EPRS | European Parliamentary Research ServiceScientific Foresight Unit (STOA)

PE 624.276 – January 2019

STOAworkshopInnovativesolutionsforresearchinhealthcareParticipants’booklet

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STOA Workshop

INNOVATIVE SOLUTIONS FOR RESEARCH IN HEALTHCARE

Developing novel approach to deliver better precision medicine in Europe

Participants’ Booklet

10 January 2019, 9:30-12:30Altiero Spinelli building, room 5E2

European Parliament, Brussels

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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

Join the conversation on Twitter by using the hashtag #healthSTOA and by tweeting at@EP_ScienceTech

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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

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11. About STOA

11.1. Mission ................................................................................................ 42

11.2. Administration ..................................................................................... 43

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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 PublicHealth, Belgium

10:00-11:15 SESSION I: CLINICAL, INDUSTRY PERSPECTIVES AND RESEARCHINFRASTRUCTURES

Moderator: Pier Franco CONTE, Professor of Oncology, University of Padua,Italy

Therapeutic innovation that matters to patients and societyRichard SULLIVAN, Professor of Cancer and Global Health, King’s CollegeLondon, UK

Integration of clinical research into heath care: treatment optimization for betteroutcome and rationale use of resourcesDenis LACOMBE, Director General of the European Organisation forResearch and Treatment of Cancer (EORTC)

Collaborations to accelerate patient focused translational research: The industryperspectiveMagda CHLEBUS, Executive Director of Scientific & Regulatory Affairs,European Federation of Pharmaceutical Industries and Associations (EFPIA)

Infrastructures for research and innovationEwan BIRNEY, Director of European Molecular Biology Laboratory (EMBL)

Q&A/short statements from the audience

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11:15-12:20 SESSION II: ROLE OF GOVERNAMENTAL & REGULATORY BODIES'

Moderator: Guy BRUSSELLE, Professor of Medicine, Ghent UniversityHospital, Belgium

The European Medicines Agency standpointGuido RASI, Executive Director, European Medicines Agency (EMA)

Why do we need new HTA methods for assessing complex and personalizedhealth technologies?Wim GOETTSCH, Professor at the University of Utrecht, Special Advisor atthe National Health Care Institute, Diemen, Zorginstituut (ZIN), TheNetherlands

A national perspective: the French caseJean-Yves BLAY, Director, Centre Léon Bérard, Lyon, France

Medicine Adaptive Pathways to Patients, an innovative development conceptbuilt 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 betterprecision medicine to patients'

Paul RÜBIG, MEP & STOA Vice Chair

Denis LACOMBE, Director General of the European Organisation forResearch and Treatment of Cancer (EORTC)

12:30–13:30 NETWORKING RECEPTION

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2. Introduction

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 righttherapeutic strategy for the right person at the right time, and/or to determine thepredisposition 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 diseasephenotype increases on the market, and as next-generation sequencing and other technologiesbring comprehensive genome-wide analyses to affordable levels, a much wider role forprecision medicine in routine practice is now a reality (Salgado, 2017).

However, once a drug enters the market following regulatory approval, each EU Member Statedetermines its real-world use based on its own criteria: pricing, reimbursement and clinicalindications. 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 tocreate a truly 'patient-centred' paradigm, with systematically coordinated treatmentoptimisation 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 grantmarketing authorisations across all its Member States (EPRS, 2015). The EMA's Committee for

SUMMARYThe current situation• Clinical research protocols are still not patient centred. Patient access is conditioned bydrug based eligibility criteria. Giving the patient the right treatment at the right time meansknowing the patient's molecular profile.• How effective is a treatment when used in real life? The question of optimal treatment useneeds 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 developmentprocess. The system should be inverted, with patients being proposed treatment protocolsmatching their molecular profile.• Improving data sharing and reducing research fragmentation in Europe is needed, as wellas 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 theEuropean level, providing access to new drugs in clinical trials as well as testing their use inreal life.

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Medicinal products for Human Use (CHMP) carries out a scientific assessment of applicationsand gives a recommendation on whether or not a medicine should be marketed. The CHMP iscomposed 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 promisingnew drugs, while guaranteeing their adequate safety and efficacy, and as far as possible, meetthe evidence requirements of other stakeholders, including patients, healthcare professionals,health technology assessment (HTA) bodies and others, who often demand evidence on relativeeffectiveness 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 aimsprimarily at regulatory approval. In this first stage, scientific issues on the efficacy of a newdrug are addressed in selected patient populations and lead up to European Medicine Agencyapproval.

Once a drug enters the market, the second stage begins, where research addresses clinicallyrelevant questions to tailor the therapeutic indications to 'real-life' clinical practice. Due to thisdiscontinuity 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 alsoaffects national healthcare budgets and adds cost to already highly priced treatments. Therefore,following the drug development phase, independent investigations are needed on the optimaluse of medicines (known as 'treatment optimisation').

Regulatory approval

The regulatory approval of new treatments does not address clinical issues relevant to patientsin real-world settings, such as: i) how to combine new treatments with the existing therapeuticoptions. Most patients may need some form of combination therapy, which is determinedindividually, based on a number of clinical and biomarker predictors (Klauschen, 2014); ii) howto 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, theabove-mentioned issues are studied mostly following EMA's approval and rely on the goodwilland agendas of independent research groups. The research gap between drug development andreal 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' andnot 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

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armamentarium of medicines, equipment, and techniques available (Kempf, 2017). Second, inorder 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 ofCTs (Kennedy-Martin, 2015). Finally, there is a lack of evidence that would make it possible torank 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 multiplepartners 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 reimbursethe 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 differentpriorities and methodology. For example, while pharmaceutical companies seek – among othersthings – profit, researchers want to develop their medical tools and academic career, regulatorsassess the therapeutic efficacy, and payers make sure that the medical innovations are worth thepublic investment (Figure 2). Each of the partners provides their support from a differentperspective, and this does not contribute to the reduction of the research gap between the firststage (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 ofresistance and relapse as patients receive treatments and/or enter in clinical trials during theevolution of their disease. Independent data collection is critically needed for all types of clinical,

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biological, imaging data and records alongside biomarker test results and all therapies received, indatabases that are constantly curated and annotated, to prepare the implementation of precisionmedicine.

