Is there an efficacyeffectiveness gap?

Transcription

1 Is there an efficacyeffectiveness gap? The observed discrepancy between effects of a health intervention in routine clinical practice as compared with the effects demonstrated in randomised controlled clinical trials. (Adapted from Eichler et al., 2011) European network for Health Technology Assessment JA September

2 Which questions do we need to address? - What are RWD? - Non-RCT data versus experimental data or EPR data - How are RWD currently being used (by HTA organisations?) - In relation to the different types of context - Guidelines on RWD versus real use RWD in HTA reports - What are possible ways forward but also hurdles? - Access to RWD for research - Quality of RWD - Usability of RWD for decision-making on pricing and reimbursement European network for Health Technology Assessment JA

3 Definition of RWD Makady A, de Boer A, Hillege H, Klungel OH, Goettsch WG,. What Is Real-World Data (RWD)? A Review of Definitions Based on Literature and Stakeholder Interviews. Value in Health 2017; 20 (7): European network for Health Technology Assessment JA

4 Some thoughts on Additional data collection through different sources Amsterdam September 14, 2017 EUnetHTA Forum

5 Starting Point Clinical Data Package The marketing authorisation shall be refused if, [ ] a. the risk-benefit balance is not considered to be favourable; or b. its therapeutic efficacy is insufficiently substantiated by the applicant; Art. 26, 2001/83/EC There is no formal requirement to include two or more pivotal studies in the phase III program. However, in most cases a program with several studies is the most, or perhaps only feasible way to provide the variety of data needed to confirm the usefulness of a product in the intended population. In the exceptional event of a submission with only one pivotal study, this has to be particularly compelling with respect to internal and external validity, clinical relevance, statistical significance, data quality, and internal consistency CPMP/EWP/2330/99 EUnetHTA Forum 2017

6 Reasons for Uncertainty Incomplete efficacy / safety data on approval Conditional marketing authorisation (2006/507/EC) Exceptional circumstances (Art. 39 No. 7, 2004/726/EC) Surrogate endpoints Rare adverse events External validity of clinical trials Population: age, (co)morbidity, co-treatments, Usage: Dosage, indication, Differences in health care systems Treatment standards Specialist availability EUnetHTA Forum 2017

7 RWD in the life cycle of technologies Use of technology in health care Comparative or full HTA / REA HTA RWD Presenting and discussing requirements studies in ED* Rapid REA STAKEHOLDERS REGU Additional data collection Assessment for market authorization Collecting evidence in Preparing submission early development. files for EMA and HTA RWD RWD RWD Time line of innovation European network for Health Technology Assessment JA *Early dialogue 15 September

8 Additional data sources Broad Categorisation Randomised Data Non-Randomised Data Randomised Clinical Trials Health Services Data, Registries, Case Series, Advantages Disadvantages Causal Relationship External validity (depends on design) Established methodology EUnetHTA Forum 2017 Recruitment of participants and investigators Advantages Disadvantages Susceptible to Bias Availability (legal and organisational framework provided) Validity and Completeness varying Methodology needs further development

9 Area of Tension Proof of Causality Prevention of Bias Closeness to Practice Best Choice? Depending on Research Question and Methodology! EUnetHTA Forum 2017

10 Value of Non-Randomised Data Norris S et al Selecting observational studies for comparing medical interventions. In: Agency for Healthcare Research and Quality. Methods Guide for Comparative Effectiveness Reviews [posted June 2010]. Rockville, MD. EUnetHTA Forum 2017

11 Availability of Health Care Data German Situation - Legal and Infrastructural constraints Possibilities Challenges Prescription data Electronic Health Records Connection of in-patient and out-patient data Validity and comprehensiveness of out-patient diagnosis information Data protection rights Legal constraints on data usage Registries EUnetHTA Forum 2017

12 Dr Michael Ermisch Pharmaceuticals Department National Association of Statutory Health Insurance Funds GKV-Spitzenverband Reinhardtstr. 28 D Berlin arzneimittel@gkv-spitzenverband.de EUnetHTA Forum 2017

13 Additional data collection through different sources Current progress in EUnetHTA JA3 Work Package 5B François Meyer HAS European network for Health Technology Assessment JA

