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EUnetHTA Training course for Stakeholders - Choice of Endpoints forReimbursement Purposes in Europe (Mira PAVLOVIC)
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EUnetHTA Training course for Stakeholders - Choice of Endpoints for Reimbursement Purposes in Europe (Mira PAVLOVIC)

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1st WP2 F-t-F training Course for all EUnetHTA stakeholders - EUnetHTA Tools and Methodology. Brussels, 16 Jan. 2014

1st WP2 F-t-F training Course for all EUnetHTA stakeholders - EUnetHTA Tools and Methodology. Brussels, 16 Jan. 2014

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EUnetHTA Training course for Stakeholders - Choice of Endpoints forReimbursement Purposes in Europe (Mira PAVLOVIC) EUnetHTA Training course for Stakeholders - Choice of Endpoints for Reimbursement Purposes in Europe (Mira PAVLOVIC) Presentation Transcript

  • Choice of Endpoints for Reimbursement Purposes in Europe Mira Pavlovic, MD HAS EUnetHTA JA2 WP7 Lead Partner European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
  • Europa • Subsidiarity principle: • a central authority should have a subsidiary function, performing only those tasks which cannot be performed effectively at a more immediate or local level • Healthcare systems are financed and organized at national level • Healthcare interventions are evaluated by national HTA bodies • Criteria, procedures, rules are defined at national level European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 2
  • Mandate for EU co-operation • Reduce duplication of assessments (*) • Consider: • early dialogue during product development to improve initial evidence generation (**) EMA – HTA cooperation: • Member States, with the involvement of the EMA, should continue their efforts to consider how EPARs can further contribute to relative effectiveness assessments. (**) • Decision to set up a permanent network • Each Member State determines: • Criteria for admission to reimbursement • Choice of HTA bodies and decision bodies • Price: no EU-HTA decision or EU appraisal of added benefit (*) Article 15 DIRECTIVE on the application of patients’ rights in cross-border healthcare (**) Pharma Forum Recommandations European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 3
  • The timeline of reaching a sustainable and permanent HTA network in Europe Health Programme 2014-2020 2005 2011 Call for joint action Call for joint action 2006-2008 2009 2010-2012 2012-2015 2016-2020 EUnetHTA Project Legislation 2009 Call for project proposals EUnetHTA Collaboration EUnetHTA JA EUnetHTA JA2 EUnetHTA Scientific and technical cooperation Financial support HTA 2008-2011 2011-12 2013 2013+ Draft Cross Border Healthcare Directive. Article 15 on HTA network CBHC Directive now decided EU Cooperation on HTA Implementing Decision HTA Network DG R&I 2011 FP7-Health Horizon 2020 2012-Innovation-1 Calls New methodologies for HTA Health Care European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu
  • Collaborative EUnetHTA actions • Reduce duplication of work • HTA core model for REA of pharmaceuticals • Reduce heterogeneities in methodology of assessment • EUnetHTA methodology guidelines • Improve the quality and appropriateness of the data produced • Initial evidence generation • Additional evidence generation European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 5
  • Reduce heterogeneities in methodology of assessment EUnetHTA Methodology guidelines • Already produced 9 guidelines for the REA of pharmaceuticals 1. Choice of comparator 2. Clinical endpoints 3. Composite endpoints 4. Surrogate endpoints 5. HRQoL 6. Safety 7. Direct and indirect comparisons 8. Internal validity 9. Applicability  Ongoing: Guidelines for methodology assessment of medical devices and procedures and disease-specific guidelines European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 6
  • Endpoints for relative effectiveness assessment for reimbursement purposes European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 7
  • Endpoints A terminology adopted by EUnetHTA • Endpoint instead of outcome • Clinical endpoint = patient relevant endpoint • a valid measure of clinical benefit due to treatment; • the impact of treatment on how a patient feels, functions and survives. • Patient relevant endpoint may or may not be assessed by patient (PRO, ClinRO, ObsRO) • Patient-reported outcome (PRO): an umbrella term used to describe any outcome evaluated directly by the patient himself/herself, without interpretation by clinicians or others, and based on patients’ perception of a disease and its treatment(s). • HRQoL represents a specific type/subset of PROs, distinguished by its multi-dimensionality. European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 8
  • Endpoints for REA Framework Clinical endpoints = Clinical endpoints relevant to patients: death, pain (symptoms), disability, effects of the disease or its treatments on activities of daily living and quality of life Clinical endpoints (How a patient feels, functions or survives) Mortality Morbidity (e.g. symptoms, clinical events, function, activities of daily living, adverse events) European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu Health-related Quality of Life 9
  • Endpoints in clinical trials Primary, secondary, others Primary endpoint: • Main symptom/sign of a disease • Valid measure of clinical benefit ˗Hard endpoint (mortality, MI, stroke) or symptoms ˗Surrogate (HbA1c, BP, HIV viral load) ˗Single or composite • Relevant • Responsive to change Depends on: • Target population • Characteristics of disease • Core symptom/sign • Intended claim • Valid measure of clinical benefit • Hierarchy of endpoints in a trial (primary, co-primary, secondary, exploratory) European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 10
  • Endpoints for REA Trial still to power on primary endpoint Simultaneous assessment of all endpoints (e.g. clinical events relevant for the disease and its treatment, symptoms, HRQoL) considered relevant for patients in parallel to the primary endpoint HRQoL, symptoms: • One of REA endpoints (mortality, morbidity, HRQoL) • Systematically assessed (if data available) • Assessed “at the same level” as other endpoints • Its improvement (for equivalent effectiveness and/or harms) may be the basis for “added benefit” of a new drug compared to an adequate comparator European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 11
  • Endpoints for REA and added clinical benefit • Added clinical benefit: ˗HT does more good than harm (has an added benefit) in a target population compared to one or more intervention alternatives (standard of care) for achieving the desired results when provided under the usual circumstances of health care practice • Added clinical benefit of a new drug is assessed: ˗In head to head trials and from indirect comparisons ˗In adequate patient population ˗In comparison to an adequate comparator(s) ˗On relevant clinical endpoints:  Appropriately measured primary endpoint (final patient-relevant endpoint or acceptable surrogate)  Other endpoints considered relevant for the disease and aim of treatment European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 12