Both traditionally and today, HTA bodies and payers make their decisions based on drugdevelopment research which remains relatively artificial (in vitro and in highly selected patientpopulations), 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/ortrials, in the best interest of the patient. New solutions are needed for optimal benchmarking ofemerging 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-termtoxicity monitoring of mechanism based therapies needs a new framework, beyond the registrationof drugs and into real-life usage over a prolonged period of time. Clinical research can be aimed atdeveloping new drugs, but also serves to validate therapeutic strategies, embedding new drugs inthe 'use' context. In short, there should be a continuum between clinical research for drugdevelopment and applied clinical research.

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A truly patient-centred solution is required, with the development of an innovative independentand collaborative central platform, sorting patients at the European level, which willsimultaneously 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 diagnosticstechnicians;ii) Drug development should be led by the commercial sector: industry in partnership withacademia;iii) Therapeutic optimisation should be led by the non-commercial sector: academia in partnershipwith 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 appliedclinical research carried out in conjunction with drug development.

The establishment of a new developmental framework through close collaboration betweenindustry, patient representatives, regulatory, governmental, academia and other stakeholderswould hopefully facilitate comparisons of assay performance before regulatory approval,harmonising the approval process. Such a framework could mitigate the somewhat problematiccurrent situation. The issue is ubiquitous in modern biomarker/drug development processesand is not related to particular targets or pathways (Salgado, 2017).

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This workshop will provide patients, clinicians, payers, HTA agencies, regulators,pharmaceutical companies, researchers, policy-makers and the public at large, with anopportunity to present their point of view and their innovative suggestions for future drugdevelopment 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 forhuman 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 ofcancer precision medicine. Oncoscience, 2014; 1: 504-509.

Martinalbo J, Bowen D, Camarero J, Chapelin M, Démolis P, Foggi P, Jonsson B, Llinares J, MoreauA, 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 therapeuticinnovations and the clinical practice in oncology: A proposal of the European Organisation forResearch and Treatment of Cancer (EORTC) to optimise cancer clinical research. European Journal ofCancer, 2017; 86: 143-149.

Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on therepresentativeness of randomized controlled trial samples and implications for the externalvalidity 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: bringingorder to chaos. European Journal of Cancer, 2017; 84: 325-334.

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3. About EORTCEuropean Organisation for Research and Treatment of Cancer

This workshop has been organised in cooperation with the European Organisation forResearch and Treatment of Cancer (EORTC). EORTC is a unique pan-European non-profitclinical cancer research organisation established in 1962 operating as an internationalassociation under Belgium law. It develops, conducts, coordinates and stimulates high-qualitytranslational and clinical trial research to improve the survival and quality of life of cancerpatients.

This is achieved through the development of new drugs and other innovative approaches, andthe testing of more effective therapeutic strategies, using currently approved drugs, surgeryand/or radiotherapy in clinical trials conducted under the auspices of a vast network ofclinical cancer researchers supported by 220 staff members based in Brussels. EORTC has theexpertise to conduct large and complex trials especially specific populations such as the olderpatient and rare tumours.

EORTC research network consists of over 5500 collaborators from all disciplines involved incancer treatment and research in more than 930 university hospitals in 27 countries. Itsresearch spans the entire spectrum from translational and preclinical research to large,prospective, multicentre, phase III clinical trials that evaluate new cancer therapies and/ortreatment strategies as well as patient quality of life.

Currently, EORTC is conducting 203 studies, and thousands of patients (85% from within theEU) participate in EORTC clinical trials. 25,000 patients continue to be followed on a yearlybasis and the EORTC clinical study database now contains outcome data for over 190,000cancer patients.

For further information, please visit the EORTC website: www.eortc.org.

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WELCOME & KEY NOTE SPEECH

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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's8th 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 2012to 2014.

Born in Northern Austria, Paul Rübig has been a member of the European Parliamentsince 1996 and belongs to the European People's Party (EPP). He is the owner of anAustrian blacksmith company and has a degree in Business Administration, Marketingand Production Engineering from the University of Linz, Upper Austria. He is marriedand has two children.

Paul Rübig is a full member of the Committee on Industry, Research and Energy and ofthe Committee on Budgets. He is Vice-Chair of the Delegation for relations with theKorean 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 ParliamentaryCommittee. Furthermore, Paul Rübig is a substitute member in the Committee onDevelopment. 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 toimprove their business environment.

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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 andImmigration, Social Integration and Poverty Reduction, between July 2014 and October2014.

She worked as State Secretary of Asylum, Migration, Social Integration and PovertyReduction, between December 2011 and July 2014.

She has served as Member of Parliament for the Brussel-Halle-Vilvoorde constituencyfrom 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 Chamberof Representatives from 2003 to 2007.

Maggie De Block graduated in Medicine in 1988 at the Vrije Universiteit Brussel.

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SESSION I

CLINICAL, INDUSTRY PERSPECTIVE ANDRESEARCH INFRASTRUCTURES

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6. Moderator Session I

6.1. Pierfranco CONTE

Professor of Oncology at the University of Padua, Director of the Division of MedicalOncology 2 at the Veneto Cancer Institute, Italy

Pierfranco Conte is Full Professor of Oncology at the University ofPadua, Director of the Division of Medical Oncology 2 at the VenetoCancer Institute in Padua and Coordinator of the Veneto OncologyNetwork which includes the Oncology Divisions of academic andcommunity hospitals in Veneto Region. He graduated in medicine atthe University of Torino in 1974, specialized in Oncology at the TorinoUniversity, Hematology at the Genova University and ClinicalImmunology at the Milan University.

Throughout his career, Prof. Conte has been involved in thedevelopment of new regimens for the treatment of solid tumors, withspecial emphasis on breast and ovarian cancer. He has been PrincipalInvestigator 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 ofEducation and Research and the Veneto Regional Government.

