merial BV Metris BV Micreos Microbiome Ltd MILabs BV Miobile Keys Miscea BV MobiHealth BV Mobile Communications in Home Care BV ModiQuest Research BV & ModiQuest BV

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Organization

Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Mondriaan Motek Medical MSD Animal Health MSD Oss Mubio Holding BV Mucosis BV Musca Biotics (i.o.) Nano4therapy BV Nanohouse Nationaal Epilepsie Fonds Ncontrol BV Nederlandse Coeliakie Vereniging Nederlandse federatie van kankerpatientorganisaties NEN Medical Technology Netherlands Diabetes Federation Netherlands Society for Clinical Chemistry and Laboratory Medicine Newtricious R&D BV Nictiz Nierpatienten Vereniging Nederland Nierstichting NIGZ the Netherlands Institute for Health Promotion Nikon Instruments Europe BV NIPED NISB, Netherlands Institute of Sport and Physical Activity NIZO food research Noldus Information Technology BV Norma groep Notox BV Novartis Oncology NL NovioGendix Research BV NPCF (Federation of Patients and Consumer Organisations in the Netherlands) NRG Nutreco Nederland BV NVTAG (Nederlandse Vereniging voor Technology Assessment Gezondheidszorg) NVvR Radiological Society of the Netherlands Nyken BV OIM Orthopedie

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Organization

Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Okklo Life Sciences BV Ommelander Ziekenhuis Groep Optometristen Collectief Rijnmond Orbis medisch en zorgconcern Össur hf. Ostendum R&D BV PAL4 BV Pantarhei Bioscience BV Paradoxys Parnassia Bavo Groep Pepscape BV Pezy Group Pfizer Pfizer Animal Health Pharmatics Ltd Philips Consumer Lifestyle Philips Electronics Nederland BV PhytoGeniX BV Pluriomics BV PlusPort BV Podiceps BV Portavita BV Preselect Diagnostics BV Presence Displays BV Product board for Livestock and Meat Product Board for Poultry and Eggs Prosensa Psoriasis Vereniging Nederland (PVN) PwC Reden BV Relitech BV Remptation Reumapatientenbond Roche Diabetes Care Nederland Roche Nederland BV Roessingh Research and Development Rotterdam Community Solutions BV Royal DSM Royal Dutch Medical Association (KNMG) Sananet Care BV

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X X

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Organization

Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Sanofi Sanquin SANYO E&E Europe BV Saxenburgh Groep Schothorst Feed Research BV Self-Management Core Group Sense Observation Systems BV Sensire Sensor Partners SenzAir BV Simac HealthCare, dept of Simac Business Solutions BV Sogeti Nederland BV SOM (Stichting Opleiding Medici) Specs Sportstad Heerenveen BV Springer Media St. Sevagram Star - Medisch Diagnostisch Centrum Stichting 0.0 Stichting Dutch Collaborative Biobank Stichting Kind en Ziekenhuis Stichting Living Lab Stichting Maastricht Radiation Oncology (Maastro Clinic) Stichting Medische Diagnostiek Stichting MedtechPartners Stichting Parent2Parent Stichting Qualitiy Assurance Ehealth Stichting September/September Multimedia Stichting Zorg Innovatie Forum Stichting Zorgdraad StroekenAdviezen STZ Sylics Syncom BV TeleMetronics Biomedical BV The Royal Dutch Society for Physical Therapy (KNGF) Thermo Fisher Scientific BV TIGRA Beheer BV Timpaan Zorgconsult

X X X X X X X X X X X X X X X X X X X X X X X X X X

X X X X X X X X X X X X X X X

X X X X X

X X

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Organization

Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Topicus Zorg BV Toshiba TropiQ Health Sciences UbiQ Bio BV Umaco BV Unilever University Utrecht Holding BV en UMC Utrecht Holding BV USGT BV (i.o.) VanP&D Professional Development in de gezondheidszorg Variass Medical Systems BV Veenstra Instrumenten BV Veenstra-Glazenborg Vereniging van Ouders van Couveusekinderen VGZ ViciniVax BV VION Food Group Virtual Proteins BV Vita Care TMS BV VitalHealth Software BV VitalinQ Lifestyle Support BV Vitaphone Telemedicine VitaValley Vither Hyperthermia BV VSOP (Vereniging Samenwerkende Ouder- en Patienenorganisaties) VTEC Lasers & Sensors Waag Society Westburg BV WinBase Groep BV Winclove BV Woonzorg Nederland Xbrane Bioscience Yurii Aulchenko consulting ZF-Pharma BV Zorgbelang Fryslân Zorgbelang Groningen ZorgDomein Nederland BV Zorgpartners Friesland Zorgverzekeraars Nederland

