STOA workshop Innovative solutions for research in healthcare Participants’ booklet
EPRS | European Parliamentary Research Service Scientific Foresight Unit (STOA) PE 624.276 – January 2019
STOA Workshop
INNOVATIVE SOLUTIONS FOR RESEARCH IN HEALTHCARE
Developing novel approach to deliver better precision medicine in Europe
Participants’ Booklet
10 January 2019, 9:30-12:30 Altiero Spinelli building, room 5E2 European Parliament, Brussels
1 Prepared by Gianluca Quaglio and Riccardo Molinari, STOA Secretariat.
Available at: http://www.europarl.europa.eu/stoa/en/events/upcoming/20181002WKS01941/innovative- solutions-for-research-in-hea
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2 Table of Contents
1. Programme 5
2. Introduction 7
3. About EORTC 13
4. Welcome
4.1. Paul RÜBIG, MEP and STOA First Vice-Chair...... 15
5. Key note speech
5.1. Maggie DE BLOCK, Belgian Minister for Social Affairs, Public Health and Asylum and Migration ...... 16
6. Moderator Session II
6.1. Pierfranco CONTE, University of Padua Italy...... 18
7. Speakers Session II
7.1. Richard SULLIVAN, King’s College London, UK...... 21
7.2. Denis LECOMBE, EORTC...... 22
7.3. Magda CHLEBUS, EFPIA...... 24
7.4. Ewan BIRNEY, EMBL-EBI ...... 26
8. Moderator Session II
8.1. Guy BRUSSELLE, Ghent University, Belgium ...... 29
9. Speakers Session II
9.1. Guido RASI, EMA ...... 32
9.2. Wim GOETTSCH, University of Utrecht, the Netherlands...... 34
9.3. Jean- Yves BLAY, Centre Léon Bérard, Lyon, France ...... 36
9.4. Mathieu BOUDES, EPF...... 38
10. Manifesto for new approach for better medicine in Europe 39
3 11. About STOA
11.1. Mission ...... 42
11.2. Administration...... 43
4 1. Programme
9:30–10:00 WELCOME & KEY NOTE SPEECH
Welcome: Paul RÜBIG, MEP & STOA Vice-Chair
Key note speech: Maggie DE BLOCK, Minister of Social Affairs and Public Health, Belgium
10:00-11:15 SESSION I: CLINICAL, INDUSTRY PERSPECTIVES AND RESEARCH INFRASTRUCTURES
Moderator: Pier Franco CONTE, Professor of Oncology, University of Padua, Italy
Therapeutic innovation that matters to patients and society Richard SULLIVAN, Professor of Cancer and Global Health, King’s College London, UK
Integration of clinical research into heath care: treatment optimization for better outcome and rationale use of resources Denis LACOMBE, Director General of the European Organisation for Research and Treatment of Cancer (EORTC)
Collaborations to accelerate patient focused translational research: The industry perspective Magda CHLEBUS, Executive Director of Scientific & Regulatory Affairs, European Federation of Pharmaceutical Industries and Associations (EFPIA)
Infrastructures for research and innovation Ewan BIRNEY, Director of European Molecular Biology Laboratory (EMBL)
Q&A/short statements from the audience
5 11:15-12:20 SESSION II: ROLE OF GOVERNAMENTAL & REGULATORY BODIES'
Moderator: Guy BRUSSELLE, Professor of Medicine, Ghent University Hospital, Belgium
The European Medicines Agency standpoint Guido RASI, Executive Director, European Medicines Agency (EMA)
Why do we need new HTA methods for assessing complex and personalized health technologies? Wim GOETTSCH, Professor at the University of Utrecht, Special Advisor at the National Health Care Institute, Diemen, Zorginstituut (ZIN), The Netherlands
A national perspective: the French case Jean-Yves BLAY, Director, Centre Léon Bérard, Lyon, France
Medicine Adaptive Pathways to Patients, an innovative development concept built on existing regulatory and access initiatives. Mathieu BOUDES, European Patients' Forum (EPF)
Q&A/short statements from the audience
12:20-12:30 CONCLUSIONS
Presentation of the Manifesto 'Developing a novel approach to deliver better precision medicine to patients'
Paul RÜBIG, MEP & STOA Vice Chair
Denis LACOMBE, Director General of the European Organisation for Research and Treatment of Cancer (EORTC)
12:30–13:30 NETWORKING RECEPTION
6 2. Introduction
SUMMARY The current situation • Clinical research protocols are still not patient centred. Patient access is conditioned by drug based eligibility criteria. Giving the patient the right treatment at the right time means knowing the patient's molecular profile. • How effective is a treatment when used in real life? The question of optimal treatment use needs to be researched before market authorisation. • No integrated European platform collects the data needed for generating evidence.
What could be done • Patient and their individual biology should be at the centre of the drug development process. The system should be inverted, with patients being proposed treatment protocols matching their molecular profile. • Improving data sharing and reducing research fragmentation in Europe is needed, as well as a major transformation in clinical research, with public support and incentives for multi- stakeholder collaboration. • Support innovative, independent and collaborative platforms to screen patients at the European level, providing access to new drugs in clinical trials as well as testing their use in real life.
The Council of the EU, while accepting that there is no common definition of the term precision (personalised) medicine, has noted that this is generally understood to refer to a medical model, which uses the characterisation of individuals' phenotypes and genotypes, for tailoring the right therapeutic strategy for the right person at the right time, and/or to determine the predisposition to disease, and/or to deliver a targeted prevention strategy (Council of the EU, 2015; Salgado, 2017).
As the number of authorised drugs that target specific proteins implicated in the disease phenotype increases on the market, and as next-generation sequencing and other technologies bring comprehensive genome-wide analyses to affordable levels, a much wider role for precision medicine in routine practice is now a reality (Salgado, 2017).
However, once a drug enters the market following regulatory approval, each EU Member State determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient- relevant issues in a real-world setting. There is a demand for reform of the current system to create a truly 'patient-centred' paradigm, with systematically coordinated treatment optimisation in conjunction with the drug development process.
Centralised EU procedure for marketing authorisation
Since 1995, the European Medicines Agency has adopted a 'centralised procedure' to grant marketing authorisations across all its Member States (EPRS, 2015). The EMA's Committee for
7 Medicinal products for Human Use (CHMP) carries out a scientific assessment of applications and gives a recommendation on whether or not a medicine should be marketed. The CHMP is composed of specialists nominated by each EU Member State and evaluates the safety, efficacy, and quality of medicinal products (EMA, 2018).
The approval process should resolve the challenge of expediting patient access to promising new drugs, while guaranteeing their adequate safety and efficacy, and as far as possible, meet the evidence requirements of other stakeholders, including patients, healthcare professionals, health technology assessment (HTA) bodies and others, who often demand evidence on relative effectiveness and/or cost-effectiveness compared with therapeutic alternatives (Martinalbo, 2016).
Two disconnected stages: from drug development to real world application
In Europe, most of the clinical research dedicated to therapeutic innovations in drugs aims primarily at regulatory approval. In this first stage, scientific issues on the efficacy of a new drug are addressed in selected patient populations and lead up to European Medicine Agency approval.
Once a drug enters the market, the second stage begins, where research addresses clinically relevant questions to tailor the therapeutic indications to 'real-life' clinical practice. Due to this discontinuity between the first and the second stage, research during the second stage results – for different reasons – in suboptimal uptake of findings into practice or clinical guidelines (Kempf, 2017).
Administration of improper treatment may generate unnecessary toxicity for patients, but also affects national healthcare budgets and adds cost to already highly priced treatments. Therefore, following the drug development phase, independent investigations are needed on the optimal use of medicines (known as 'treatment optimisation').