In the last years, he has designed and conducted trials of preoperative treatment with correlativestudies to identify biomarkers of treatment sensitivity/resistance in the different molecularsubtypes of breast cancer.

Prof. Conte has served in the editorial board of numerous oncology journals including: ClinicalBreast Cancer, Journal of Clinical Oncology, Oncologie, The Breast Journal, The Oncologist, Trends inMedicine.

Prof. Conte sits in several Committees: Faculty Member for Breast Cancer of the European Societyfor 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 OvarianCancer of the Italian Association for Medical Oncology (AIOM).

He has published more than 400 papers in peer-reviewed journals, most of whom focused on thebiological 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 andgenomic dysregulations of human tumors, in the dynamic inter-relationships between host andtumor and in the development of molecular targeted drugs. These achievements have allowed toestablish the frame of modern ‘4 Ps medicine’: Preventive, Predictive, Personalized, Participatory.

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However, we have to acknowledge that many patients develop and die because of cancer, withepidemiologic data still showing increasing incidence and mortality rates in many countries. It istherefore time to review the present model of drug development and delivery to patients. Severalsteps need to be revisited and challenged:

Trial design: Regulatory Authorities privilege statistical significance over clinical value. Arandomized 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 trialshowing a clinically worthwhile end point, in a well selected for prognostic/predictivecharacteristics’ patient population would not be accepted.

Trial end points: classic end points such as Progression Free Survival, Disease Free Survival, Overallsurvival, Objective Response Rates, Quality of Life should be adapted and valued differentlyaccording to the specific setting of disease and drug under study. A major example are trials withimmune checkpoint inhibitors where neither Response rates nor Progression Free Survival and noteven median Overall Survival are good predictors of patients’ outcomes, while landmark analysessuch as the percentage of patients alive at a fixed time point, better describe the efficacy of thetreatment.

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 lifeexperienced 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 sufficientstatistical 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 RegulatoryAuthorities also allowing for an HTA estimate of the new intervention.

Clinical Value Scales: both the American Society of Clinical Oncology (ASCO) and the EuropeanSociety of Medical Oncology (ESMO) have developed scales to evaluate the clinical value ofapproved drugs. These scales take into account different parameters according to the setting:curative versus palliative/non curative. Interestingly, a non-negligible proportion of drugsapproved 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 misalignementbetween Regulatory Authorities and scientific societies is not justifiable or sustainable and sharedvalues are now eagerly needed.

Evidence from experience: there is an increasing gap between evidence provided by pivotal trials andreal 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 allowedin clinical trials);

ii) applicability/transferability of modern technologies (NGS, ctDNA etc.) in the real world settingcan 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 populationwhich has not been pre-exposed to state-of-art treatments or compared to a suboptimal (or not theBEST) available comparator. Moreover, pivotal trials in most of the cases cannot address someimportant clinical questions such as sequences of treatments versus best treatment upfront;

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iv) safety and efficacy data provided by trials are based on limited time frames while in real worldsetting, patients are often treated for much longer period of times. Long term efficacy and safetydata derived from real world patients are necessary to better understand the risk/benefit ratio ofinnovative 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 untiltolerability or disease progression or, in responding patients with no evidence of disease, is it safeto stop the treatment? This question is becoming increasingly important since the use ofmonoclonal antibodies and immune checkpoint inhibitors: there are hundreds/thousands ofpatients with advanced cancers responding to antiHER2 antibodies or antiPD1/PDL1 antibodiesreceiving treatment for years and no data to support neither unlimited administration norstopping at some point.

Only data from registries or specifically designed trials in the frame of planned cooperationbetween all stakeholders (pharma companies, regulatory agencies, payers) might address theseissues.

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7. Speakers Session I

7.1. Richard SULLIVAN

Professor of Cancer and Global Health at King’s College London, Director of theInstitute of Cancer Policy and co-Director of the Conflict and Health ResearchGroup.

Richard Sullivan studies health systems, particular non-communicablediseases (NCDs) policy and the impact of conflict on health. He isProfessor of Cancer and Global Health at King’s College London, andDirector of the Institute of Cancer Policy (ICP) and co-Director of theConflict and Health Research Group.

As well as holding a number of Visiting Chairs, Richard is an NCDadvisor to the WHO, civil-military advisor to Save the Children, and amember of the National Cancer Grid of India.

His research focuses on global cancer policy and planning, and healthsystems strengthening, particularly conflict ecosystems. He is principleinvestigator on research programs ranging from automatedradiotherapy planning for low resource settings to use ofaugmented/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 theMiddle East and North Africa, as well as studies of the basic package of health services inAfghanistan, civil-military co-operation in health security, polio eradication and insecurity inPakistan, and use of intelligence in high security disease outbreaks.

Professor Sullivan qualified in medicine and trained in surgery (urology), gaining his PhD fromUniversity College London. He was also clinical director of Cancer Research UK between 1999 and2008. Following a period at the London School of Economics working on complex healthcaresystems he moved to King’s College London in 2011.

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7.2. Denis LECOMBE

Director General of the European Organisation for Research and Treatment ofCancer (EORTC)

Denis Lacombe graduated in medicine at the University ofMarseilles (France) in 1988 and obtained a Master Post DoctoralFellowship at The Roswell Park Cancer Institute (Buffalo, NY, USA)for research in pharmacology and pharmacokinetics from 1989to 1991. From 1991 to 1993, he worked as a Clinical ResearchAdvisor in charge of the development of a new drug inoncology in the pharmaceutical industry.

Dr Lacombe joined the EORTC in 1993 as a research fellowand quickly became a clinical research physician involved inthe conduct of clinical research from protocol development,through publication o f a number of oncology indicationsfrom phase I to phase III. He contributed to the strategicevolution of the EORTC pan-European clinical and translational research infrastructure bysetting up various supportive assets, such as regulatory and pharmacovigilance expertise aswell as partnership models with the pharmaceutical industry.