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Organization

Roadmaps of interest

PUBLIC RESEARCH INSTITUTES

Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag ZuidOostZorg AIMMS (Amsterdam Institute for Molecules, Medicines and Systems) Alan Turing Institute Almere CBO CVI (The Central Veterinary Institute, part of Wageningen UR) CVI + WLR (The Central Veterinary Institute and Wageningen Lifestock Research, both part of Wageningen UR) Emma Children's Hospital-AMC Erasmus University Medical Center Rotterdam (ErasmusMC) Hogeschool Rotterdam Hogeschool Utrecht Hogeschool Utrecht, University of Applied Sciences Hogeschool van Arnhem en Nijmegen iBMG/Erasmus University Rotterdam Leiden University Medical Center and Leiden University Leyden Academy Maastricht University and Maastricht UMC+ Maastricht University Medical Center, dept. Medical Microbiology Netherlands Federation of University Medical Centers (NFU) Nijmegen School of Management NIVEL the Netherlands Institute for Health Services Research Radboud Reshape & Innovation Center Radboud University Nijmegen MC Radboud University Nijmegen, Faculty of Science Rijksinstituut voor Volksgezondheid en Milieu (RIVM) Rijksuniversiteit Groningen + Universitair Medisch Centrum Groningen Rijksuniversiteit Groningen RIKILT School of Sports and Nutrition, Amsterdam University of Applied Sciences SOMT Stenden Knowledge Centre Social Innovation SVGB Centre of expertise and education Syntens Innovatiecentrum

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Organization

Roadmaps of interest

OTHER

Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag The Abdominal Infections Research Group AMC The Academic Medical Center of the University of Amsterdam The Dutch HealthTec Academy The Royal Tropical Institute (KIT) TNO Trimbos Instituut TU Delft TU Eindhoven Twente University, dept Psychology, Health & Technology Universitair Medisch Centrum Groningen Universiteit Utrecht, Executive Board Universiteit Utrecht, Faculty of Sciences Universiteit Utrecht, Faculty of Social and Behavioral Sciences Universiteit Utrecht, Faculty of Veterinary Medicine University Medical Centre Utrecht University of Twente Vilans, Centre of Expertise for Long-term care VU Althena Institute VU NeuroScience Campus Amsterdam VU University Medical Center VU University Medical Center, Alzheimer Center Amsterdam VU University Medical Center, Department of Medical Microbiology & Infection Control Windesheim Flevoland University of Applied Sciences Windesheim University of Applied Sciences Zuyd Hogeschool Amsterdam Economic Board Amsterdam Innovation Motor and Amsterdam BioMed Cluster Brainport Development BV Carbohydrate Competence Center Centre for Care Technology Research (CCTR) CLIMB Consortium CSG Centre for Society and the Life Sciences Deltaplan Dementie Gemeente Enschede Health Valley

X X

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X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

X X X X

X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

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X X

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Organization

Roadmaps of interest Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Healthy Ageing Network Nothern Netherlands Institute for Evidence-based Medicine in Old Age IEMO Medical Delta Netherlands Toxicogenomics Centre (NTC) NeuroBasic PharmaPhenomics Ontwikkelingsmaatschappij Flevoland BV SPRINT (one of the IMDI-Centers of Research Excellence) Stichting Immuno Valley

X X X X X X X X X X

Number of times roadmap has been mentioned in letters

80 146 135 84 89 111 65 249 87 116

X X

X X X X X X X X X X X X X X X X X X X X X

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Organizations have signed the following letter of intent or letter of support.

To the Minister of Economic Affairs, Agriculture and Innovation, Mr. M.J.M. Verhagen To the Regiegroep Life Sciences & Health

[Date]

Letter of Intent for the participation in one or more roadmaps of the Life Sciences & Health topsector On behalf of [name organization] (from here called the “Organization”), I would like to express support for one or more of the roadmaps in the innovation contract of the Life Sciences and Health topsector, as indicated below. The Organization believes that these roadmaps support the international competitive position and growth of the topsector, and the development of health solutions that improve quality of life and the affordability and productivity of healthcare. The roadmaps of interest as indicated below are closely connected to the innovation activities and goals of the Organization and offer the Organization good opportunities to participate in public-private partnerships that may include industry, academia, health foundations, health insurers, patient organizations, healthcare providers, governments and other stakeholders. The roadmaps of interest to the Organization are: Roadmaps

Interest Roadmaps of interest are indicated with a cross (X) in this column

Molecular diagnostics Imaging & image-guided therapies Homecare & self-management Regenerative medicine Pharmacotherapy One health Specialized nutrition, health & disease Health technology assessment & quality of life Enabling technologies & infrastructure Global health, emerging diseases in emerging markets The Organization intends to invest in public-private partnership in the roadmaps of interest for an amount of [amount] euro per year between 2012 and [year]. This intended investment can be in kind and/or in cash. The Organization has the right to reconsider stated intentions if:

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• • • •

the activities of the roadmaps turn out to be insufficiently connected to the goals of the Organization agreement cannot be reached with other parties about the details of partnership, including intellectual property rights the public-private partnership that the Organization intends to invest in does not obtain sufficient investment from the Dutch government changes in the economic climate, the Organization’s financial situation, strategy or focal business areas, or any other situation would necessitate the Organization to reconsider intentions, to be determined by the Organization in its sole discretion

The Organization trusts that the Dutch government also recognizes the importance of these roadmaps and thus invests in the realization of public-private partnership in this area. Yours faithfully, [Name] [Function] [Organization]

To the Minister of Economic Affairs, Agriculture and Innovation, Mr. M.J.M. Verhagen To the Regiegroep Life Sciences & Health

[Date]