Regulatory approval
The regulatory approval of new treatments does not address clinical issues relevant to patients in real-world settings, such as: i) how to combine new treatments with the existing therapeutic options. Most patients may need some form of combination therapy, which is determined individually, based on a number of clinical and biomarker predictors (Klauschen, 2014); ii) how to evaluate the clinical outcomes when new treatments are administered in off-label indications; iii) how to determine the optimal scheme/treatment duration and at which benefit/risk ratio; iv) what the long-term issues related to the treatment are (Kempf, 2017). When addressed, the above-mentioned issues are studied mostly following EMA's approval and rely on the goodwill and agendas of independent research groups. The research gap between drug development and real world health care delivery is illustrated in Figure 1.
Reasons for a lack of real-world evidence
There are a number of reasons for such lack of real-world evidence, mentioned briefly here. First, regulatory approval of new treatments requires data on 'quality, safety and efficacy' and not on 'comparability' (Martinalbo, 2016). This approach is centred on the innovative treatment, as its value is assessed in absolute terms, not relatively to the pre-existing therapeutic
8 armamentarium of medicines, equipment, and techniques available (Kempf, 2017). Second, in order to maximise the experimental treatment effect, patients included in clinical trials (CTs) represent only 2-4 % of the overall targeted population, leading to a poor external validity of CTs (Kennedy-Martin, 2015). Finally, there is a lack of evidence that would make it possible to rank the multiple therapeutic options available and define the conditions for optimal care (Kempf, 2017). ______
______Figure 1.Research gap between drug development and real world healthcare delivery. Copyright: Pot Regnier/STOA
Role of key stakeholders in the current drug development system
Developing a drug and bringing it into clinical practice is a complex process involving multiple partners in several areas, namely: i) pharmaceutical industry; ii) regulatory agencies; iii) payers (in healthcare, this term generally refers to entities other than patients that finance or reimburse the cost of health services); iv) Health Technology Assessment (HTA) agencies; iv) clinicians; v) patients; iv) academia.
Although they have a common goal (the benefit of the patient), they work with different priorities and methodology. For example, while pharmaceutical companies seek – among others things – profit, researchers want to develop their medical tools and academic career, regulators assess the therapeutic efficacy, and payers make sure that the medical innovations are worth the public investment (Figure 2). Each of the partners provides their support from a different perspective, and this does not contribute to the reduction of the research gap between the first stage (regulatory approval) and the second stage (real world application) of drug development (Kempf, 2017).
Infrastructural gaps
No integrated European solution exists to optimally learn, across cohorts of patients, patterns of resistance and relapse as patients receive treatments and/or enter in clinical trials during the evolution of their disease. Independent data collection is critically needed for all types of clinical,
9 biological, imaging data and records alongside biomarker test results and all therapies received, in databases that are constantly curated and annotated, to prepare the implementation of precision medicine.
Both traditionally and today, HTA bodies and payers make their decisions based on drug development research which remains relatively artificial (in vitro and in highly selected patient populations), when their decision should be from the result of applied research.
______
______Copyright: Pot Regnier/STOA
Conceptual changes are needed
Access to patients for clinical research needs new means of rapid identification of patients by sub- groups in a pre-competitive manner for swift assignment according to target, treatment and/or trials, in the best interest of the patient. New solutions are needed for optimal benchmarking of emerging technologies across and within classes of agents. The 'one drug, one target, one protocol' concept is no longer the way forward.
Key questions anticipating the real-life implementation of new drugs need to be addressed early. These questions are crucial not only for patients but also for HTA bodies and payers. Long-term toxicity monitoring of mechanism based therapies needs a new framework, beyond the registration of drugs and into real-life usage over a prolonged period of time. Clinical research can be aimed at developing new drugs, but also serves to validate therapeutic strategies, embedding new drugs in the 'use' context. In short, there should be a continuum between clinical research for drug development and applied clinical research.
10 A truly patient-centred solution is required, with the development of an innovative independent and collaborative central platform, sorting patients at the European level, which will simultaneously take into account access as well as anticipated real-life questions. The transition should be established taking account of the interests and needs of all stakeholders. Here below some suggestions (Figure 3): i) Patient triage (molecular screening) and trial access should be led by non-commercial sector: academia in partnership with pharmaceutical companies, biotech organisations, and diagnostics technicians; ii) Drug development should be led by the commercial sector: industry in partnership with academia; iii) Therapeutic optimisation should be led by the non-commercial sector: academia in partnership with HTA and payers; iv) Real life implementation and long term monitoring of treatments should be led by the non- commercial sector: academia in partnership with registries, HTA and payers. ______
______Figure 3. A new paradigm for the drug development process. Copyright: Pot Regnier/STOA.
Aim of the STOA workshop
This workshop is an opportunity to discuss the implementation of an 'innovation-centred' system, exploring a truly 'patient-centred' paradigm with systematically coordinated applied clinical research carried out in conjunction with drug development.
The establishment of a new developmental framework through close collaboration between industry, patient representatives, regulatory, governmental, academia and other stakeholders would hopefully facilitate comparisons of assay performance before regulatory approval, harmonising the approval process. Such a framework could mitigate the somewhat problematic current situation. The issue is ubiquitous in modern biomarker/drug development processes and is not related to particular targets or pathways (Salgado, 2017).
11 This workshop will provide patients, clinicians, payers, HTA agencies, regulators, pharmaceutical companies, researchers, policy-makers and the public at large, with an opportunity to present their point of view and their innovative suggestions for future drug development in Europe.
References
Council of the European Union. Personalised medicine for patients. Council conclusions. (15054/15). Available at: http://data.consilium.europa.eu/doc/document/ST-15054-2015- INIT/en/pdf.
Scholz N. Medicinal products in the European Union. The legal framework for medicines for human use. EPRS, European Parliament, 2015. Available at: http://www.europarl.europa.eu/RegData/etudes/IDAN/2015/554174/EPRS_IDA(2015)554174_ EN.pdf
European Medicines Agency (EMA). About us. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/08/WC500211862.pdf
Klauschen F, Andreeff M, Keilholz U, Dietel M, Stenzinger A. The combinatorial complexity of cancer precision medicine. Oncoscience, 2014; 1: 504-509.
Martinalbo J, Bowen D, Camarero J, Chapelin M, Démolis P, Foggi P, Jonsson B, Llinares J, Moreau A, O'Connor D, Oliveira J, Vamvakas S, Pignatti F. Early market access of cancer drugs in the EU. Annals of Oncology, 2016; 27: 96-105.
Kempf E, Bogaerts J, Lacombe D, Liu L. 'Mind the gap' between the development of therapeutic innovations and the clinical practice in oncology: A proposal of the European Organisation for Research and Treatment of Cancer (EORTC) to optimise cancer clinical research. European Journal of Cancer, 2017; 86: 143-149.
Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials, 2015; 16: 495.
Salgado R, Moore H, Martens JWM, Lively T, Malik S, McDermott U, Michiels S, Moscow JA, Tejpar S, McKee T, Lacombe D, IBCD-Faculty. Societal challenges of precision medicine: bringing order to chaos. European Journal of Cancer, 2017; 84: 325-334.
12 3. About EORTC European Organisation for Research and Treatment of Cancer
This workshop has been organised in cooperation with the European Organisation for Research and Treatment of Cancer (EORTC). EORTC is a unique pan-European non-profit clinical cancer research organisation established in 1962 operating as an international association under Belgium law. It develops, conducts, coordinates and stimulates high-quality translational and clinical trial research to improve the survival and quality of life of cancer patients.
This is achieved through the development of new drugs and other innovative approaches, and the testing of more effective therapeutic strategies, using currently approved drugs, surgery and/or radiotherapy in clinical trials conducted under the auspices of a vast network of clinical cancer researchers supported by 220 staff members based in Brussels. EORTC has the expertise to conduct large and complex trials especially specific populations such as the older patient and rare tumours.
EORTC research network consists of over 5500 collaborators from all disciplines involved in cancer treatment and research in more than 930 university hospitals in 27 countries. Its research spans the entire spectrum from translational and preclinical research to large, prospective, multicentre, phase III clinical trials that evaluate new cancer therapies and/or treatment strategies as well as patient quality of life.