Denis Lacombe rose to the position of Director EORTC Headquarters in 2010: in 2015 h ewas appointed EORTC Director General. In his current position, Denis Lacombe is involvedin the coordination and administration of all EORTC activities in order to promote theEORTC as a major European organization in Cancer Clinical and Translational Research andis responsible for the organization of scientific activities, public relations and medium termstrategies as defined by the EORTC Board as well as for internal and externalcommunications.

He is the author of over 100 peer reviewed publications and communications on cancertherapy.

Key message

Bringing therapeutic innovation and latest science to patients while keeping patient interests atthe center is a challenging mission. Precision medicine and new approaches to clinical researchhave dramatically changed the field of treatment, notably for cancer. New treatments becomeavailable based on solid scientific rationale thanks to the understanding of molecular biology andimmunology.

However, optimal use of new anti-cancer treatments remains poorly documented. Patientpopulations (defined for example by biomarkers), treatment duration, sequence and combinationof treatments within the current treatment pathways are often poorly defined by clinicaldevelopments for regulatory purposes.

Therefore, major limiting factors to delivering cost-effective and affordable, evidenced-based careto clinical practice remain unaddressed. This leaves many gaps in the knowledge concerning theefficacy and therapeutic use of medicines; in addition, this can impose a significant financial

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burden on the health care systems. A new balance between the interests and needs of allstakeholders need to be re-defined around patient centeredness.

We argue that the evidence generated during the clinical development of these new products forthe purpose of getting marketing authorisations often does not address fundamental questionsconcerning the impact of these new interventions on the most relevant clinical outcomes; qualityof 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 marketingauthorization, after which the commercial sector may no longer pursue research for treatmentoptimisation.

Applied clinical research is needed to define effective practice-changing approaches, to bringtherapeutic innovation efficiently and consistently to cancer patients, and to address patientpopulations 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 morespecifically check point inhibitors changed the approach to treat melanoma. However, the clinicaldevelopment 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 clinicalstudies which were specifically designed to address this crucial question after the authorisation ofthese products.

Clinical research and the healthcare systems are long due for transformation. Access, affordabilityand effective use of treatments need intimate cross-links between research and care for successfulimplementation of precision medicine for European patients. Equality, affordability and the highquality utilisation of new treatments need intimate cross-links between research and care forprecision medicine to become a paradigm with real impact.

Re-engineering the forms and methods of therapeutic innovation around the understanding ofbiology, through applied clinical research would benefit to all, facilitating access while deliveringmore adequate information on value of treatments.

Europe should develop solutions generating the appropriate datasets that patients and healthcaresystems need for access. Independent applied clinical research should play a critical role in atransformative society.

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7.3. Magda CHLEBUS

Executive Director of Scientific & Regulatory Affairs at the European Federation ofPharmaceutical Industries and Associations (EFPIA)

Magda Chlebus is Executive Director of Scientific & RegulatoryAffairs at the European Federation of Pharmaceutical Industriesand Associations (EFPIA), representing the R&D-basedpharmaceutical industry in Europe.

Magda and her team are in charge of following policy andlegislative developments that influence the research andregulatory environments for the healthcare industry in Europe.This includes public private collaborations (inter alia theInnovative Medicines Initiative), enabling and sensitivetechnologies and the interface between new science andtechnology 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 tomedicines 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 supportingmedical and health system innovation, patient access to innovative healthcare solutions, Europe’scohesion and growth, as well as the continuing attractiveness of Europe as a location for lifesciences and investment.

And research-intensive health industries are reliant on a vibrant and connected health andresearch ecosystem. With dedicated tools - European Research Infrastructures, SME tools orinstitutional 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 fundamentalscience discoveries, and turns them into standardised processes that can be industrialized andupscaled so that the results can reach all patients and citizens. The pharmaceutical industry alongwith other life science industries plays an essential part in this process, also bearing most of therisks 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 healthfield, played an important role in setting new collaboration models where a neutral broker (theIMI office) brings together the demand and the supply side, the regulated and the regulators, theenablers and the gatekeepers from the continuum of health, research and care.

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This “radical collaboration” based on a community of brains and sharing what is not routinelyshared thanks to the concept of in-kind contributions, was heralded by Commissioner Moedas atthe IMI’s 10th anniversary: it is both a unique European specialty and an essential enabler turningfundamental science into solutions for the patients.

This unique European partnership for health delivers tangible, meaningful results to patients andsociety: Ebola, COPD, Asthma, Autism, Alzheimer, Epilepsy, Diabetes, Frailty, and more generallymedicines safety and health data management - all saw first in class developments which get usever closer to effective, safe and personalised treatments.

Having successfully tested the concept of radical collaboration and pushed boundaries ofprecompetitive research in one sector in IMI, we are ready to push it into new and completelyuncharted territory where different sectors could join forces with research and healthcarecommunities 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 asongoing IMI projects such as EPAD, C4C, ND4BB, PREFER or PARADIGM and others, withillustrate the case of radical collaboration to enhance Europe’s translational power and impact ofresearch activities and research infrastructures.

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7.4. Ewan BIRNEY

Director of European Molecular Biology Laboratory and European BioinformaticsInstitute (EMBL-EBI)

European Molecular Biology Laboratory and EuropeanBioinformatics Institute (EMBL-EBI) makes the world’s publicbiological data freely available to the scientific community via arange of services and tools, perform basic research and provideprofessional training in bioinformatics.They are part of the European Molecular Biology Laboratory(EMBL), an international, innovative and interdisciplinaryresearch organisation funded by 23 member states and twoassociate member states.Ewan is also a non-executive Director of Genomics England, andis a consultant and advisor to a number of companies, includingOxford Nanopore Technologies and GSK.Ewan Birney works in annotating the genome sequences of human, mouse, chicken and severalother 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 isdefining functional elements in the human genome.Ewan’s main areas of research include functional genomics, assembly algorithms, statisticalmethods to analyse genomic information (in particular information associated with individualdifferences) and compression of sequence information.

Ewan completed his PhD at the Wellcome Trust Sanger Institute with Richard Durbin, andworked 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 2005Benjamin Franklin Award for contributions in Open Source Bioinformatics. Ewan was elected aFellow of the Royal Society in 2014 and a Fellow of the Academy of Medical Sciences in 2015.