Letter of Support for one or more roadmaps of the Life Sciences & Health topsector On behalf of [name organization] (from here called the “Organization”), I would like to express support for one or more of the roadmaps in the innovation contract of the Life Sciences and Health topsector, as indicated below. The Organization believes that these roadmaps support the international competitive position and growth of the topsector, and the development of health solutions that improve quality of life and the affordability and productivity of healthcare. The roadmaps of interest as indicated below are closely connected to the innovation activities and goals of the Organization and offer the Organization good opportunities to participate in public-private partnerships that may include industry, academia, health foundations, health insurers, patient organizations, healthcare providers, governments and other stakeholders. The roadmaps of interest to the Organization are: Roadmaps

Interest Roadmaps of interest are indicated with a cross (X) in this column

Molecular diagnostics Imaging & image-guided therapies

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Homecare & self-management Regenerative medicine Pharmacotherapy One health Specialized nutrition, health & disease Health technology assessment & quality of life Enabling technologies & infrastructure Global health, emerging diseases in emerging markets The Organization trusts that the Dutch government also recognizes the importance of these roadmaps and thus invests in the realization of public-private partnership in this area. Yours faithfully, [Name] [Function] [Organization]

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Appendix C: Inventory of new and ongoing public-private partnerships The table below provides the results of an inventory of new and ongoing public-private partnerships in the topsector Life Sciences & Health. The table is not exhaustive. More details on these partnerships are available. Name of partnership

Roadmaps of which it is part Global health Enabling technologies & infrastructure (ET&I) Health technology assessment & quality of life (HTA&QoL) Specialized nutrition, health & disease (Spec Nutr, H&D) One health Pharmacotherapy (Pharma) Regenerative medicine (RM) Homecare & self-management (HomeC&SM) Imaging & image-guided therapies(Imaging&IT) Molecular diagnostics (MolDiag)

Aposense project Chlamydia subfertility diagnostics CTMM-LeARN Demyeliserende aandoeningen Dierproeven Begrensd Diverse samenwerkingen 1 op 1 tussen RUNMC Exploring possibilities for patient involvement in translational molecular medicine: dialogue as a means to enhance ethical reflection Ispro Lying awake of insomnia MARS Neurodegeneratieve aandoeningen On Time One Day Diagnostics© for metabolic diseases Ontwikkeling van diagnostiek en therapie van (cholestatische) jeuk Optical mapping bacterial genomes Opzetten van een HTS faciliteit op Nijmeegse campus Patiëntenregistratie Hematologie en Patiëntenregistratie niercelkanker

X X X X X X X X X X X X X X X

X X

X X X X X X X X

X X X

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Regiegroep Life Sciences & Health

Name of partnership

Roadmaps of which it is part Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Pilotmodule "Ethical and social aspects of translational X molecular medicine" The effect of PTCA on biomarkers X Valorisatie moleculaire testen X 1-DaTE X 4DCT X AAA perfect X Brain Image Analysis X BrainGain X X Breast Density Risk Assessment X CAD Chest Radiography X CAD Diabetic Retinopathy X CAD4TB X Carisma: Cardiovascular Risk Management by X X Advanced Medical Image Analysis Care4Me – Cooperative Advanced REsearch for X Medical Efficiency Care4Me ITEA2 Project X COPD phenotyping and treatment selection X DETACT - High Risk Psychose X Developing new imaging biomarkers X DNP X Early lung cancer detection with chest CT X Endoliner X EXACTA X FPGA image analysis X HAMAM X Hidden Health X Holland PTC X Image-Guided Surgery Network Netherlands (IGS-NL) X IMDI-CMI-nen X IMDI-IDII X IMDI-MDII X IMDI-NIMIT X IMDI-QuantiVision X Improved carotid imaging X IOP Photonics X KWF PROG Subsidie X Mammography CAD X Mediate - Patient Friendly Medical Intervention X

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Name of partnership

Roadmaps of which it is part Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Mediate4Me ITEA2 project Medical Delta Operatiekamer v/d toekomst & Imaging Lab Miniman MIRIAM MR prostate HIFU MRS acquisition & processing Multiterm Needle Guidance Neuromodulation NGE Ecoil Nutrient supplementation in Alzheimer One Day Diagnosis and Treatment Environment ParisK – The Assessment of the Plaque At RISK by non-invasive (molecular) PARticle therapy Research Center (PARTREC) PCaMAP PIDON Arthur PIDON Endovascular repair Population imaging Infrastructure in the Netherlands (EPI): an node of EUROBioimaging PREDICCT RV Segmentation Single Point Imaging SOLO Spinoza Super-resolution microscopy (“Nanoscopy”): from sharp images towards imaging of molecular interaction STW OTP project Syngo.Via TMS Toshiba Ultrasound Towards an appropriate societal embedding of neuroimaging U-LONO IOP Photonics Ultrasense Visualase Acuut en chronisch darmfalen in een poliklinische setting en thuiszorg

X X X X X X X X X X X X X X X X X X

X X X X X X X X X X X X X X X X X

176

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Name of partnership

Roadmaps of which it is part Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