Currently, EORTC is conducting 203 studies, and thousands of patients (85% from within the EU) participate in EORTC clinical trials. 25,000 patients continue to be followed on a yearly basis and the EORTC clinical study database now contains outcome data for over 190,000 cancer patients.
For further information, please visit the EORTC website: www.eortc.org.
13 WELCOME & KEY NOTE SPEECH
14 4. Welcome
4.1. Paul RÜBIG
MEP and STOA First Vice-Chair
Paul Rübig was elected as the STOA Chair for the first half of the European Parliament's 8th legislature and as First Vice-Chair for the second half of the 8th legislature. Previously, he served as STOA Chair from 2009 to 2012 and as First Vice-Chair from 2012 to 2014.
Born in Northern Austria, Paul Rübig has been a member of the European Parliament since 1996 and belongs to the European People's Party (EPP). He is the owner of an Austrian blacksmith company and has a degree in Business Administration, Marketing and Production Engineering from the University of Linz, Upper Austria. He is married and has two children.
Paul Rübig is a full member of the Committee on Industry, Research and Energy and of the Committee on Budgets. He is Vice-Chair of the Delegation for relations with the Korean Peninsula and substitute member of the Delegation for relations with Switzerland, Norway and of the EU-Iceland Joint Parliamentary Committee.
He is also a substitute member of the European Economic Area (EEA) Joint Parliamentary Committee. Furthermore, Paul Rübig is a substitute member in the Committee on Development. Paul Rübig is very active in the field of the small-scale business promotion.
He is president of SME Global, a working group of the International Democrat Union (IDU), whose objective it is to support small and medium-sized enterprises (SME) and to improve their business environment.
15 5. Key note speech
5.1. Maggie DE BLOCK
Belgian Minister for Social Affairs, Public Health and Asylum and Migration
Maggie De Block is Belgian Minister for Social Affairs and Public Health since October, 11th 2014.
Previously she acted as Minister for Justice with responsibility for Asylum and Immigration, Social Integration and Poverty Reduction, between July 2014 and October 2014.
She worked as State Secretary of Asylum, Migration, Social Integration and Poverty Reduction, between December 2011 and July 2014.
She has served as Member of Parliament for the Brussel-Halle-Vilvoorde constituency from 1999 to 2011 and President of the Commission for Infrastructure from 2010 to 2011.
She was Vice-President and Permanent Member of the Commission for Social Affairs. Previously to these experiences she spent four years as Former Secretary of the Chamber of Representatives from 2003 to 2007.
Maggie De Block graduated in Medicine in 1988 at the Vrije Universiteit Brussel.
16 SESSION I
CLINICAL, INDUSTRY PERSPECTIVE AND RESEARCH INFRASTRUCTURES
17 6. Moderator Session I
6.1. Pierfranco CONTE
Professor of Oncology at the University of Padua, Director of the Division of Medical Oncology 2 at the Veneto Cancer Institute, Italy
Pierfranco Conte is Full Professor of Oncology at the University of Padua, Director of the Division of Medical Oncology 2 at the Veneto Cancer Institute in Padua and Coordinator of the Veneto Oncology Network which includes the Oncology Divisions of academic and community hospitals in Veneto Region. He graduated in medicine at the University of Torino in 1974, specialized in Oncology at the Torino University, Hematology at the Genova University and Clinical Immunology at the Milan University.
Throughout his career, Prof. Conte has been involved in the development of new regimens for the treatment of solid tumors, with special emphasis on breast and ovarian cancer. He has been Principal Investigator of numerous research projects supported by the National Research Council (CNR), the Italian Association for Cancer Research (AIRC), the Italian Ministry of Health, the Ministry of Education and Research and the Veneto Regional Government.
In the last years, he has designed and conducted trials of preoperative treatment with correlative studies to identify biomarkers of treatment sensitivity/resistance in the different molecular subtypes of breast cancer.
Prof. Conte has served in the editorial board of numerous oncology journals including: Clinical Breast Cancer, Journal of Clinical Oncology, Oncologie, The Breast Journal, The Oncologist, Trends in Medicine.
Prof. Conte sits in several Committees: Faculty Member for Breast Cancer of the European Society for Medical Oncology (ESMO), referee for the CME Program of the Italian Ministry of Health, Chairman of the Veneto Oncology Network, Chairman of the Guidelines Committee for Ovarian Cancer of the Italian Association for Medical Oncology (AIOM).
He has published more than 400 papers in peer-reviewed journals, most of whom focused on the biological characterization of breast, ovarian and lung cancer and clinical trials in these disorders.
Contribution to the discussion
Over the last years, we have acknowledged impressive progress in the decryption of genetic and genomic dysregulations of human tumors, in the dynamic inter-relationships between host and tumor and in the development of molecular targeted drugs. These achievements have allowed to establish the frame of modern ‘4 Ps medicine’: Preventive, Predictive, Personalized, Participatory.
18 However, we have to acknowledge that many patients develop and die because of cancer, with epidemiologic data still showing increasing incidence and mortality rates in many countries. It is therefore time to review the present model of drug development and delivery to patients. Several steps need to be revisited and challenged:
Trial design: Regulatory Authorities privilege statistical significance over clinical value. A randomized trial large enough to demonstrate a statistically significant difference (the “mythical” p-value which has nothing to do with 4Ps medicine!), is judged positive while a single arm trial showing a clinically worthwhile end point, in a well selected for prognostic/predictive characteristics’ patient population would not be accepted.
Trial end points: classic end points such as Progression Free Survival, Disease Free Survival, Overall survival, Objective Response Rates, Quality of Life should be adapted and valued differently according to the specific setting of disease and drug under study. A major example are trials with immune checkpoint inhibitors where neither Response rates nor Progression Free Survival and not even median Overall Survival are good predictors of patients’ outcomes, while landmark analyses such as the percentage of patients alive at a fixed time point, better describe the efficacy of the treatment.
Risk-benefit ratio: A positive risk/benefit ratio is the requirement needed to get a drug approved. This ratio is based on the benefit (primary trial end point) and the toxicities/quality of life experienced by the patients and represents the “average” ratio for the “average” patient. However, this ratio can be completely useless or even misleading in case of large trials with a sufficient statistical power to demonstrate small differences. In these cases, the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH) should be taken into account by the Regulatory Authorities also allowing for an HTA estimate of the new intervention.
Clinical Value Scales: both the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) have developed scales to evaluate the clinical value of approved drugs. These scales take into account different parameters according to the setting: curative versus palliative/non curative. Interestingly, a non-negligible proportion of drugs approved by FDA and EMA score very poorly according to ASCO and ESMO scales. Even worse, there is no relation between drug prices and ASCO/ESMO values. Clearly, this misalignement between Regulatory Authorities and scientific societies is not justifiable or sustainable and shared values are now eagerly needed.
Evidence from experience: there is an increasing gap between evidence provided by pivotal trials and real world needs. Multiple reasons can account for this gap, including but not limited to: i) patient selection (elderly/comorbidities/ co-medications are all under represented/not allowed in clinical trials); ii) applicability/transferability of modern technologies (NGS, ctDNA etc.) in the real world setting can delay access and quality control can be an issue; iii) place in therapy is often “out-dated”: the new treatment has been tested in a patient population which has not been pre-exposed to state-of-art treatments or compared to a suboptimal (or not the BEST) available comparator. Moreover, pivotal trials in most of the cases cannot address some important clinical questions such as sequences of treatments versus best treatment upfront;
19 iv) safety and efficacy data provided by trials are based on limited time frames while in real world setting, patients are often treated for much longer period of times. Long term efficacy and safety data derived from real world patients are necessary to better understand the risk/benefit ratio of innovative drugs; v) treatment duration (continuous versus interrupted). For the same reasons discussed above, pivotal trials cannot address the issue of optimal treatment duration: shall I treat patients until tolerability or disease progression or, in responding patients with no evidence of disease, is it safe to stop the treatment? This question is becoming increasingly important since the use of monoclonal antibodies and immune checkpoint inhibitors: there are hundreds/thousands of patients with advanced cancers responding to antiHER2 antibodies or antiPD1/PDL1 antibodies receiving treatment for years and no data to support neither unlimited administration nor stopping at some point.