Key message

Big data genomics is transforming medicineDue 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, dataemanating from genome sequencing has become increasingly relevant to clinical research and tothe practice of medicine[1]. Simultaneously, human genetics and genomics at scale offeropportunities to change how we approach therapeutic target validation, which remains central todrug discovery research in both multinational pharmaceutical companies as well as smallbiotechnology companies[2].Data is critical to achieving the goals of precision medicine and the application of biologicalunderstanding to create clinically useful treatments or drugs has been greatly enhanced by

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genomic data, to the point where basic research and translational research now overlap. The vastswathes of human genomic data emanating from sequencing can be used to help in theidentification of genomic variations which, in turn, can be transformative in the diagnosis of raredisease, critical in the appropriate use of therapies in cancer and can serve as indicators of chronicdisease. The benefits of genomics are clear in the diagnosis of cancer, for example, where there isincreased 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 thechallenge of integrating and analysing data from multiple settings which acts as bottleneck to thedelivery of many of the potential benefits for European patients.

Research Infrastructure for R&I and precision medicine in EuropeA number of European governments are currently developing national genomic medicine plans toderive healthcare benefits from the genomics revolution Over the coming decade it is likely thatgenomic medicine will be mainstream in the developed world. It is against this backdrop thatEMBL-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, withthe goal of transfering knowledge and skills in the area of genomics and biodata to its 25 plusmember states in Europe.

Beyond the point of making data available for research and innovation, ultimately the next stepwould be the development of at least one biomedical informatics institute or network in each EUmember state, which would act as a coordinating centre of biomedical informatics networks. Theestablishment of such biomedical informatics institutes would in turn facilitate the availability ofdata for research and innovation as well as the translation of molecular biology information intothe clinic.

About the European Molecular Biology Laboratory and the European Bioinformatics InstituteThe European Molecular Biology Laboratory (EMBL) is Europe’s flagship intergovernmentalresearch 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 openbiological data repository for the storage, analysis and dissemination of large biological datasetsfor 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 Targetspublic-private collaboration, a unique, precompetitive partnership between companies and not-for-profit research institutes aimed at transforming drug discovery by improving the success ratefor developing new medicines. It was set up to systematically improve the identification andprioritisation of drug targets for safe and effective medicines.

References1. J. Vamathevan, E. Birney. A Review of Recent Advances in Translational Bioinformatics: Bridgesfrom 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 ReviewsGenetics, 2015: 16; 561–562.

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SESSION II

ROLE OF GOVERNAMENTAL AND REGOLATORY BODIES

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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) andinterleukin-5 (IL-5) in allergic asthma, he obtained his PhD in 1997. Asa respiratory physician with a keen clinical and scientific interest inasthma, 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” tomedical and biomedical students, respectively. Since 2015, he teachesthe course “Methods and design of clinical studies”. Currently, he ishead of the Laboratory for Translational Research of ObstructivePulmonary Diseases at Ghent University.

From September 2012 to October 2015, he has served the European Respiratory Society (ERS) asGuidelines Director. Since September 2016, he is the chair of the ERS Science Council. SinceSeptember 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 needfor bridging the gap between regulatory trials and healthcare through international collaboration ofall stakeholders. National governamental and European regulatory bodies need to be proactive andexpand the architecture of clinical research to maximize the benefit of scientific advances forpatients 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 becollected and analyzed to optimize the use of resources and maximize patient benefits [1]. The gapthat currently exists between market approval and real-life clinical practice requires a newinfrastructure for applied clinical research which truly serves the needs of patients, generates thedata needed to inform clinical practice, and needs to be fully integrated into the cycle of drugdevelopment, market approval and clinical application.

Patients’ needs are multiple; most commonly they do not depend on a single intervention and arelikely to change with the natural history of the disease. Therefore, the concept that therapeuticinterventions are developed with the sole purpose of market access – not anticipating anyquestions beyond registration – needs to be revisited. After market authorization, manyquestions still remain to be addressed by all stakeholders through applied clinical research,investigating long-term safety and real life effectiveness of treatments in broader patientpopulations [2, 3].

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Regulatory agencies such as the European Medicines Agency (EMA) are already beginning torequire such information, which is crucial not only for patients, but also for Health TechnologyAssessment (HTA) bodies and payers[4, 5]. It is vital that regulatory authorities and HTAbodies engage with the non-commercial sector over the disruptive knowledge thataccompanies the advent of precision medicine.

Patients have the right to participate at each strategic level in health research, ranging fromtreatment development and clinical studies to implementation in clinical practice [6]. Patients havealso the right to benefit from the latest scientific discoveries and to be treated according to thehighest level of clinical evidence.

Technologies allowing the stratification of patients according to biological/genetic features shouldlead to a major change in the healthcare research model: from “drug protocols/trials looking forpatients” to (fully biologically/genetically characterized) “patients looking for matchingprotocols/treatments” [7]. The novel model of healthcare research thus places patients truly at thecenter of the research and development (R&D) process. Moreover, trial endpoints should take intoaccount 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 researchinto healthcare. There needs to be an integrated pan-European infrastructure to support the use ofpatient data for health research. Such a system circumvents the expense of active long-term followup (and thus, allows adequate assessment of safety and cost-effectiveness of interventions) andprovides information that is accessible for independent assessment by health authorities.

Independent data capture (e.g., via electronic patient records) for all types of clinical, biologicaland imaging data, therapies received, and outcomes obtained, is critical for the affordableimplementation and validation of precision medicine. Combining this integrated infrastructurewith the patient-centered healthcare research at a European level maximizes the potential ofscientific advances for individual patients, but also will bring economic benefit to healthcareservices through the ability to target new and established treatments to those who are certain tobenefit from it.