ADMIRE & PERISCOPE: eHealth based zelfmanagement en telemonitoring supportsysteem, incl homebased medical devices Aliz-E Ashley / ePartner Astma Fonds, Astra Zenica, Achmea Beter Samen In Noord BrainGain Breath Coöperatie Slimmer Leven 2020 Delft Health Initiative ‘proeftuin zorg & techniek’ Digeketen Breda Digicoach Disseminatie van farmaceutische innovaties Domotica en zorgtechnologie voor thuiswonende cliënten Draagbare Kunstnier Duurzame implementatie Ehealth Noord Nederland eAsi Easycare / Zorg- en WelzijnsInfoPas / Care well (ZWS) eCoach ter ondersteuning van gecombineerde leefstijl interventies E-health en logopedische interventie E-Health in COPD zorg E-HealthNu Eolus EU-GEI E-works Parnassia Bavogroep Expertise Center Zorg en Technologie Brainport Gemeente Rotterdam Happy Walker Health Bridge Health-Lab Het ziekenhuis van de toekomst. Ontwerp van een helende ziekenhuisomgeving (HEZO) Home is where the heart is ICT zelfmanagement behandelingen voor patiënten met somatische aandoeningen iKOP, Internationale kenniscirculatie, Onderzoek- en Praktijkuitwisseling e-Health IMDI-CCTR

X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

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Name of partnership

Roadmaps of which it is part Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

IMDI-NeuroControl IMDI-SPRINT Implementatie EASYcare en Ouderen netwerken Implementatie van programma van eisen t.a.v. zelfmanagement in de ICT systemen van de eerstelijns fysiotherapie Innovatieprogramma kwetsbare ouderen Innovatieve zoutreductie Investing and Stimulating long Term walking activity in stroke (SUSTAIN) InZicht iVitality Kerngroep Zelfmanagement KSYOS TeleMedicine Living Lab Limburg (LLL) Living Lab voor Zorginnovaties Lying Awake of Insomnia Mantelzorgplaats Medical Delta Centrum voor bewegen & leefstijl Medicinfo - Mijn gezondheidsplatform Mobiele digitale ondersteuning Multilab Chip NeurasBus for home-patient research On Time Ontwikkeling instrumenten voor selectie, implementatie, evaluatie en bekostiging/exploitatie van zorgvernieuwingen Ontwikkeling internationale diabetes zelfzorg vragenlijst PAL4, Persoonlijke Assistent voor het Leven PatiëntCoach: Ondersteuning van zelfmanagement middels e-health PAZIO Pelikaan Portal Mijnnierinzicht Predictors voor gebruik van e-Health door ouderen en professionals in de Zorg (PETZ) Pre-operatief functioneel van trainen van ouderen in de thuissituatie Rationalisatie van zorginnovatie in de ggz Revalidatieonderzoek RijnCoepel

X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

178

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Name of partnership

Roadmaps of which it is part Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Robocom Rosetta SAAS zelfmanagement portal voor het versterken van de mentale gezondheid Signaleren van valrisico met behulp van de Philips Lifeline valalarmering Smart ICT for well being @home and @work SmartCoaching Spectrum Programma Speech and Hearing Technology Suikerplein Ouders TechnoCare: centre of expertise op het terrein van zorginnovatie en technologie TELECOPD Transparante fysiotherapie in achterstandswijken (TransFysA) UCCI Vitale Vechtdal VoedingsKompas WeCare ZATO Vallen en Dwalen Zelfmanagement voor Reumapatiënten Zorg Binnen Bereik, Research Program Interactive Care Platform Zorg op afstand bij Espria Artificial gametes: dynamics and ethics BARBAPAPA Biomaterials as biosynthetichybrids: assessing the prospects of synthetic biology for therapy and enhancement BMM consortium Biokid BMM consortium BONE-IP BMM consortium Trammpolin Calgel KNAW-PSA Molecular target finding for Parkinson and Alzheimer disease Nieuw experimenteel vaccin voor behandeling van Alzheimer patiënten NIRM work package Bioinspired materials NovioTissue Ontwikkeling van gentherapie voor neurotrauma

X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

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Name of partnership

Roadmaps of which it is part Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

SpheRepair Stimuleren van lichaamseigen stamcellen TeRM Development of vanin inhibitors E-consulting Eetgedrag en verslaving Endotheelfunctie en TNF-alfa inhibitie EU-AIMS Humane antilichamen tegen infectieziekten, kanker en autoimmuun ziekten In vitro skin models for drug testing Insulin like drug for treatment of non-alcoholic steatitis Kinase remmers voor kanker bij kinderen Life Sciences park Oss Lokale gentherapie voor reumatoïde artritis Molecular and cellular mechanisms of drug influx transporters (A08-0586) Namisol-studie Nanoscience as a tool for improving bioavailability and BBB penetration of CNS drugs (T5-105) NeuroSIPE Northern Drug Targeting and Delivery cluster (NDTDC) Nutrients to modulate obesity-associated brain inflammation The human microbiome as a target for therapy TI Pharma follow up Towards novel translational safety biomarkers for adverse drug toxicity (D3-201) Translational Pharmacogenetics Zeldzame ziekten en het bedrijfsleven (BioFarmind) ALTANT ARTEMIS CASTELLUM onderzoeksprogramma en nieuwbouw nationale hBSL faculteit CTMM AMVACS, MARS, Tracer gericht op inf. Ziekten en vaccins Emerging disease campus i-Boost LA-screen Multiflex PneumoProtect, IOP Genomics