14 EUnetHTA actions with regard to evidence generation Objective of EUnetHTA Work Package 5 on Evidence Generation To help to generate, all along the technology lifecycle, optimal and robust evidence for different stakeholders, bringing benefits for patient access and public health. Initial evidence generation: Early dialogues / WP 5 strand A Post-launch evidence generation (PLEG) / WP5 Strand B Objectives of WP5B improving post-launch evidence generation, special focus on the use of registries as data source: main activity: PLEG pilots (B1) supporting activity: Standards Tool for Registers in HTA (B2) European network for Health Technology Assessment JA

15 Overview of Strand B (PLEG & Registries) Based on previous work of EUnetHTA JA2 and the PARENT Joint Action develop collaboration for cross-border PLEG in the form of pilots for drugs and non-drug technologies (B1) Enhance the use of high-quality registries in HTA through the PLEG pilots (B1), and through the definition of Standards Tool for Registers in HTA (B2) Develop a document on the best practices for PLEG and support permanent collaboration in the field European network for Health Technology Assessment JA

16 WP5B on PLEG and registries Coordination Global coordination by HAS (WP5 lead partner) Activity centers Pilots on drugs: AIFA (Italy), TLV (Sweden) Pilots on devices: Avalia-t (Spain) Quality standards for registries: NICE (UK) European network for Health Technology Assessment JA

17 Main activity : Pilots on PLEG What are the possible levels of cross-border cooperation for PLEG: definition of the research question advice on methodology for data collection once data are produced, re-assessment of the technology (link to EUnetHTA WP4) Out of scope of EUnetHTA: Organisation and financing of data collection Cooperation is key Preparatory work necessary to identify possibilities and conditions for best cooperation European network for Health Technology Assessment JA

18 Work plan for Year 1 of the Joint Action Preparatory work : identification/analysis of: projects to collaborate with stakeholders to involve in pilots legal and practical barriers to perform pilots Done To be communicated in October 2017 PLEG pilots: In parallel, start pilot(s) on technologies in cooperation with EMA for drugs and/or H2020 projects for medical devices No technology identified at EMA or H2020 Possibility of a disease specific pilot emerged European network for Health Technology Assessment JA

19 First pilot for PLEG : Qualification of registries Qualification of registries for a rare disease, cooperation with EMA I itatio to pa ti ipate y EMA s e so t of S ie tifi Ad i e to ualify disease registries Procedure = EMA Qualification of novel methodologies for drug development: First time this exercise is performed for registries at EMA Applicant: An academic society Topics that are discussed are both quality aspects and the parameters to be recorded in registries (so that they are adapted for regulatory assessment and HTA for this condition) Outcome: qualification opinion or qualification advice PLEG pilot: 4 participants (AQuAS, HAS, INFARMED, ZIN) 4 observers (AIFA, NICE, GBA, AEMPS-HTA) European network for Health Technology Assessment JA

20 Preview of next year (WP5B1 PLEG pilots) Completion of first PLEG (disease specific) pilot (October 2017) Launch next pilots: - continue topic selection discussions by WP5B1 activity centers (deadline for second pilot topic selection: December 2017) - explore the possibility to perform disease specific pilots with other projects (e.g. IMI RoadMap, Harmony etc.) - New H2020 projects for medical devices? European network for Health Technology Assessment JA

21 Quality standards for registries WP5B Year 1 Report on current use of register data by HTA bodies Done Submitted for publication Standards for Registers in HTA First draft done and circulated to EUnetHTA partners Year 2 Production of the upgraded version of the standards tool in light of received comments First testing of the standars Pilots begin in testing agencies (AVALIA-T, AQuAS, INFARMED) using draft standards tool Completion of vision paper for independently accrediting or assuring registered using the standards tool European network for Health Technology Assessment JA

22 Conclusion Action on PLEG at EUnetHTA level Not an easy path Very necessary in the context of innovative technologies with uncertainty: innovative medical devices, orphan drugs ATMPs likely to boost the production of PLEG Cooperation to be further developed Important role of payers (Decions on CED, MEA..) European network for Health Technology Assessment JA