References1. Moher D, Glasziou P, Chalmers I, et al. Increasing value and reducing waste in biomedicalresearch: 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 therapeuticresearch framework. Lancet Respir Med 2013;1.3. Pilette C, Brightling C, Lacombe D, Brusselle G. Urgent need for pragmatic trial platforms insevere asthma. The Lancet Respiratory Medicine 2018;6:581-3.4. Gassman AL, Nguyen CP, Joffe HV. FDA Regulation of Prescription Drugs. New EnglandJournal 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.

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7. Rothwell PM. External validity of randomised controlled trials: "To whom do the results of thistrial apply?". The Lancet 2005;365:82-93.8. Concato J. Study Design and “Evidence” in Patient-oriented Research. American Journal ofRespiratory and Critical Care Medicine 2013;187:1167-72.

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9. Speakers Session II

9.1. Guido RASI

Executive Director of European Medicines Agency (EMA)

Professor Guido Rasi began his second term as Executive Directorof EMA on 16 November 2015. From November 2014 to mid-November 2015, Professor Guido Rasi served as EMA’s PrincipalAdviser in Charge of Strategy.

From November 2011 to November 2014 he was the ExecutiveDirector of the European Medicines Agency and a member of itsManagement Board in the three years prior to this. He wasDirector-General of the Italian Medicines Agency from 2008 to 2011and member of the Management Board from 2004 and 2008. He wasmade full professor of microbiology at the University of Rome 'TorVergata' in 2008.

From 2005 to 2008 he was Director of Research at the Institute of Neurobiology and MolecularMedicine of the National Research Council (CNR) in Rome. From 1990 to 2005 Professor Rasiworked at the Institute for Experimental Medicine of the National Research Council, Italy. He hadteaching 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 workedas a physician in a hospital, researched and uptained his private practice. He is also the author ofmore than 100 scientific publications. Prof Rasi was born in Padova, Italy and is married with twochildren.

Key message

The public health potential inherent within the promise of precision medicine translating into realpatient access is recognised as a top priority across the European Regulatory Network. I believethe EMA in conjunction with its key stakeholders is critically positioned to support the deliveryof better precision medicines in Europe. The Agency must enable science and innovation to betranslated into real patient access through its advice and review mechanisms. We must alsorecognise the dramatic evolution within healthcare systems across Europe and adapt ourregulatory models accordingly.

We have just launched a public consultation on EMA’s regulatory science vision to 2025. As part ofthis vision the Agency sets out its ambition to foster an environment to support precisionmedicines development. In view of the extensive nature of this challenge a series ofrecommendations are proposed. These range from supporting early stage scientific developmentsin precision medicine, biomarkers and “omics” to promotion of the use of Real World Data indecision making.

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A significant reinforcement of patient relevance in evidence generation is proposed. Theimportance of collaborating with HTAs, payers and patients in progressing these developments isrecognised, in particular the establishment of a core health related quality of life Patient ReportedOutcome measure to implement in trials thus bridging the gap with comparative effectivenessassessment.

The challenges of increased utilisation of “big data” and medical device/companion diagnosticshave particular applications in precision medicine. The EMA/HMA task force on Big Data has justconcluded a two year reflection on this field and has issued a series of recommendationsaddressing issues such as harmonisation of data standards, characterisation of data quality andguidance on acceptability of evidence. The development of network competencies and specialistcollaborations and platforms to address both the challenges of big data and the convergence ofmedical device /diagnostics and medicinal products development is seen as an absolute priorityacross the network.

None of the above can be successfully delivered without an extensive outreach and collaborationwith our key stakeholders. The Agency strongly believes that this can be greatly advanced byworking in close conjunction with our European Commission colleagues through our key focalpoint of coordination within DG-Santé and reaching across to DG Research and Innovation, inparticular as they develop the Horizon Europe agenda.

Leveraging the potential inherent in such collaborations will greatly enable research andinnovation in regulatory science to be translated to real patient access to precision medicine. Thiswill allow us to apply cutting edge regulatory science to the advice and review processes, to becontinuously informed of scientific innovation relevant to decision making and to capitalise on acollaborative framework to articulate regulatory needs and challenges in the precision medicinespace.

It has been noted that there is a research gap between the drug development to regulatoryapproval stage and real world healthcare delivery that ultimately hampers access to precisionmedicine. I believe that the Agency and the wider network through the actions proposed within itsregulatory science strategy will actively pursue bridging that gap, developing novel approachesthat will deliver better precision medicines in Europe.

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9.2. Wim GOETTSCH

Affiliate Associate Professor at the University of Utrecht, the Netherlands, andSpecial Advisor at the National Health Care Institute, Diemen, the Netherlands

Wim Goettsch is currently Special Advisor HTA at theDutch National Health Care Institute.

He was the Director of the European network HealthTechnology Assessment (EUnetHTA). He has also aposition as an affiliate associate professor at UtrechtUniversity (The Netherland).

He has a PhD in immunology and an advancededucation 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) hasdeveloped gradually in response to greater emphasis on evidence-based decision-making inhealthcare, alongside increasing pressures on financing and delivery of healthcare. Much of thefunction of HTA and the use of its outputs in healthcare systems has advanced organically to someextent. Developments on both fronts have been reactive to political, societal and financial needsrather than being proactively ‘designed’ to address the needs of diverse and changing healthcaresystems.

That may also explain why the current use of HTA – as well as how its principles are applied – assupporting tools for making decisions on reimbursement/procurement and use of (new) healthtechnologies varies considerably across different healthcare systems in Europe, thus resulting ininefficiency in actual reporting of HTA in Europe. In response to these developments, Europeancollaboration on HTA has increased in recent years with greater emphasis on developing jointmethods and producing joint clinical assessments, also defined as relative effectivenessassessments, through the European network for HTA (EUnetHTA).

However, due to the complex nature of these European collaborations, the focus withinEUnetHTA has been predominantly on the clinical evaluation of single technologies, also knownas rapid relative effectiveness assessment (REA). At the same time, the treatment of patients hasbecome much more complicated due to the development of tailored health technologies includingcombinations of technologies, co-dependent technologies and personalised medicine.