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Name of partnership

Roadmaps of which it is part Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Pneumovac, internationaal innoveren-opkomende markten TI Pharma (Leishamnia, TBC, Malaria, MRSA, Chikungunya) Vaccin competence Centre (unit vaccinoplogie RIVM) VIRGO Zoönosen expertise centrum Efficacy of dopamine receptor agonists L-Dopa and Nutrition MRS studie Platform technologies and expectation management Bio-CAPTURE: continuous assessment of psoriasis treatment use registry with biologics Databases neuromusculaire aandoeningen, CRAMP, TREAT-NMD Doelmatigheidsonderzoek duch*enne EMSCI Health economic evaluation and transferability Pro- en ortheseologie, CVA Rationalisatie van zorginnovatie in de ggz Animal MDMT Brain-Machine interfacing through WhisKid Center for Advanced Bioresource Services (CABS) Cerebrospinal fluid biobank DREAM registry Dutch Collaborative Biobank E-Brain Erasmus ladder Eugenda HeBot ICT for Brain, Body & Behavior (i3B) Instruct-NL Mouse Clinic for Cancer and Aging Research (MCCA) Neurochirurgische technologie NPO-LDB Prism RAMP SheBot Spike Train European Vaccine Initiative (EVI)/Euvadis

X X

X X X

X X X X

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Name of partnership

Roadmaps of which it is part Global health ET&I HTA&QoL Spec Nutr, H&D One health Pharma RM HomeC&SM Imaging&IT MolDiag

Malaria Drug Development Malaria GAP vaccins Malaria PF10C vaccins Platform technologies and expectation managment TI Pharma Neglected Disease portfolio "euSEND"

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Appendix D: Participants in public-private partnerships The table below lists participants in new and ongoing public-private partnerships in the topsector Life Sciences & Health. The list is not exhaustive. Life Sciences & Health companies 2M engineering aap bioImplants Netherlands BV AB SCIEX Netherlands BV Abakus Abbott Ablynx NV Absea Biotechnology Ltd Acetelion Pharmaceuticals

Dionex Benelux BV Dolphys Medical BV Dorc DoubleSense BV DSM Biomedical Materials BV DSM Dyneema BV DSM Food Specialties DSM Resolve

Luminostix BV

Maastricht R2Pro Instruments MagnaMedics Raam Fysio Diagnostics BV Mallinckrodt Medical Rabobank BV Radboud Reshape Materiomics BV Innovation Centre Maxon motor Realive Isolectra McRoberts, Den Rijk Zwaan Haag River Diagnostics MdxHealth BV Roche Nederland Med-Engineers BV BV MeDaVinci HealthRogan Delft care Services BV Medical Europe BV Rotterdam CS

ACS Biomarker BV

DSM Solutions

Actelion

DSV Innovatie

Adaptive Planet

Duodecim

Adesys/Livind

Durea

Adimec Advanced Bionics LLC

E.M.C.M. BV

Medical Field Lab BV medicinfo

Eaton

Mediconsult

Advanced Neuro Technology Agamyxis BV Agendia BV

Eemagine Medical Imaging Solutrions GmbH Elekta Ltd, Elektronikmekanik AB

QVQ BV i.o.

Medimate BV

RQ Sports&Health Concepts RRD RSscan International Saint Joseph's Translational Research Institute Saltro

Medipark BV

Sananet Care BV

Medifactory

AIMM Therapeutics BV ALMA IT Systems

Medis medical imaging systems bv Embedded Systems MediShield

Almende

EMCM BV

Meditas, Drachten

Encapson BV

Medtronic

Endo Control

Mercachem

SANYO E&E Europe Sapiens Scalene Cybernetics Ltd Scientific Volume Imaging BV Semantoya

Enraf Nonius

Merck Serono

Sendandsee Ltd

Ericsson

MeVis

Sense IT BV

Amarna Therapeutics Ambient Systems, Ambroise, Enschede Amgen

Eli Lilly

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Amsterdam Cardiovascular Therapeutics BV io Amsterdam Scientific Instruments

Erres grupo de comunicación hipermedia

Mextal

Sense OS

Esaote Europe BV

MHC+ BV

Sensor Universe

AMT

ESV

MI Labs

Ansys

Euro-Diagnostics

Microbiome

Antibodies for Research Applications BV (ARA)