23 Thank you Any questions? European network for Health Technology Assessment JA

24 Registries- Regulatory Expectations Session 4: Additional data collection through different sources EUnetHTA Forum Presented by Jane Moseley on 14 September 2017 Senior Scientific Officer Scientific Advice Office An agency of the European Union

25 Disclaimer The views presented are those of the individual and may not be understood or quoted as being made on behalf of the European Medicines Agency (EMA) or reflecting the position of EMA or one of its committees or working parties Please refer to legal texts and published guidance for decision making purposes No conflicts of interest 25 Registries - Regulatory Expectations 14 September 2017

26 Regulators expectations Primary concern: benefit risk assessment through out product lifecycle For scientific question on safety/efficacy right study - high quality timely data (control of chance, bias and confounding) Important considerations 26 Definition- what is a registry What is the role of registries in evidence generation for regulators in complete data landscape Real-life Regulatory experience of registry proposals and data collection Understanding /optimising the data collected from registries Engage early with regulators for evidence generation Registries - Regulatory Expectations 14 September 2017

27 Role of registries Not about lowering regulatory standards at marketing authorisation Not to replace RCT But primarily to address important questions that we cannot answer in standard RCTs or to better understand single arm data when RCTs are not/less feasible To facilitate a strengthened life-cycle approach Recognise that today that there are important questions that we do not answer prior to first approval and cannot be addressed through RCTs 27 Registries - Regulatory Expectations 14 September 2017

28 Regulatory guidances on registries 1) PAES- Scientific guidance on post-authorisation efficacy studies Categories of uncertainties (subpopulations, co-mediation, time, endpoints, real-life use, changes in understanding/science) Registries can allow wide variety of observational study design options Data quality is crucial. Measures to ensure data quality include common terminologies, quality control and standards Limitations confounding, disease or exposure classification is not specific enough, follow-up is missing, appropriate controls cannot be identified, representativeness and generalisability, effect of time period 28 Registries - Regulatory Expectations 14 September 2017

29 Registries in regulatory guidance 2) Guideline on good pharmacovigilance practices (GVP) Module VIII Postauthorisation safety studies (Rev 2) EMA/813938/2011 Rev 2* Corr** Most suitable - rare disease, rare exposure or special population. Not normally be used to demonstrate efficacy. For: post Marketing aurhtorisaton study effectiveness in heterogeneous populations, effect modifiers, compare risks different groups 3) Guideline on safety and efficacy follow-up and risk management of Advanced Therapy Medicinal Products EMA/CHMP/65416/2016 rev.1: 4) Guideline On The Exposure To Medicinal Products During Pregnancy: Need For Postauthorisation Data EMEA/CHMP/313666/ September 2017

30 Regulatory use and experience Experiences from scientific advice (SA) 12 months advices July to June procedures, 6 advices on registries Examples proposed uses of registry data in scientific advice and regulatory responses Rare condition, for natural history, to identify prognostic markers and endpoints suitable for phase III. Regulators suggested additional clinical parameters for collection but it was questioned whether the registry could provide sufficient patients, or for long enough duration and whether a broader group of registries might be needed. Rare condition; for natural history controls for pivotal study. Regulators :- regarding historical controls, besides the suggested matches, the applicant is advised to consider a match based on country/centre to reduce bias due to different treatment methods. A confirmatory trial will still be needed. 30 Registries - Regulatory Expectations 14 September 2017

31 Regulatory use and experience Current discussions in scientific advice Rare condition; ATMP: pre-marketing Authorisation Application (MAA) discussions on nature of registry (drug vs product) for post authorisation data collection safety and effectiveness Common neurological condition: for further PreMAA discussion of use of registries/cohorts post authorisation for longer term outcomes Rare condition, imposed registry for Post Authorisation Safety Study (PASS) for preparatory advice prior to PRAC submission - Post MAA discussion Presents opportunities for parallel consultations involving other stakeholders in planning Post Launch Evidence Generation?? 31 Registries - Regulatory Expectations 14 September 2017