Only data from registries or specifically designed trials in the frame of planned cooperation between all stakeholders (pharma companies, regulatory agencies, payers) might address these issues.
20 7. Speakers Session I
7.1. Richard SULLIVAN
Professor of Cancer and Global Health at King’s College London, Director of the Institute of Cancer Policy and co-Director of the Conflict and Health Research Group.
Richard Sullivan studies health systems, particular non-communicable diseases (NCDs) policy and the impact of conflict on health. He is Professor of Cancer and Global Health at King’s College London, and Director of the Institute of Cancer Policy (ICP) and co-Director of the Conflict and Health Research Group.
As well as holding a number of Visiting Chairs, Richard is an NCD advisor to the WHO, civil-military advisor to Save the Children, and a member of the National Cancer Grid of India.
His research focuses on global cancer policy and planning, and health systems strengthening, particularly conflict ecosystems. He is principle investigator on research programs ranging from automated radiotherapy planning for low resource settings to use of augmented/virtual reality for cancer surgery, through to political economy to build affordable, equitable cancer control plans.
Richard has led five Lancet Oncology Commissions and worked on four others. In conflict systems, his research teams have major programs in capacity building in conflict medicine across the Middle East and North Africa, as well as studies of the basic package of health services in Afghanistan, civil-military co-operation in health security, polio eradication and insecurity in Pakistan, and use of intelligence in high security disease outbreaks.
Professor Sullivan qualified in medicine and trained in surgery (urology), gaining his PhD from University College London. He was also clinical director of Cancer Research UK between 1999 and 2008. Following a period at the London School of Economics working on complex healthcare systems he moved to King’s College London in 2011.
21 7.2. Denis LECOMBE
Director General of the European Organisation for Research and Treatment of Cancer (EORTC)
Denis Lacombe graduated in medicine at the University of Marseilles (France) in 1988 and obtained a Master Post Doctoral Fellowship at The Roswell Park Cancer Institute (Buffalo, NY, USA) for research in pharmacology and pharmacokinetics from 1989 to 1991. From 1991 to 1993, he worked as a Clinical Research Advisor in charge of the development of a new drug in oncology in the pharmaceutical industry.
Dr Lacombe joined the EORTC in 1993 as a research fellow and quickly became a clinical research physician involved in the conduct of clinical research from protocol development, through publication o f a number of oncology indications from phase I to phase III. He contributed to the strategic evolution of the EORTC pan-European clinical and translational research infrastructure by setting up various supportive assets, such as regulatory and pharmacovigilance expertise as well as partnership models with the pharmaceutical industry.
Denis Lacombe rose to the position of Director EORTC Headquarters in 2010: in 2015 h e was appointed EORTC Director General. In his current position, Denis Lacombe is involved in the coordination and administration of all EORTC activities in order to promote the EORTC as a major European organization in Cancer Clinical and Translational Research and is responsible for the organization of scientific activities, public relations and medium term strategies as defined by the EORTC Board as well as for internal and external communications.
He is the author of over 100 peer reviewed publications and communications on cancer therapy.
Key message
Bringing therapeutic innovation and latest science to patients while keeping patient interests at the center is a challenging mission. Precision medicine and new approaches to clinical research have dramatically changed the field of treatment, notably for cancer. New treatments become available based on solid scientific rationale thanks to the understanding of molecular biology and immunology.
However, optimal use of new anti-cancer treatments remains poorly documented. Patient populations (defined for example by biomarkers), treatment duration, sequence and combination of treatments within the current treatment pathways are often poorly defined by clinical developments for regulatory purposes.
Therefore, major limiting factors to delivering cost-effective and affordable, evidenced-based care to clinical practice remain unaddressed. This leaves many gaps in the knowledge concerning the efficacy and therapeutic use of medicines; in addition, this can impose a significant financial
22 burden on the health care systems. A new balance between the interests and needs of all stakeholders need to be re-defined around patient centeredness.
We argue that the evidence generated during the clinical development of these new products for the purpose of getting marketing authorisations often does not address fundamental questions concerning the impact of these new interventions on the most relevant clinical outcomes; quality of life and survival of the patients. Therefore, a gap in clinical and translational research exists, between early and late drug development often artificially split by the process of marketing authorization, after which the commercial sector may no longer pursue research for treatment optimisation.
Applied clinical research is needed to define effective practice-changing approaches, to bring therapeutic innovation efficiently and consistently to cancer patients, and to address patient populations who do not fall within the primary interests of the commercial sector.
We illustrate these issues with a specific example: Trials addressing immuno-therapy and more specifically check point inhibitors changed the approach to treat melanoma. However, the clinical development of these products did not adequately inform the optimum treatment duration, which is a critical issue for clinical practice. DANTE trial in the United Kingdom and the STOP- GAP trial in Canada, both supported by independent funders, are applied research clinical studies which were specifically designed to address this crucial question after the authorisation of these products.
Clinical research and the healthcare systems are long due for transformation. Access, affordability and effective use of treatments need intimate cross-links between research and care for successful implementation of precision medicine for European patients. Equality, affordability and the high quality utilisation of new treatments need intimate cross-links between research and care for precision medicine to become a paradigm with real impact.
Re-engineering the forms and methods of therapeutic innovation around the understanding of biology, through applied clinical research would benefit to all, facilitating access while delivering more adequate information on value of treatments.
Europe should develop solutions generating the appropriate datasets that patients and healthcare systems need for access. Independent applied clinical research should play a critical role in a transformative society.
23 7.3. Magda CHLEBUS
Executive Director of Scientific & Regulatory Affairs at the European Federation of Pharmaceutical Industries and Associations (EFPIA)
Magda Chlebus is Executive Director of Scientific & Regulatory Affairs at the European Federation of Pharmaceutical Industries and Associations (EFPIA), representing the R&D-based pharmaceutical industry in Europe.
Magda and her team are in charge of following policy and legislative developments that influence the research and regulatory environments for the healthcare industry in Europe. This includes public private collaborations (inter alia the Innovative Medicines Initiative), enabling and sensitive technologies and the interface between new science and technology and regulation.
She joined EFPIA in 1995. Her experience covers public and government affairs mainly at EU level, on a range of legislative and non-legislative files in the area of research, development and access to medicines and enabling technologies.
Magda Chlebus holds a Master Degree in Applied Linguistics from the University of Warsaw, Poland.
Key message
European Research Framework Programmes have a proven track record of directly supporting medical and health system innovation, patient access to innovative healthcare solutions, Europe’s cohesion and growth, as well as the continuing attractiveness of Europe as a location for life sciences and investment.
And research-intensive health industries are reliant on a vibrant and connected health and research ecosystem. With dedicated tools - European Research Infrastructures, SME tools or institutional public private partnerships – framework programmes create a still unique pan- European infrastructure for translational research.
The role of translational research cannot be underestimated – it validates (or not) the fundamental science discoveries, and turns them into standardised processes that can be industrialized and upscaled so that the results can reach all patients and citizens. The pharmaceutical industry along with other life science industries plays an essential part in this process, also bearing most of the risks of failures if the scientific idea does not prove as promising as anticipated.
European institutional partnerships, such as the Innovative Medicines Initiative (IMI) in the health field, played an important role in setting new collaboration models where a neutral broker (the IMI office) brings together the demand and the supply side, the regulated and the regulators, the enablers and the gatekeepers from the continuum of health, research and care.
24 This “radical collaboration” based on a community of brains and sharing what is not routinely shared thanks to the concept of in-kind contributions, was heralded by Commissioner Moedas at the IMI’s 10th anniversary: it is both a unique European specialty and an essential enabler turning fundamental science into solutions for the patients.