EuroBioImaging

Microcandela BV i.o. ServiceXS BV

Eurocept BV

Microline

Sevagram

SensorTagSolutions BV Serious Toys

Applied Maths NV Araim Pharmaceuticals, Inc. Arbo Unie Arcarios BV

Europroxima BV

Microscan BV

ShareCare

Evalan Evocare

Microsoft MiLabs

Siemens Nederland Signifix

Aris

Exact Dynamics

Minddistrict

Silenti Solutions

Aritinis Medical systems BV Arthrogen BV Artinis Medical Systems BV Asimotion

FABPulous BV

Minimotor Benelux BV Miscea afd. R&D

Simac

FEI Company BV

MMS BV

Simendo BV

Feyecon Development & Implementation BV

MobiHealth BV

Singular Romania Computer Appl. SRL

Expand BV

Silverfit afd. R&D

Fietsenmakers Product Developers Fifthplay FlexGen BV

Modiquest BV

Sioux

MOOG BV Morphyosis

Skyline Diagnostics Smarthomes

FLIR

Motek Medical BV

Smith and Nephew

Astra Zeneca

Focal Meditech

Motion Control AB

SolMateS BV

ATOS Origin

ForceLink BV

Motion Projects, Utrecht

Solvay Pharmaceuticals

AtosOrigin Consultancy, Utrecht

Forensic Technologies BV io

MRC Holland BV

Sonosite

Avantes BV

Fortimedix BV

MSD

Avics

Fraunhofer Mevis

Mubio BV

aXion, Groningen

Ft Innovations BV

Nanodialysis

ASkin Nederland Asolutions BV Assistobot Astellas Pharma Europe BV

Spinnovation Analytical BV Ssens BV St Jude Medical Coordination Center BVBA

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Axis media ontwerpers BV

FUJIFILM Manufacturing Europe BV

Nanomi BV

Stichting Daelzicht

Axle International BV

Furore BV

NCB Naturalis

Storz

Ayton BV

Future Diagnostics

Nefarma

Stryker

Galapagos

Netherlands Translational STT, Tolbert Research Center BV (NTRC)

Baat Engineering, Hengelo BAC BV Bactimm BV Bakken Research Center (Medtronic)

General Electric HC GenMab Genome Diagnostics BV Genus Biotech Barcelona Digital SA Corporation Barco Genzyme Nederland Baxter GeWa Bayer Healthcare GlaxoSmithKline Beckman Coulter Glycostem Nederland BV Therapeutics Becton Dickinson BV (BD Biosciences) bedrijvenkring Lelystad Bedrijvennetwerk Innovlerend BeeldzorgAdvies

Neurasmus BV SupraPolix BV New Compliance BV Surgiqual Institute NewCom, Opende

SurgOptix BV

NICE Software BV

SyMO-Chem BV

Nikon NIPED NN Nobilon International BV

Synapse BV Syncom BV Synns Syntens

Graanpletterij De Halm BV

Nokia

Synvolux Therapeutics

Grendel Games

Noldus IT BV

Technobis Group BV

Noppe

Technolution

NOTOX BV

TEFA

Groene Kruis Domicura Guerbet Nederland BV

Bender Analytical Holding BV BG Medicine Biocartis Biocartis BV BioClinica BioComp Industries bv

H. Lundbeck A/S

Novartis BV

Tegema

Handicare BV Hankamp Gears Hans Mak Instituut Hansen medical

Novay NovioGendix NovioTech Novirun BV

Haption

Nucletron

Telefónica SAE TEMEC Instruments Terarecon Inc TEVA Thales Research & Technology NL

BioConnection BV

Harbour Antibodies BV

Nycomed

The factor e

Biodetection Systems

Healthcare over Internet Protocol Company

Nyken BV

The Hygenic Corporation

Biofocus BV

HemoLab

O2View BV

Biogen Idec

Ocean Optics

Theraband Academy Therenva

185

Regiegroep Life Sciences & Health

BioMaDe Groningen

Hycult Biotechnology BV i-Optics BV

OIM Orthopedie, Assen Okotech

ThermoFisher Scientific TiViPE

Biomet BiOrion Technologies BV BioTxs

I+

Oldelft

TKH Group NV

IBM Nederland BV

TMS International

Biqualys BV

ico-Metrix

Blanxx bmc advies

IDquest bv IDretailpartners Image Analysis Center Imaging Rheumatology BV

Olympus Oncomethylome Sciences BV ONO Pharma Optimum BV io Orbis Medisch Centrum Orbus Neich Medical BV

Bonstato BV Booz en Co

TMSi ToBBB TomTec Topic Embedded Systems BV Toshiba Med Syst Europe BV Trajectum Pharma BV

Boston Scientific Inc IMDS, Roden

Orca Therapeutics

Bracco Research SA

Immunetrics Inc.

Brainlab

Immunomedics BV

OrgaNext Research Tripel-OZ BV Oroboros Triskel Therapeutics Instruments GmbH b.v

Braintronics

Imotec

Össur, Son en Breugel, Reyjavik (IJsland)

Tubascan

Branching Tree BV

Imtech

OSTENDUM R&D BV

Tulser

Incubation Center Yes Delft

Otto Bock Benelux BV

Tunstall

Indes

OvQ BV

U-protein Express BV

Pamgene

UCB Pharma BV

PCI Biotech AS

Umaco, Groningen

PDEngineers

Unitron BV

Pep Tx Inc.

Use-lab GmbH Van Aarle De Laat Gezondheidszorg Van Berlo Van de Geijn Partners Van Leeuwen Internationaal VanP&D Professional Development in de gezondheidszorg

Brevidius CrossMedia Projecten BV Bristol - Meyers Squibb BV Bruker Nederland BV Bull SAS Bureauvijftig