32 Regulatory experience at Marketing Authorisation Registries as % total MA by category 100% a legally binding requirement for a registry was included as a condition of the marketing authorisation (Annex II) 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Categories N= 32 all orphan non-orphan conditional exceptional 9% 6% 3% 1% 4% Registries - Regulatory Expectations Bouvy, J. C., Blake, K., Slattery, J., De Bruin, M. L., Arlett, P., and Kurz, X. (2017) Registries in European postmarketing surveillance: a retrospective analysis of centrally approved products, Pharmacoepidemiol Drug Saf, doi: /pds Total MA September 2017

33 Regulatory experience at Marketing Authorisation Registries % of MA category 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Categories 33 orphan non-orphan conditional exceptional 29% 4% 12% 67% Registries - Regulatory Expectations Issues: Delayed completion Delayed start Slow accrual low data quality or missing data, Disease registries preferred 14 September 2017

34 Regulatory use of registries: Conclusions 1 Existing regulatory guidance on strengths, limitations and role of registries Role in evidence generation post authorisation mainly for very rare populations post authorisation safety Endpoint development and disease epidemiology Not replacing RCT data in the main for pivotal evidence Exiting- closing the circle with the availability of post authorisation data from registries and Impact of data collection Gap in workability of registries, and scope for improvement in quality and timeliness for post authorisation evidence generation EMA registries Initiative: better use of registry data, communication, awareness raising, harmonisation tools and tasks, qualifications 34 Registries - Regulatory Expectations 14 September 2017

35 Engage early Standard Scientific Advice Why apply Conceptual/protocol agreement before implementation and investment in study protocols Focused questions associated with products, before MAA, peri MAA, early post MAA Registry holders as (part) of consortium Multiple committee engagement (paediatrics, licensing, safety, advanced therapies) Agency advice on study protocol- scientifically/morally binding Some examples as per SA 35 Registries - Regulatory Expectations 14 September 2017

36 Engage early Qualification Procedure (advice or opinion) Not product specific, consortium, 2 way or 3 way engagement with registry holders, industry, both Why apply? Definitive regulators advice /answers on specific questions, on what to improve or opinion on the suitability of the registry for regulatory purposes, committee engagement (Safety, efficacy, advanced therapies..) Supports harmonisation, quality, interoperability, usability, managing risks, across lifecycle Example disease registry X: Target population for post-approval Registry Pharmacoepidemiology/Pharmaco-economic purposes which countries, and outcomes, Which variables, data retrieval frequency, summary data vs patient level raw-data What are the barriers? Balance pragmatism vs perfectionism? 36 Registries - Regulatory Expectations 14 September 2017

37 Engage early Parallel Consultation with other stakeholders Product Specific advice Applicant questions for stakeholder e.g. will the proposed study meet the stakeholder needs in post licensing evidence generation Develop applicant s position e.g. effectiveness objective and how this is sufficient for different stakeholders needs post licensing. how a product is/will be used locally, registry only? health care expenditure/organisation of care Need to understand how registry data will be used in decision making by stakeholders in subsequent evaluations Case due to start soon; applicants encouraged to come forward 37 Registries - Regulatory Expectations 14 September 2017

38 Conclusions 2 To progress use of registry data in the regulatory context: Need for on registry based discussions on actual products and proposals for specific uses (scientific question, study design, data source) in scientific advice/parallel consultation/ qualification procedure Optimisation of data quality, timeliness, and access Identification of perceived barriers for stakeholders 38 Registries - Regulatory Expectations 14 September 2017

39 Thank you for your attention Further information Contact me at European Medicines Agency 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0) Facsimile +44 (0) Send a question via our website Follow us

40 The Innovative Medicines Initiative: Discovery and validation of novel Role, especially in projects on big data and focus on interaction with stakeholders Nathalie Seigneuret EUnetHTA Forum, Amsterdam

41 IMI Europe s partnership for health IMI mission IMI facilitates open collaboration in research to advance the development of, and accelerate patient access to, personalised medicines for the health and wellbeing of all, especially in areas of unmet medical need

42 IMI Europe s partnership for health Agreement of industrial partners to work together on a real challenge for industry (non-competitive) and commit resources in kind contributions Bring new ideas from public sector, universities, SMEs etc. to address the challenge and work with industry partners competitive Calls for proposals Key to success: Scale provided through IMI funding Open collaboration in public-private consortia Outcomes should be transformative for pharma industry as well as having a clear public value to ensure that innovative medicines are developed efficiently and accessible to patients