This unique European partnership for health delivers tangible, meaningful results to patients and society: Ebola, COPD, Asthma, Autism, Alzheimer, Epilepsy, Diabetes, Frailty, and more generally medicines safety and health data management - all saw first in class developments which get us ever closer to effective, safe and personalised treatments.
Having successfully tested the concept of radical collaboration and pushed boundaries of precompetitive research in one sector in IMI, we are ready to push it into new and completely uncharted territory where different sectors could join forces with research and healthcare communities and maintain Europe at the forefront of medical and health systems innovation.
The examples of projects such as the recently launched Integrated Research Platforms, as well as ongoing IMI projects such as EPAD, C4C, ND4BB, PREFER or PARADIGM and others, with illustrate the case of radical collaboration to enhance Europe’s translational power and impact of research activities and research infrastructures.
25 7.4. Ewan BIRNEY
Director of European Molecular Biology Laboratory and European Bioinformatics Institute (EMBL-EBI)
European Molecular Biology Laboratory and European Bioinformatics Institute (EMBL-EBI) makes the world’s public biological data freely available to the scientific community via a range of services and tools, perform basic research and provide professional training in bioinformatics. They are part of the European Molecular Biology Laboratory (EMBL), an international, innovative and interdisciplinary research organisation funded by 23 member states and two associate member states. Ewan is also a non-executive Director of Genomics England, and is a consultant and advisor to a number of companies, including Oxford Nanopore Technologies and GSK. Ewan Birney works in annotating the genome sequences of human, mouse, chicken and several other organisms; this work has had a profound impact on our understanding of genomic biology. He led the analysis group for the Encyclopaedia of DNA Elements (ENCODE) project, which is defining functional elements in the human genome. Ewan’s main areas of research include functional genomics, assembly algorithms, statistical methods to analyse genomic information (in particular information associated with individual differences) and compression of sequence information.
Ewan completed his PhD at the Wellcome Trust Sanger Institute with Richard Durbin, and worked in the laboratories of leading scientists Adrian Krainer, Toby Gibson and Iain Campbell. He received a number of awards including the 2003 Francis Crick Award from the Royal Society, the 2005 Overton Prize from the International Society for Computational Biology and the 2005 Benjamin Franklin Award for contributions in Open Source Bioinformatics. Ewan was elected a Fellow of the Royal Society in 2014 and a Fellow of the Academy of Medical Sciences in 2015.
Key message
Big data genomics is transforming medicine Due to a radical drop in the cost of automated data-generating technologies over the past decade, most notably high throughput DNA sequencing but also proteomics and metabolomics, data emanating from genome sequencing has become increasingly relevant to clinical research and to the practice of medicine[1]. Simultaneously, human genetics and genomics at scale offer opportunities to change how we approach therapeutic target validation, which remains central to drug discovery research in both multinational pharmaceutical companies as well as small biotechnology companies[2]. Data is critical to achieving the goals of precision medicine and the application of biological understanding to create clinically useful treatments or drugs has been greatly enhanced by
26 genomic data, to the point where basic research and translational research now overlap. The vast swathes of human genomic data emanating from sequencing can be used to help in the identification of genomic variations which, in turn, can be transformative in the diagnosis of rare disease, critical in the appropriate use of therapies in cancer and can serve as indicators of chronic disease. The benefits of genomics are clear in the diagnosis of cancer, for example, where there is increased evidence that molecular stratification can aid specialists in treatment decisions. Europe has the opportunity to be at the forefront of the new era of medicine but is faced by the challenge of integrating and analysing data from multiple settings which acts as bottleneck to the delivery of many of the potential benefits for European patients.
Research Infrastructure for R&I and precision medicine in Europe A number of European governments are currently developing national genomic medicine plans to derive healthcare benefits from the genomics revolution Over the coming decade it is likely that genomic medicine will be mainstream in the developed world. It is against this backdrop that EMBL-EBI, which gathers and adds value to the world’s largest collection of molecular data, making it freely available for academic and industrial research, launched its medical strategy, with the goal of transfering knowledge and skills in the area of genomics and biodata to its 25 plus member states in Europe.
Beyond the point of making data available for research and innovation, ultimately the next step would be the development of at least one biomedical informatics institute or network in each EU member state, which would act as a coordinating centre of biomedical informatics networks. The establishment of such biomedical informatics institutes would in turn facilitate the availability of data for research and innovation as well as the translation of molecular biology information into the clinic.
About the European Molecular Biology Laboratory and the European Bioinformatics Institute The European Molecular Biology Laboratory (EMBL) is Europe’s flagship intergovernmental research organisation for the life sciences. Founded as an intergovernmental organisation in 1974, EMBL is today six sites across Europe. EMBL’s European Bioinfomatics Insitute (EMBL-EBI), located at the Wellcome Genome Campus near Cambridge, provides the world’s largest open biological data repository for the storage, analysis and dissemination of large biological datasets for academia and industry.
These databases covering the gamut of genes, proteins and small molecules, receive around ~30,000,000 web visits per day. EMBL-EBI is also one of the main partners in the Open Targets public-private collaboration, a unique, precompetitive partnership between companies and not- for-profit research institutes aimed at transforming drug discovery by improving the success rate for developing new medicines. It was set up to systematically improve the identification and prioritisation of drug targets for safe and effective medicines.
References 1. J. Vamathevan, E. Birney. A Review of Recent Advances in Translational Bioinformatics: Bridges from Biology to Medicine. Yearbook of Medical Informatics 2017; 26: 178-187.
2. Barrett JC, Dunham I, Birney E. Using human genetics to make new medicines. Nature Reviews Genetics, 2015: 16; 561–562.
27 SESSION II
ROLE OF GOVERNAMENTAL AND REGOLATORY BODIES
28 8. Moderator Session II
8.1. Guy BRUSSELLE
Professor of Medicine at Ghent University Hospital, Ghent, Belgium
Guy Brusselle received his medical degree at Ghent University in 1990. Investigating the functional role of cytokines interleukin-4 (IL-4) and interleukin-5 (IL-5) in allergic asthma, he obtained his PhD in 1997. As a respiratory physician with a keen clinical and scientific interest in asthma, severe asthma and Chronic Pulmonary Obstructive Disorders (COPDs), he joined the Ghent University Hospital in 2002.
Since 2008, he is professor of medicine at Ghent University, teaching “Study design” and “Immunopathology of airway diseases” to medical and biomedical students, respectively. Since 2015, he teaches the course “Methods and design of clinical studies”. Currently, he is head of the Laboratory for Translational Research of Obstructive Pulmonary Diseases at Ghent University.
From September 2012 to October 2015, he has served the European Respiratory Society (ERS) as Guidelines Director. Since September 2016, he is the chair of the ERS Science Council. Since September 2017, he is member of the Scientific Committee of the Global Initiative for Asthma (GINA) and he has joined the Board of Directors of GINA.
Contribution to the discussion
To maximize the potential of precision medicine for patients and society, there is an urgent need for bridging the gap between regulatory trials and healthcare through international collaboration of all stakeholders. National governamental and European regulatory bodies need to be proactive and expand the architecture of clinical research to maximize the benefit of scientific advances for patients and society. It is well known that new drugs reaching the market is not an end but a start.
Information that is critical for the integration of new treatments in daily practice needs to be collected and analyzed to optimize the use of resources and maximize patient benefits [1]. The gap that currently exists between market approval and real-life clinical practice requires a new infrastructure for applied clinical research which truly serves the needs of patients, generates the data needed to inform clinical practice, and needs to be fully integrated into the cycle of drug development, market approval and clinical application.
Patients’ needs are multiple; most commonly they do not depend on a single intervention and are likely to change with the natural history of the disease. Therefore, the concept that therapeutic interventions are developed with the sole purpose of market access – not anticipating any questions beyond registration – needs to be revisited. After market authorization, many questions still remain to be addressed by all stakeholders through applied clinical research, investigating long-term safety and real life effectiveness of treatments in broader patient populations [2, 3].