Inertia Technology BV InfraReDx InGell Labs BV (Branching Tree BV) Inmote

BV Cyclotron VU CAM Bioceramics BV Cap Gemini

INN

Pepscan Presto BV

InnoCore BV

Peptx

Cardialysis

Innospence

Percuros BV

CareFusion

Innotronic GmbH

Personal Space Technologies

CareVisual

INNOVITING

Peters Metaalbewerking BV, Wanroij

186

Regiegroep Life Sciences & Health

Pezy

Variass

Cavadis

Inpaqt Business Solutions BV Inroads

Pfizer

CEA List

Institut Telecom

PharmaCell BV

Vaxinostics Verathon Medical Europe BV

Carintreggeland

CED Cedrat CellCoTec BV

Intelligent Developments Ltd Interface Biomaterials inteRNA Technologies BV

CellMed AG

Intespring

Cellution BV

Intramet BV

Celsion Corporation IOTA Centocor Centre for Human Drug Research BV Checkpoints Chipsoft

IPD Therapeutics BV IPPZ BV Ipsen Ipsen Farmaceutica BV

ChrisFit

IQ Corporation BV

CIBEK

IQ Products

CIMNE Circle Cardiovascular Imaging

iRx Reminder LLC

Cofely Coherent Europe BV Compass Ing. Sistemas Controllab Products BV Covidien Cristal Delivery Crosslinks

IS Diagnostics

Pharmapartners

Verklizan BV

Pharmeon

Vertex

Pharming Technologies BV PHI: Personal Health Institute International Philips Philips Applied Technologies Philips Consumer Lifestyle Philips Electronica Nederland BV Philips Healthcare

ViNotion VION Food Nederland

Philips Lighting

VisEn Medical BV

Philips Medical Systems Philips New Wellness Solutions Philips Research Philips Robots in remote surgery

ISA Photonics Pharmaceuticals BV Healthcare BV ISA Therapeutics Pie Medical BV ISI iThera Medical Jalaco Jansen Pharmaceutical Johnson & Johnson PRD

PiEXT

Vicar Vision Vicinivax Groningen

Viroclinics Virosome Biologicals BV Virtual Proteins BV

Visual Sonics BV Vita Care Vital Health Vital Images Vitalis, Drachten VitaValley Vivomicx BV Groningen

PinkRoccade Healtcare Pluriomics BV

Volcano

Plusport BV

VSL

Pohjola Insurance

VTT

Cruden

JoyinCare BV

PolyGanics BV

Curatec BV

Kite

PolyVation BV

Vodafone

W&H Dentalwerk Burmoos GmBH Waag Society

187

Regiegroep Life Sciences & Health

CuraTrial BV

Koraal Groep

PR Sys Design

Cyclotron BV

KPN Zorg

PRA International

D&L Graphics VOF

Kreatech Biotechnology BV

Prescient

WINAp

Da Vinci Europe bv

L.M. Meijers BV/Meijers Fit & Gezond

Preselect Diagnostics BV

Wingz

PresenceDisplays

WinVision

Danone Research, Centre for Lacquey BV Specialised Nutrition DAXX software Daza Opticare DCPrime

Lantheus Medical Priva Imaging Laser 2000 Benelux Probotics BV Lavoisier, Prodrive Groningen

Westburg BV Wieslab/EuroDiagnostica ABDB

Wyeth Pharmaceuticals BV Xendo Drug Development BV Xivent

De Koningh Medical Lead Pharma Systems BV

Progenica SA

DEAM

Leica

Progenika

Delft Diagnostic Imaging

LiCor Bioscience

Promedico

Ytec Imaging BV

Prosensa

ZF-screens BV

Proteion

Zibber

Little Chicken

PROXY Laboratories BV

ZioSoft

Live

Purac Biomaterials

Lode

PWC

Logic Data BV

QTIS/e BV

Logica Healthcare

Quo Vadis

LogiMedical

Quress Rijnland BV

Delft Prosthetics Delphys Demcon Development Laboratories UA Dexter Medical DiagnOptics Technologies BV Dialoc ID BV DigiFit

Life Sciences Park Oss Limagrain Nederland BV

Xpand Biotechnology BV Xsens Technologies BV

Zirbus Tech Benelux BV ZOFIEZO Zorgdomein Nederland BV ZorgGemak BV Zorgnmarktadvies BV

Digisens Academic and applied research institutes & initiatives (public & private) AMC Amsterdam

In-HAM

Netherlands Institute St. Maartenskliniek for Neuroscience

BBRMI-NL/NBIC

INRIA

Netherlands Metabolomics Centre

Technische Universiteit Delft

188

Regiegroep Life Sciences & Health

Brain Science Tools BV Institute for Pig (www.brainsciencet Genetics BV ools.com)

Netherlands Organization for Applied Scientific Research

Technische Universiteit Eindhoven

Center for Human Drug Research

Interuniversity Cardiology Institute of the Netherlands

Netherlands Proteomics Centre

Technische Universiteit Twente

Centre for Genome Diagnostics

Julius Centre UMCU

Netherlands Vaccine Institute

TNO

Centre for Society and the Life Sciences

Kenniscentrum Ketenzorg Zwolle

NIGZ

Trimbos-instituut

LEI/WUR

NIKHEF

UMC Groningen

LUMC

NKI

UMC St Radboud

Maastricht UMC

NIN

UMC Utrecht

MC Haaglanden

NIPED

Univeristeit Utrecht

Noordelijke Hogeschool Leeuwarden

Universiteit Leiden

Consument en Veiligheid CVSS Radiologia Clinica CWI Donders Institute Nijmegen

Drugs for Neglected Medicines Diseases Initiative Evaluation Board Erasmus Medisch Centrum