43 IMI2 overall objectives improve the current drug development process through development of tools, standards &approaches to assess efficacy, safety & quality of health products. develop diagnostic & treatment biomarkers for diseases clearly linked to clinical relevance & approved by regulators reduce time to clinical proof of concept (e.g. for cancer, immunological, respiratory, neurological/neurodegen. diseases) increase success rate in clinical trials of priority meds (WHO) develop new therapies for diseases with high unmet need, (e.g. Alzheimer s) & limited market incentives (e.g. AMR) reduce failure rate of vaccine candidates in phase III trials through new biomarkers for efficacy & safety checks - IMI2 legislation, Article 2b

44 Examples of key areas addressed by IMI End-to-end approach from discovery through all the way to patient access of innovative medicines; Focus on unmet medical needs e.g AMR, neurodegenerative diseases Vision of personalised medicines : prevention, treatment and health management New taxonomy New targets Better understanding of disease burden Drug discovery New hits-to-lead candidates Manufacturing technologies Drug delivery Early research Early development New models Novel biomarkers Predictive models for safety Development of assays New endpoints, PROs, Clinical networks Innovative trials designs Modelling/simulation Late development Regulatory review & Patients access Benefit risk methodologies New outcome measures Digital health Patient engagement MAPPs

45 IMI Ecosystem for innovative collaborations IMI is a neutral platform where all involved in drug development can engage in open collaboration on shared challenges. All partners needed to be find transformative solutions to reduce late stage attrition, speed patient access and improve health outcomes and find solutions for a sustainable healthcare system Regulators Academia Charities SMEs Pharma companies HTA bodies Diagnostic companies Payers Healthcare practitioners Public health bodies Patients Other sectors (e.g imaging, nutrition )

46 An integrated approach closer to real life practice: real world data / big data / digital health Use of social media & novel technologies for Pharmacovigilance purposes WEB-RADR Recognising Adverse drug reactions Defining outcome based health care system Call 12 health data eco-system RADAR programme Remote Assessment of Disease and Relapse BD4BO Define and measures outcomes EHDN European Health Data Network EHR4CR Electronic health records for clinical research EMIF European Medical Information framewerk Re-use of patients level data GETREAL Incorporating Rear world data into drug development Potential of wearable devices to help prevent and treat conditions RADAR-CNS on depression, multiple sclerosis and epilepsy ADAPTSMART Medicines Adaptive Pathways to Patients Use of Electronic health records for clinical research

47 Big Data for Better Outcomes (BD4BO ) Programme Objectives: Exploit the opportunities offered by large data sets from variable sources to increase medical innovation and deliver better quality healthcare systems (= network of different health data sources) Support the evolution towards value-based and outcomes-focused sustainable healthcare delivery systems through engagement of key stakeholders

48 BD4BO programme at a glance

49 What s in the pipeline Ongoing 12th Call for proposals (deadline: 24 Oct 2017) Development and validation of technology enabled, quantitative and sensitive measures of functional decline in people with early stage Alzheimer s disease (RADAR-AD) Development of sensitive and validated clinical endpoints in primary Sjögren s syndrome (PSS) European Health Data Network (EHDN) Analysing the infectious disease burden and the use of vaccines to improve healthy years in aging populations For more info IMI 2018 scientific priorities under discussion IMI Think Big initiative Big data & digital health one of the areas under consideration

50 Why should HTA bodies involved in IMI? Scientific knowledge derived from many of IMI projects have direct impact on regulatory authorities, health technology assessment (HTA) bodies and payers process. Drug development more and more focused on patient experience; demonstration of real value to patients and society as a whole To ultimately ensure an end-to-end integration and maximise impact on the pharmaceutical value chain, need for engagement not only with regulators but also HTA bodies and payers. Applicant consortium asked to have in their proposal a plan for interaction with relevant milestones, resources allocated, when relevant.