As a result, the need has arisen for personalised HTA that is capable of identifying for whomhealth technologies work, hereby guaranteeing that the right treatment is provided, to the right

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patient, at the right time and leading to an increase in societal healthcare benefits. However, thedata to inform these types of decisions still do not exist. Moreover, limited data-sets for innovativemedicines and medical devices will make decision-making even harder. To add to this, companiondiagnostics, target therapies and digital health interventions are being introduced into healthcaresystems 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 throughoutEurope. Such a framework will facilitate the development of methodologies to deliver morecustomized information on the effectiveness and cost-effectiveness of complex and personalisedcombinations of health technologies.

The framework will be built on the concept of learning healthcare systems that link to treatmentcare pathways in which patients are treated with different combinations of therapies over time. Arobust data infrastructure is an essential requirement to realise this concept. It requires expediteddata analysis to allow more dynamic decision-making and circumvent limitations of the currentassessment paradigm (single assessments at market access for relatively large heterogeneouspatient groups).

This framework should be aligned with the European Commission’s strategy based on a singledigital market and digital society which is moving towards systems and decision makers that aremuch more dynamic than those of today: living guidelines, rapid update systems, making use ofhealth-related artificial intelligence applications, big-data, wearables, and digital technology.

Additionally, this framework will show how this concept of learning healthcare systems is linkedto the political reality of organising reimbursement for pathways for treatment within a broaderframework of solidarity-based healthcare funding. Finally, we need to work in close collaborationwith the European HTA organisations and its stakeholders pilot the implementation of thesemethods that will be derived from this framework in Europe.

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9.3. Jean- Yves BLAY

Director of the Centre Léon Bérard, Lyon, France

Jean-Yves Blay is the Director of the Centre Léon Bérard, thecomprehensive cancer center of Lyon and the Rhône-Alpes regionin France, since December 2014. He is an oncologist, researcher andprofessor at the University Claude Bernard Lyon 1.

Professor Blay has published over 400 peer-reviewed articles. Hehas been President of the European Organization for Research andTreatment of Cancer (EORTC) from 2009 to 2012. He has alsoreceived numerous awards such as the Hamilton Fairley Award in2012 from the European Society for Medical Oncology (ESMO) andthe Henry and Mary-Jane Mitjavile Prize in 2013 from the NationalAcademy of Medicine.

His research interests focus on clinical and basic research insarcomas, targeted treatment of cancer, the biology of breastcarcinoma and relation between tumor immunologic microenvironment and malignant cells withthe 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), theAmerican 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 therapidly growing knowledge on the genomics, biology and immunology of different cancers,informed by worldwide research projects characterizing the genome (TCGA, and ICGC) andimmune characteristics of human cancers.

In parallel to this effort, a large number of novel medications targeting activated mutated proteinson 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 arenow built to be informative for efficacy, phase II and phase III studies are frequently merged fora faster drug development. Clinical practice guidelines are also changing rapidly, following theimprovement of survival obtained with these treatment in late metastatic phase, first linemetastatic setting, adjuvant or neo-adjuvant phases.

Evaluation by governmental and regulatory bodies are very much challenged by this rapidlymoving scientific context. A fragmentation of cancers into rare and homogenous entities on themolecular standpoint is now operated in a routine setting. These results in smaller groups ofpatients, with no historical control groups. In this context, clinical and translational research isclosely linked to routine treatment.

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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 bearingthese proteins, across histological subtypes. With few exceptions, only 0.1 to 1% of most cancerpresent translocations involving these genes ; this is challenging the notion that the activity of atargeted agent is necessarily dependent on the histotype. In this new scenario, the definition of thecontrol arms is extremely challenging. Standard treatment and guidelines have to evolve quicklyto 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 toinnovation, while limiting the access to reimbursement of less proven therapies. Importantly,improper management of patients is often costly, and optimal health care management is actuallyan important source of savings as demonstrated in several models in oncology. This revolution ofprecision medicine in oncology is linked to a rapidly developing competition worldwide for drugdevelopment.

In this context of a challenging international competition, the governmental and regulatorybodies have key roles to play : 1) to ensure a timely and efficient administrative, scientific and ethicapprovals of innovative clinical research, 2) to facilitate the access to genomic characterization ofsamples ; 3) to work closely with academic and private partners to agree on the design of theresearch protocol, 4), to delineate a smooth and consistent health technology assessmentpathway to enable patients to have rapidly access to innovation.

We will describe in this presentation the strategy, accomplishment, limitations and ways forimprovement in these different topics in France.

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9.4. Mathieu BOUDES

European Patients Forum

Mathieu Boudes joined the European Patients Forum in2018 as the coordinator of the IMI-funded public/privatepartnership initiative - PARADIGM - on patientengagement during the lifecycle of medicines. Previously,he worked at the EU Rare Disease umbrella patientgroup, EURORDIS (2013-2017) in advocating for actionsthat foster the access of innovation to patients. He holds aPhD in Bio-Medical science from the University ofMontpellier and an Accelerated Management Programfrom Solvay Business School.

Key message

The timely access to innovative medicines is of paramount importance for the patientcommunity and it should resonate in other stakeholder groups. One innovative way to developnew medicines, is to optimise the terms of the early access versus the evidence trade-off. Thisconcept is explicitly described in the idea of Medicine Adaptive Pathways to Patients (orMAPPs). MAPPs uses an iterative development and assessment plan with evidence generationover the entire life-span of the drug, harnesses real world data to inform follow-on licensingand reimbursement decisions and to manage risks, provides for the adjustment of thetreatment-eligible population, manages utilization of the assets, facilitates the collaboration ofall stakeholders and should ensures the sustainability of the innovation and healthcaresystems.

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 bothEURORDIS-Rare Diseases Europe and European Patients’ Forum were members. MAPPS is anot new thing, it is a new way to engage with all actors and builds on willingness to someactors to engage concretely existing initiatives or activity that already exist at the EU or at themember 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 thecreation of a pathway, including all stakeholders, from patient organisations to member state torea when and where it is possible, when and where positive energies meet infrastructures. Itwould be a bold move, a timely move, and it would be welcome by the patient community thatare waiting for better health outcomes.