Nationaal Kennis Centrum Alternatieven voor Dierproeven

NOVAY

Universiteit Maastricht

Espria

National Initiative Brain & Cognition

Plant Research International

Universiteit van Amsterdam

Fontys Hogeschool

Nederlands Huisartsen Genootschap

PSI

Universiteit van Tilburg

Fraunhofer

Nederlands Kanker Instituut (NKI)

Radboud Universiteit Nijmegen

VGZ

GH Zwolle

Nederlands NeuroImaging Netwerk

Rijksuniversiteit Groningen

Vilans

Hanze Hogeschool

Netherlands Centre for Bioinformatics

RIVM

Vrije Universiteit Amsterdam

Hogeschool Rotterdam

Netherlands Centre for Electron Nanoscopy (NeCEN)

ROC Eindhoven

VU Medisch Centrum

Hospital Sant Pau

Netherlands Centre Royal Tropical for Systems Biology Institute Rudolf Magnus Netherlands Instituut voor Consortium for NeurowetenHealthy Aging schappen

Wageningen University Yulius Academie

189

Regiegroep Life Sciences & Health

Netherlands eScienceCenter

Hubrecht Institute

Sanquin

Zuyd Hogeschool

IBBT (Health) foundations and patient organizations ALS Stichting

Hart & Vaatgroep

Nierpatiënten vereniging Diavaria

Reumapatientenbond (RPB)

ANBO

Hartstichting

Nierpatienten Vereniging Nederland

Steunpunt Informele Zorg Breda

Hersenstichting

Nierstichting Nederland

Volwassenen, Kinderen en Stofwisselingsziekten (VKS)

Huis van de Zorg

NPCF

VSOP

LCM

NPV Parkinson Vereniging

WKK

Astma Fonds (binnenkort Long Fonds) Clientenbelang Utrecht Diabetesfonds Diabetes Vereniging Nederland duch*enne parent project

LP GGZ

Mantelzorgmakelaar PGGM

Zorgbelang

Psoriasis Vereniging Zorgbelang Drenthe Nederland (PVN)

Epilepsie Vereniging Metakids Fundacion Robotiker

ZonMw

Nederlandse Reuma Fonds Coeliakie Vereniging

Zorgbelang NoordHolland

Health insurers Achmea

DSW

Agis

De Friesland

LCM

ONVZ SNS Real/Proteq/Zelf.nl

Other Fysiotherapiepraktijk Albert Sweiterschool Maatschap BredaHaarlem Fysiotherapie Fysiotherapiepraktijk Paramedisch Amnitrans Eyebank Centrum Heusdenhout Fysiotherapiepraktijk Praktijk voor Fysiotherapie, Amphia Ziekenhuis Manuele Therapie, Breda Kinderfysiotherapie K. van Gurp - J. Mertens

Huisartspraktijk: de heer Drs. R. Roothans, Breda.

Provincie Flevoland

Indigo

Provincie NoordBrabant

Isala Klinieken

Provincie Utrecht

ANBO

KNGF

Provincie ZuidHolland

GEEF

190

Regiegroep Life Sciences & Health

Arcus College

Gemeente Breda

ASIS Benelux, DHL

Gemeente Delft

Betrouwbare Bron

Gemeente Enschede

Brabantse Ontwikkelings Maatschappij Brainport Development NV Careyn Thuizorg Centraal Veterinair Instituuut Centrum Huisartsen Schiedam Charis Huisartsengroep Coronelschool Amsterdam De Wever Diakonessenhuis Utrecht

Gemeente Hardenberg

Leeuwenborgh College

Raad voor de Rechtspraak. Revalidatie Leidse Rijn Julius Friesland, Gezondheids-centra Leeuwarden Lentis (GGZ RIBW Midden Groningen en PsyQ) Brabant Roessingh Libertas Revalidatie, Enschede

Gemeente Heerlen

LIOF

Saxenburgh Groep

Gemeente Leiden Gemeente Maastricht Gemeente Rotterdam

Logius Maartenskliniek, Nijmegen

St Jozefoord

Maasduinen

St. Zorgdraad

Gemeente Utrecht

Mediportaal

Stichting Daelzicht

St. September

Gezondheids-centra Mentalshare Maarsenbroek GGZ Breburg Mezzo

Surplus welzijn

Gilde Opleidingen

Mondriaan

SWO Radius

MRC, Doorn

Vitazorg

NHG

WIJ Breda

Stichting Saltro

Dutch Collaborative Biobank

Groene Hart Ziekenhuis Groene Kruis Domicura

Dutch Health Hub

HANNN

Nictiz

Espria Forensisch Psychiatrisch Centrum De Rooyse Wissel en Ottho Gerhard Heldringstichting Fysiotherapiepraktijk Breda West Paramedisch Centrum Fysiotherapiepraktijk Doornbos Fysiogroep

Happy

Ons Doel

Woonzorg Nederland Yulius GGZ

Het Bolwerk Franeker

Politie AmsterdamAmstelland

Zorg Innovatie Forum

Huisartsen-centrum Dokkum

Portavita

Zorggroep Drenthe

Dürrer Centrum

Huisartsencentrum Huizen

191

[PDF] Innovation contract 2012 from the topsector Life Sciences & Health - Free Download PDF (2024)

References