51 How to get involved As full project partners by forming or joining an applicant consortium in response to an IMI Call for proposals. As members of project advisory boards to provide input to the consortium; no receipt of IMI funding (but costs may be covered by project); need to interact directly with he project. By proposing ideas for topics Benefits of engagement Influence relevance of project outputs Have access to the latest emerging science and be prepared to adapt Liaise with the network Receive funding when part of a project

52 More information Visit our website Sign up to our newsletter bit.ly/iminewsletter Follow us on Join our LinkedIn group bit.ly/linkedinimi us

53 Contact IMI

54 Disruptive Thinking Drug Development Transformation and Beyond Get ready for real life research! EORTC-EUnetHTA Denis Lacombe, MD, MSc EORTC, Director General Brussels, Belgium

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56 3 central challenges for real life data Methodological research to assess uncertainty Appropriate infrastructure and data structuring solutions A global vision to integrate new knowledge in the process leading to access in health care

57 Uncertainty in real life: Methodological gap

58 EORTC Capacities in Real-World Data Research Two cornerstones: Data The th ee pilla s of real-world data collection at EORTC Pillar 1: Merging with cancer registries Pillar 2: Registry-mediated high-resolution data collection Pillar 3: Self-reported data Research & Methodology External validity assessment ¹,² Long-term toxicity and outcome surveillance Comparative Effectiveness Research³ Randomization VS non-randomization ¹ L Liu et al Survival differences between patients with Hodgkin lymphoma treated inside and outside clinical trials. A study based on the EORTC-Netherlands Cancer Registry linked data with 20 years of follow-up Br J Haematol 176 (1), ² M Thong et al A Population-Based Approach to Compare Patient-Reported Outcomes of Long-Term Hodgkin's Lymphosma Survivors According to Trial Participation: A Joint Study From the Patient-Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship Registry and European Organisation for Research and Treatment of Cancer Eur J Cancer Prev Jun ³ E Kempt et al "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 optimize cancer clinical research. Eur J Cancer (in press)

59 Evidence-based strategy of working with registries -a comparison of follow-up time based on 1584 patients recorded in cancer registry (IKNL) and clinical trials (EORTC)

60 50-year long-term survival, disease progression, second primary cancers, cardiovascular disease in trial participants (N=1123) VS real-world patients (N=1741) Note: Results are adjusted for baseline differences of the two populations using inverse probability weight matching method.

61 Self-reported economic status among 2026 trial patients with Hodgki s Ly pho a VS healthy controls (EUROSTAT Labor Force Survey) in 4 European countries (NL, BE, IT, Fr) General employment status Perceived impact of cancer

62 Randomization VS Non-Randomization in HTA

63 Appropriate infrastructure Data structuring

64 Real life research: the challenge of data structuring DATA PROVIDERS (DP) STEERING COMMITTEE GOUVERNANCE DATA ACCESS RULES SCIENTIFIC PEER REVIEWED DP 2 DP 3 DP DP 5 DATA REQUESTORS (R) R1 PSEUDOANONYMISED DATA IN STANDARDIZED FORMAT Access to clinical trials CENTRAL DATA REPOSITORY EORTC R2 ANONYMISED AGGREGATED DATA OUT R3 R4 R5 MANDATORY REPORTING PUBLICATION RULES --- DP 1 DATA FORMAT STANDARDIZATION VARYING ELECTRONIC MEDICAL RECORDS HOSPITALS REGISTRIES Other real life providers

65 The EORTC YOU project

66 Integration in the process to access

67 Towards a data driven healthcare From o i s to e o o i s Fo t ials desig ed to lea Early clinical trials (R&D) Biology / imaging driven Integrated TR Screening platforms Collection of high quality data from various sources to eal life situatio Pivotal trials Highly targeted Large differences Population-based studies Real world data Quality of life Health economics HTA Pragmatic trials Burock et al. Eur.J.Cancer (2013),

68 Solutions Data structuring Robust clinical evidence

69 Opportunities

70 H2020 call topic SC1-BHC : HTA research to support evidence-based healthcare Final version to be released during fall Single stage. Deadline: 10th April EU contribution: between 5 to 10 million euros. Overall project goal: To develop new or improved HTA methodological approaches and frameworks, and foster methodological consensusbuilding at the European level.

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