29 Regulatory agencies such as the European Medicines Agency (EMA) are already beginning to require such information, which is crucial not only for patients, but also for Health Technology Assessment (HTA) bodies and payers[4, 5]. It is vital that regulatory authorities and HTA bodies engage with the non-commercial sector over the disruptive knowledge that accompanies the advent of precision medicine.
Patients have the right to participate at each strategic level in health research, ranging from treatment development and clinical studies to implementation in clinical practice [6]. Patients have also the right to benefit from the latest scientific discoveries and to be treated according to the highest level of clinical evidence.
Technologies allowing the stratification of patients according to biological/genetic features should lead to a major change in the healthcare research model: from “drug protocols/trials looking for patients” to (fully biologically/genetically characterized) “patients looking for matching protocols/treatments” [7]. The novel model of healthcare research thus places patients truly at the center of the research and development (R&D) process. Moreover, trial endpoints should take into account outcomes that reflect the needs and priorities of patients [8].
There should be a continuum between drug development, regulatory assessment, clinical research, and applied clinical research. There is much room for improvement for integrating clinical research into healthcare. There needs to be an integrated pan-European infrastructure to support the use of patient data for health research. Such a system circumvents the expense of active long-term follow up (and thus, allows adequate assessment of safety and cost-effectiveness of interventions) and provides information that is accessible for independent assessment by health authorities.
Independent data capture (e.g., via electronic patient records) for all types of clinical, biological and imaging data, therapies received, and outcomes obtained, is critical for the affordable implementation and validation of precision medicine. Combining this integrated infrastructure with the patient-centered healthcare research at a European level maximizes the potential of scientific advances for individual patients, but also will bring economic benefit to healthcare services through the ability to target new and established treatments to those who are certain to benefit from it.
References 1. Moher D, Glasziou P, Chalmers I, et al. Increasing value and reducing waste in biomedical research: who's listening? The Lancet 2016;387:1573-86. 2. Roche N, Reddel HK, Agusti A, et al. Integrating real-life studies in the global therapeutic research framework. Lancet Respir Med 2013;1. 3. Pilette C, Brightling C, Lacombe D, Brusselle G. Urgent need for pragmatic trial platforms in severe asthma. The Lancet Respiratory Medicine 2018;6:581-3. 4. Gassman AL, Nguyen CP, Joffe HV. FDA Regulation of Prescription Drugs. New England Journal of Medicine 2017;376:674-82. 5. Ford I, Norrie J. Pragmatic Trials. New England Journal of Medicine 2016;375:454-63. 6. Kirwan JR, de Wit M, Frank L, et al. Emerging Guidelines for Patient Engagement in Research. Value in Health 2017;20:481-6.
30 7. Rothwell PM. External validity of randomised controlled trials: "To whom do the results of this trial apply?". The Lancet 2005;365:82-93. 8. Concato J. Study Design and “Evidence” in Patient-oriented Research. American Journal of Respiratory and Critical Care Medicine 2013;187:1167-72.
31 9. Speakers Session II
9.1. Guido RASI
Executive Director of European Medicines Agency (EMA)
Professor Guido Rasi began his second term as Executive Director of EMA on 16 November 2015. From November 2014 to mid- November 2015, Professor Guido Rasi served as EMA’s Principal Adviser in Charge of Strategy.
From November 2011 to November 2014 he was the Executive Director of the European Medicines Agency and a member of its Management Board in the three years prior to this. He was Director-General of the Italian Medicines Agency from 2008 to 2011 and member of the Management Board from 2004 and 2008. He was made full professor of microbiology at the University of Rome 'Tor Vergata' in 2008.
From 2005 to 2008 he was Director of Research at the Institute of Neurobiology and Molecular Medicine of the National Research Council (CNR) in Rome. From 1990 to 2005 Professor Rasi worked at the Institute for Experimental Medicine of the National Research Council, Italy. He had teaching and research experience at the University of California, Berkeley in 1999.
Professor Rasi holds a degree in medicine and surgery, with specialisations in internal medicine, allergology and clinical immunology from the University of Rome. From 1978 to 1990, he worked as a physician in a hospital, researched and uptained his private practice. He is also the author of more than 100 scientific publications. Prof Rasi was born in Padova, Italy and is married with two children.
Key message The public health potential inherent within the promise of precision medicine translating into real patient access is recognised as a top priority across the European Regulatory Network. I believe the EMA in conjunction with its key stakeholders is critically positioned to support the delivery of better precision medicines in Europe. The Agency must enable science and innovation to be translated into real patient access through its advice and review mechanisms. We must also recognise the dramatic evolution within healthcare systems across Europe and adapt our regulatory models accordingly. We have just launched a public consultation on EMA’s regulatory science vision to 2025. As part of this vision the Agency sets out its ambition to foster an environment to support precision medicines development. In view of the extensive nature of this challenge a series of recommendations are proposed. These range from supporting early stage scientific developments in precision medicine, biomarkers and “omics” to promotion of the use of Real World Data in decision making.
32 A significant reinforcement of patient relevance in evidence generation is proposed. The importance of collaborating with HTAs, payers and patients in progressing these developments is recognised, in particular the establishment of a core health related quality of life Patient Reported Outcome measure to implement in trials thus bridging the gap with comparative effectiveness assessment. The challenges of increased utilisation of “big data” and medical device/companion diagnostics have particular applications in precision medicine. The EMA/HMA task force on Big Data has just concluded a two year reflection on this field and has issued a series of recommendations addressing issues such as harmonisation of data standards, characterisation of data quality and guidance on acceptability of evidence. The development of network competencies and specialist collaborations and platforms to address both the challenges of big data and the convergence of medical device /diagnostics and medicinal products development is seen as an absolute priority across the network. None of the above can be successfully delivered without an extensive outreach and collaboration with our key stakeholders. The Agency strongly believes that this can be greatly advanced by working in close conjunction with our European Commission colleagues through our key focal point of coordination within DG-Santé and reaching across to DG Research and Innovation, in particular as they develop the Horizon Europe agenda. Leveraging the potential inherent in such collaborations will greatly enable research and innovation in regulatory science to be translated to real patient access to precision medicine. This will allow us to apply cutting edge regulatory science to the advice and review processes, to be continuously informed of scientific innovation relevant to decision making and to capitalise on a collaborative framework to articulate regulatory needs and challenges in the precision medicine space. It has been noted that there is a research gap between the drug development to regulatory approval stage and real world healthcare delivery that ultimately hampers access to precision medicine. I believe that the Agency and the wider network through the actions proposed within its regulatory science strategy will actively pursue bridging that gap, developing novel approaches that will deliver better precision medicines in Europe.
33 9.2. Wim GOETTSCH
Affiliate Associate Professor at the University of Utrecht, the Netherlands, and Special Advisor at the National Health Care Institute, Diemen, the Netherlands
Wim Goettsch is currently Special Advisor HTA at the Dutch National Health Care Institute.
He was the Director of the European network Health Technology Assessment (EUnetHTA). He has also a position as an affiliate associate professor at Utrecht University (The Netherland).
He has a PhD in immunology and an advanced education in (pharmaco)- epidemiology and pharmaco- economics. He has more than 70 publications in peer- reviewed international journals.
Key message
Over the past few decades, the role and importance of health technology assessment (HTA) has developed gradually in response to greater emphasis on evidence-based decision-making in healthcare, alongside increasing pressures on financing and delivery of healthcare. Much of the function of HTA and the use of its outputs in healthcare systems has advanced organically to some extent. Developments on both fronts have been reactive to political, societal and financial needs rather than being proactively ‘designed’ to address the needs of diverse and changing healthcare systems.