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10.MANIFESTO FOR NEW APPROACH FOR BETTER MEDICINE IN EUROPEEstablishing treatment optimization as part of personalized medicine development

Forewords

Personalized medicine refers to a medical model that tailors the therapy to the patient’smolecular profile and other individual information. The principles apply to medicines as wellas other treatment modalities, including surgery and radiotherapy. The concept though hasspecifically emerged due to the increased number of drugs targeting specific proteinsresponsible for a specific disease. The commercial promotion of genome-wide analyses has ledto an increasing expectation among patients.

On the other hand, there are numerous drugs authorized on the market, with limitedknowledge on how to use them for dose, sequence, combination and duration of treatment.Sub-optimal administration of costly treatments may generate unnecessary toxicity for thepatients and negatively affects national healthcare budgets. Thus, there is a need forinvestigating the optimal way to use medicines (applied research or “TreatmentOptimization”)1.

In Europe, most of the clinical research dedicated to therapeutic innovations aims primarily atregulatory approval. Once a drug enters the common market, each member state determines itsreal-world use based on its own criteria: pricing, reimbursement and clinical indications.Such an regulatory approval-centred clinical research landscape may neglect patient-relevantissues in real-world setting, such as comparative effectiveness of distinct treatment options orlong-term safety monitoring.

There is call for reforming the current system to a truly ‘patient-centred’ paradigm withsystematically coordinated Treatment Optimisation in conjunction with drug development.2The purpose of this manifesto is to gain stakeholders support for making TreatmentOptimization 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. 2017Feb 23;376(8):710-713.2 Kempf E, Bogaerts J, Lacombe D, Liu L. 'Mind the gap' between the development of therapeutic innovations andthe 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.

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This manifesto was prepared by the European Organisation for Research and Treatment ofCancer (EORTC).

Direction for changes

1. Appropriate use of treatments is essential for optimizing patients’ health outcomes andpreserving public health and healthcare budgets.Knowing the optimal dosage and duration of a treatment, used alone or in combination, is key forusing 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 initiatedbefore the medicine’s full deployment on the market i.e. as soon as the safety and efficacy profilesare known but without delaying patients’ access to innovative treatments.

2. Treatment Optimization must cover all treatment options and modalities available for agiven medical condition.Research investigating the optimal way to use a treatment should comply with high scientificstandards 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 doingso 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 forconducting 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 researchas an official and mandatory step in the treatment access path to market, while ensuring thisdoes not lead to further delays in patients’ access to innovative treatments.

National legislation should include provisions allowing for publicly funded internationalresearch to address collective therapeutic challenges. Member States should agree on aframework for joint optimization research whenever there is need for an internationalapproach.

The EU’s next mission-oriented framework programme for research and innovation, HorizonEurope, should provide funding opportunities specifically aimed at supporting TreatmentOptimization.

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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.

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11.ABOUT STOA

11.1. Mission

The Science and Technology Options Assessment (STOA) Panel forms an integral part of thestructure of the European Parliament. Launched in 1987, STOA is tasked with identifying andindependently 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 EuropeanParliament (MEPs) in developing options for long-term, strategic policy-making.

The STOA PanelThe STOA Panel consists of 25 MEPs nominated from the eight permanent parliamentarycommittees: 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 (LegalAffairs), 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 forSTOA and member of the Panel. The STOA Chair for the second half of the 8th legislature isEva Kaili, with Paul Rübig and Evžen Tošenovský elected as 1st and 2nd Vice-Chairs.

The STOA approachSTOA fulfils its mission primarily by carrying out science-based projects. Whilst undertakingthese projects, STOA assesses the widest possible range of options to support evidence-basedpolicy decisions. A typical project investigates the impacts of both existing and emergingtechnology options and presents these in the form of studies and options briefs. These arepublicly 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, withthe aim to support MEPs in anticipating the consequences of developments in science.Alongside its production of 'hard information', STOA communicates its findings to theEuropean Parliament by organising public events throughout the year.

Focus areasSTOA activities and products are varied and are designed to cover as wide a range of scientificand 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 energysolutions; sustainable management of natural resources; potential and challenges of theInternet; health and life sciences; science policy, communication and global networking.

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11.2. Administration

Directorate-General for Parliamentary Research Services (DG EPRS)European ParliamentRue Wiertz 60B-1047 BrusselsE-mail: stoa@europarl.europa.eu

Director-GeneralAnthony TEASDALE

DirectorWolfgang HILLER

Head of Unit - Scientific Foresight Unit (STOA)Theo KARAPIPERIS

STOA SecretariatZsolt G. PATAKI, Head of ServiceMihalis KRITIKOSNera KULJANIĆGianluca QUAGLIO

Scientific Foresight ServiceLieve VAN WOENSEL, Head of ServicePhilip BOUCHERChristian KURRER

European Science-Media Hub (ESMH)Svetla TANOVA, CoordinatorVitalba CRIVELLOEszter FAYSilvia POLIDORI

AssistantsEmilia BANDEIRA MORAISSerge EVRARDRachel MANIRAMBONADamir PLEŠE

TraineesRiccardo MOLINARIJens VAN STEERTEGHEM

As the number of authorised drugs that target specificproteins implicated in the disease phenotype increaseson the market, and as next-generation sequencing andother technologies bring comprehensive genome-wideanalyses to affordable levels, precision medicine beginsto play a much wider role in routine practice.

However, once a drug enters the market followingregulatory approval, each EU Member State determinesits real-world use based on its own criteria: pricing,reimbursement and clinical indications. Such aninnovation-centred clinical research landscape mightneglect patient-relevant issues in a real-world setting.

The STOA workshop ‘Innovative solution for research inhealthcare’, is an opportunity to discuss theimplementation of an 'innovation-centred' system,exploring a truly 'patient-centred' paradigm withsystematically coordinated applied clinical researchcarried out in conjunction with drug development.

PE 624.276

This is a publication of Scientific Foresight Unit (STOA)EPRS | European Parliamentary Research Service, European Parliament