That may also explain why the current use of HTA – as well as how its principles are applied – as supporting tools for making decisions on reimbursement/procurement and use of (new) health technologies varies considerably across different healthcare systems in Europe, thus resulting in inefficiency in actual reporting of HTA in Europe. In response to these developments, European collaboration on HTA has increased in recent years with greater emphasis on developing joint methods and producing joint clinical assessments, also defined as relative effectiveness assessments, through the European network for HTA (EUnetHTA).
However, due to the complex nature of these European collaborations, the focus within EUnetHTA has been predominantly on the clinical evaluation of single technologies, also known as rapid relative effectiveness assessment (REA). At the same time, the treatment of patients has become much more complicated due to the development of tailored health technologies including combinations of technologies, co-dependent technologies and personalised medicine.
As a result, the need has arisen for personalised HTA that is capable of identifying for whom health technologies work, hereby guaranteeing that the right treatment is provided, to the right
34 patient, at the right time and leading to an increase in societal healthcare benefits. However, the data to inform these types of decisions still do not exist. Moreover, limited data-sets for innovative medicines and medical devices will make decision-making even harder. To add to this, companion diagnostics, target therapies and digital health interventions are being introduced into healthcare systems for which no HTA frameworks exist.
Therefore, we will need to create a framework for next HTA generation that supports patient- centred, societally oriented, real-time decision-making for integrated healthcare throughout Europe. Such a framework will facilitate the development of methodologies to deliver more customized information on the effectiveness and cost-effectiveness of complex and personalised combinations of health technologies.
The framework will be built on the concept of learning healthcare systems that link to treatment care pathways in which patients are treated with different combinations of therapies over time. A robust data infrastructure is an essential requirement to realise this concept. It requires expedited data analysis to allow more dynamic decision-making and circumvent limitations of the current assessment paradigm (single assessments at market access for relatively large heterogeneous patient groups).
This framework should be aligned with the European Commission’s strategy based on a single digital market and digital society which is moving towards systems and decision makers that are much more dynamic than those of today: living guidelines, rapid update systems, making use of health-related artificial intelligence applications, big-data, wearables, and digital technology.
Additionally, this framework will show how this concept of learning healthcare systems is linked to the political reality of organising reimbursement for pathways for treatment within a broader framework of solidarity-based healthcare funding. Finally, we need to work in close collaboration with the European HTA organisations and its stakeholders pilot the implementation of these methods that will be derived from this framework in Europe.
35 9.3. Jean- Yves BLAY
Director of the Centre Léon Bérard, Lyon, France
Jean-Yves Blay is the Director of the Centre Léon Bérard, the comprehensive cancer center of Lyon and the Rhône-Alpes region in France, since December 2014. He is an oncologist, researcher and professor at the University Claude Bernard Lyon 1.
Professor Blay has published over 400 peer-reviewed articles. He has been President of the European Organization for Research and Treatment of Cancer (EORTC) from 2009 to 2012. He has also received numerous awards such as the Hamilton Fairley Award in 2012 from the European Society for Medical Oncology (ESMO) and the Henry and Mary-Jane Mitjavile Prize in 2013 from the National Academy of Medicine.
His research interests focus on clinical and basic research in sarcomas, targeted treatment of cancer, the biology of breast carcinoma and relation between tumor immunologic microenvironment and malignant cells with the goal of clinical applications in the fields of diagnosis, prognosis and treatment.
Jean-Yves Blay is an active member of the European Society of Medical Oncology (ESMO), the American Society of Clinical Oncology and the American Association of Cancer Research (AACR). He has been a reviewer for the Journal of Clinical Oncology, Blood, Cancer, Annals of Oncology, European Journal of Cancer, among others.
Key message Precision medicine is developing rapidly in oncology. This development is supported by the rapidly growing knowledge on the genomics, biology and immunology of different cancers, informed by worldwide research projects characterizing the genome (TCGA, and ICGC) and immune characteristics of human cancers.
In parallel to this effort, a large number of novel medications targeting activated mutated proteins on tumor cells, or activated immune checkpoint pathways in infiltrating immune cell (anti PD1, PDL1, CTLA4) are changing the medical practices at an unprecedented pace. Phase I studies are now built to be informative for efficacy, phase II and phase III studies are frequently merged for a faster drug development. Clinical practice guidelines are also changing rapidly, following the improvement of survival obtained with these treatment in late metastatic phase, first line metastatic setting, adjuvant or neo-adjuvant phases.
Evaluation by governmental and regulatory bodies are very much challenged by this rapidly moving scientific context. A fragmentation of cancers into rare and homogenous entities on the molecular standpoint is now operated in a routine setting. These results in smaller groups of patients, with no historical control groups. In this context, clinical and translational research is closely linked to routine treatment.
36 As a recent example, several basket studies exploring new classes of tyrosine kinase inhibitors (TKI) acting on mutated NTRK proteins yielded tumor control rates in >95% of tumors bearing these proteins, across histological subtypes. With few exceptions, only 0.1 to 1% of most cancer present translocations involving these genes ; this is challenging the notion that the activity of a targeted agent is necessarily dependent on the histotype. In this new scenario, the definition of the control arms is extremely challenging. Standard treatment and guidelines have to evolve quickly to these rapid changes.
The cost of these novel approaches are of course important, and will impact on the health costs. Health care professional and governmental bodies have to work together to enable access to innovation, while limiting the access to reimbursement of less proven therapies. Importantly, improper management of patients is often costly, and optimal health care management is actually an important source of savings as demonstrated in several models in oncology. This revolution of precision medicine in oncology is linked to a rapidly developing competition worldwide for drug development.
In this context of a challenging international competition, the governmental and regulatory bodies have key roles to play : 1) to ensure a timely and efficient administrative, scientific and ethic approvals of innovative clinical research, 2) to facilitate the access to genomic characterization of samples ; 3) to work closely with academic and private partners to agree on the design of the research protocol, 4), to delineate a smooth and consistent health technology assessment pathway to enable patients to have rapidly access to innovation.
We will describe in this presentation the strategy, accomplishment, limitations and ways for improvement in these different topics in France.
37 9.4. Mathieu BOUDES
European Patients Forum
Mathieu Boudes joined the European Patients Forum in 2018 as the coordinator of the IMI-funded public/private partnership initiative - PARADIGM - on patient engagement during the lifecycle of medicines. Previously, he worked at the EU Rare Disease umbrella patient group, EURORDIS (2013-2017) in advocating for actions that foster the access of innovation to patients. He holds a PhD in Bio-Medical science from the University of Montpellier and an Accelerated Management Program from Solvay Business School.
Key message
The timely access to innovative medicines is of paramount importance for the patient community and it should resonate in other stakeholder groups. One innovative way to develop new medicines, is to optimise the terms of the early access versus the evidence trade-off. This concept is explicitly described in the idea of Medicine Adaptive Pathways to Patients (or MAPPs). MAPPs uses an iterative development and assessment plan with evidence generation over the entire life-span of the drug, harnesses real world data to inform follow-on licensing and reimbursement decisions and to manage risks, provides for the adjustment of the treatment-eligible population, manages utilization of the assets, facilitates the collaboration of all stakeholders and should ensures the sustainability of the innovation and healthcare systems.
The underlying principles were fleshed out in an Innovative Medicines Initiative (IMI) project, Accelerated development of appropriate patient therapies (ADAPT) and sustainable, multi- stakeholder approach from research to treatment-outcomes (SMART) in which both EURORDIS-Rare Diseases Europe and European Patients’ Forum were members. MAPPS is a not new thing, it is a new way to engage with all actors and builds on willingness to some actors to engage concretely existing initiatives or activity that already exist at the EU or at the member state level, such as the adaptive licensing at the European Medicines Agency (EMA), the Beneluxa, the MoCA and PRIME for instance.
The role of European Union and the European Commission would be to coordinate the creation of a pathway, including all stakeholders, from patient organisations to member state to rea when and where it is possible, when and where positive energies meet infrastructures. It would be a bold move, a timely move, and it would be welcome by the patient community that are waiting for better health outcomes.
38 10. MANIFESTO FOR NEW APPROACH FOR BETTER MEDICINE IN EUROPE Establishing treatment optimization as part of personalized medicine development
Forewords
Personalized medicine refers to a medical model that tailors the therapy to the patient’s molecular profile and other individual information. The principles apply to medicines as well as other treatment modalities, including surgery and radiotherapy. The concept though has specifically emerged due to the increased number of drugs targeting specific proteins responsible for a specific disease. The commercial promotion of genome-wide analyses has led to an increasing expectation among patients.
On the other hand, there are numerous drugs authorized on the market, with limited knowledge on how to use them for dose, sequence, combination and duration of treatment. Sub-optimal administration of costly treatments may generate unnecessary toxicity for the patients and negatively affects national healthcare budgets. Thus, there is a need for investigating the optimal way to use medicines (applied research or “Treatment Optimization”)1.
In Europe, most of the clinical research dedicated to therapeutic innovations aims primarily at regulatory approval. Once a drug enters the common market, each member state determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an regulatory approval-centred clinical research landscape may neglect patient-relevant issues in real-world setting, such as comparative effectiveness of distinct treatment options or long-term safety monitoring.
There is call for reforming the current system to a truly ‘patient-centred’ paradigm with systematically coordinated Treatment Optimisation in conjunction with drug development.2 The purpose of this manifesto is to gain stakeholders support for making Treatment Optimization a standard step in medicine development in Europe.
1 Lieu TA; Platt R. Applied Research and Development in Health Care - Time for a Frameshift. N Engl J Med. 2017 Feb 23;376(8):710-713. 2 Kempf E, Bogaerts J, Lacombe D, Liu L. 'Mind the gap' between the development of therapeutic innovations and the clinical practice in oncology: A proposal of the European Organisation for Research and Treatment of Cancer (EORTC) to optimise cancer clinical research. Eur J Cancer. 2017 Nov;86:143-149.
39 This manifesto was prepared by the European Organisation for Research and Treatment of Cancer (EORTC).
Direction for changes
1. Appropriate use of treatments is essential for optimizing patients’ health outcomes and preserving public health and healthcare budgets. Knowing the optimal dosage and duration of a treatment, used alone or in combination, is key for using it efficiently for the benefit of the patient and the society.
1. Treatment Optimization has to take place early. Treatment Optimization generating evidence for HTA, payers and clinicians should be initiated before the medicine’s full deployment on the market i.e. as soon as the safety and efficacy profiles are known but without delaying patients’ access to innovative treatments.
2. Treatment Optimization must cover all treatment options and modalities available for a given medical condition. Research investigating the optimal way to use a treatment should comply with high scientific standards and be free of commercial consideration.
3. Member states and payers should support Treatment Optimization at a relevant scale. Research addressing medical practice oriented questions must be funded by public sources. Member states should pool their resources for supporting Treatment Optimization when doing so on an international scale is justified.
4. Treatment Optimization will benefit from new models of partnership. Pooling expertise and resources from clinicians, patients, HTA and industry is essential for conducting sound Treatment Optimization research.
5. Treatment Optimization will support industry competiveness and reputation. Optimised usage will improve medecines’ impact on health and justify fair price.
Policy action
Europe in partnership with Member States should establish Treatment Optimization research as an official and mandatory step in the treatment access path to market, while ensuring this does not lead to further delays in patients’ access to innovative treatments.
National legislation should include provisions allowing for publicly funded international research to address collective therapeutic challenges. Member States should agree on a framework for joint optimization research whenever there is need for an international approach.
The EU’s next mission-oriented framework programme for research and innovation, Horizon Europe, should provide funding opportunities specifically aimed at supporting Treatment Optimization.
40 The manifesto is currently supported by:
European Organisation for Research and treatment of Cancer, Denis Lacombe. Biomedical Alliance in Europe, Axel R. Pries. European Patient Forum, Nicola Bedlington. European Federation of Pharmaceutical Industries, Nathalie Moll. European Alliance for Personalised Medicine, Denis Horgan. European Biopharmaceutical Enterprises, Barbara Freischem. European Cancer Patient Coalition, Antonella Cardone.
41 11. ABOUT STOA
11.1. Mission
The Science and Technology Options Assessment (STOA) Panel forms an integral part of the structure of the European Parliament. Launched in 1987, STOA is tasked with identifying and independently assessing the impact of new and emerging science and technologies.
The goal of its work is to assist, with independent information, the Members of the European Parliament (MEPs) in developing options for long-term, strategic policy-making.
The STOA Panel The STOA Panel consists of 25 MEPs nominated from the eight permanent parliamentary committees: AGRI (Agriculture & Rural Development), CULT (Culture & Education), EMPL (Employment & Social Affairs), ENVI (Environment, Public Health & Food Safety), IMCO (Internal Market & Consumer Protection), ITRE (Industry, Research & Energy), JURI (Legal Affairs), LIBE (Committee on Civil Liberties, Justice and Home Affairs) and TRAN (Transport & Tourism).
Mr Ramon Luis Valcarcel Siso MEP is the European Parliament Vice-President responsible for STOA and member of the Panel. The STOA Chair for the second half of the 8th legislature is Eva Kaili, with Paul Rübig and Evžen Tošenovský elected as 1st and 2nd Vice-Chairs.
The STOA approach STOA fulfils its mission primarily by carrying out science-based projects. Whilst undertaking these projects, STOA assesses the widest possible range of options to support evidence-based policy decisions. A typical project investigates the impacts of both existing and emerging technology options and presents these in the form of studies and options briefs. These are publicly available for download via the STOA website: www.europarl.europa.eu/stoa/.
Some of STOA's projects explore the long-term impacts of future techno-scientific trends, with the aim to support MEPs in anticipating the consequences of developments in science. Alongside its production of 'hard information', STOA communicates its findings to the European Parliament by organising public events throughout the year.
Focus areas STOA activities and products are varied and are designed to cover as wide a range of scientific and technological topics as possible, such as nano-safety, e-Democracy, e-Health and m-Health, bio-engineering, assistive technologies for people with disabilities, waste management, cybersecurity, smart energy grids, responsible research & innovation, etc.
They are grouped in five broad focus areas: eco-efficient transport and modern energy solutions; sustainable management of natural resources; potential and challenges of the Internet; health and life sciences; science policy, communication and global networking.
42 11.2. Administration
Directorate-General for Parliamentary Research Services (DG EPRS) European Parliament Rue Wiertz 60 B-1047 Brussels E-mail: [email protected]
Director-General Anthony TEASDALE
Director Wolfgang HILLER
Head of Unit - Scientific Foresight Unit (STOA) Theo KARAPIPERIS
STOA Secretariat Zsolt G. PATAKI, Head of Service Mihalis KRITIKOS Nera KULJANIĆ Gianluca QUAGLIO
Scientific Foresight Service Lieve VAN WOENSEL, Head of Service Philip BOUCHER Christian KURRER
European Science-Media Hub (ESMH) Svetla TANOVA, Coordinator Vitalba CRIVELLO Eszter FAY Silvia POLIDORI
Assistants Emilia BANDEIRA MORAIS Serge EVRARD Rachel MANIRAMBONA Damir PLEŠE
Trainees Riccardo MOLINARI Jens VAN STEERTEGHEM
43
As the number of authorised drugs that target specific proteins implicated in the disease phenotype increases on the market, and as next-generation sequencing and other technologies bring comprehensive genome-wide analyses to affordable levels, precision medicine begins to play a much wider role in routine practice. However, once a drug enters the market following regulatory approval, each EU Member State determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient-relevant issues in a real-world setting. The STOA workshop ‘Innovative solution for research in healthcare’, is an opportunity to discuss the implementation of an 'innovation-centred' system, exploring a truly 'patient-centred' paradigm with systematically coordinated applied clinical research carried out in conjunction with drug development.
This is a publication of Scientific Foresight Unit (STOA) EPRS | European Parliamentary Research Service, European Parliament
PE 624.276