  • Clinical endpoints EUnetHTA guideline Clinical endpoint: a valid measure of clinical benefit due to treatment; the impact of treatment on how a patient feels, functions and survives. The relevance and hierarchy of the different endpoints will depend on: the research question, the disease/condition and the aim of treatment investigated (preventive, curative, symptomatic, palliative) REA: preference for ˗ objectively measured clinical EP ˗ long-term or final EP whenever possible (OS, all-cause mortality); Short-term endpoints acceptable for acute conditions with no long-term consequences European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 13
  • Surrogate Endpoints • In the absence of evidence on final patient-relevant clinical endpoint that directly measures clinical benefit, both biomarkers and intermediate endpoints are considered as surrogate endpoints in REA if they ˗reliably substitute for a clinical endpoint and ˗predict the effect of therapy (clinical benefit and/or harm). • The acceptability of an endpoint as a surrogate for a specific clinical endpoint is based on its biological plausibility and empirical evidence (validation) European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 14
  • Surrogate Endpoints (2) • The HTA should be based whenever possible on final patientrelevant clinical endpoints (e.g. morbidity, overall mortality). However, ˗for the initial (first) assessment, surrogate endpoints accepted if the validity of the surrogate/final clinical endpoint relationship has been previously clearly established. Sufficient safety database important. ˗For the re-assessment, effectiveness should be demonstrated whenever possible on final clinical morbidity and mortality endpoints (e.g. stroke, myocardial infarction, fracture). • The absence of data on clinical endpoints relevant for REA might be acceptable when a clinical endpoint is difficult or impossible to study (very rare or delayed) or target population is too small to obtain meaningful results on relevant clinical endpoints even after very long follow-up (very slowly progressive and/or rare diseases). European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 15
  • Composite Endpoints – To avoid if suitable single primary EP available – Number of components to be limited to 3 or 4 of similar clinical importance – Prior empirical evidence of the value of each components to be defined – Each component of a composite EP should be reported in the way it contributed to the result within the composite EP. All components should also be reported separately as secondary EP according to hierarchical levels – Effect of the intervention on all components – If a significant difference is obtained on the composite EP, but the effect is not homogeneous, it cannot be concluded that the treatment has an effect on the composite EP as a whole. European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 16
  • HRQoL HRQoL: • One of REA endpoints (mortality, morbidity, HRQoL) • Systematically assessed (if data is available) • Assessed “at the same level” as other endpoints • Relevance and hierarchy of the different endpoints will depend on the research question, on the disease and the aim of treatment investigated. The improvement in HRQoL alone (for equivalent effectiveness and/or harms) may be the basis for “added benefit” of a new drug compared to an adequate comparator European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 17
  • HRQoL (2) • The appropriateness of the HRQoL measure used depends on the purpose of the relative effectiveness assessment (REA): • to inform patients and health care professionals about the HRQoL benefit of an intervention as compared to its comparator • to inform health care policy makers about the relative value of a product • In the latter case, the decision-making context plays a crucial role: • is cost-effectiveness taken into account in drug reimbursement decisions and • are decisions taken within indications only or also comparing relative values across indications? European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 18
  • HRQoL (3) Across indications: ˗Generic HRQoL measures preferred, disease-specific measures may be added in necessary ˗Utility measures for cost-effectiveness Within indications to inform clinical decision making: ˗Disease-specific HRQoL sufficient ˗Generic measures may be added ˗Utility measures for cost-effectiveness Methodological considerations ˗cf EMA, FDA European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 19
  • Adequate comparator • A health care intervention or a HT with which a new pharmaceutical is compared in order to establish if this new pharmaceutical has an added therapeutic benefit. • Can be another pharmaceutical, medical device, procedure, radiotherapy, physiotherapy, surgery, providing advice, a combination of health care interventions carried out simultaneously or in sequence, watchful waiting • If drug, of a similar pharmaceutical class or not • Ideally: ˗the reference treatment in EU with good quality evidence on effect size and adverse effects ˗an EU marketing authorisation in the indication and line of treatment, optimally dosed or scheduled ˗Allows for a randomised controlled comparison. ˗Additional comparators if different severity/stages of disease (subpopulations) are considered. European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 20
  • What if Comparator: “standard of care” ˗ What to do when SC is an off-label drug? “Investigator’s best choice” (BSC? Routine practice?) ˗ Can it include an active treatment or only supportive care? ˗ Can it be both? What if a “traditional” primary endpoint is considered not (directly) relevant for patients? (e.g. BP, HbA1c) EUnetHTA multi-HTA early dialogue recommended European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 21
  • Endpoints for HTA and added clinical benefit Added clinical benefit of a new drug is assessed: ˗in adequate patient population ˗in comparison to an adequate comparator ˗Direct and indirect comparisons ˗on relevant clinical endpoints: ˗Primary endpoint (final patient-relevant endpoint or acceptable surrogate) ˗Other endpoints considered relevant for the disease or its treatment European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 22
  • Relative effectiveness assessment USA - FDA road map European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 23
  • Understanding the Disease or Condition European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 24
  • Conceptualizing Treatment Benefit European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 25
  • Selecting/Developing the Measure • Measure: ˗ exists, ˗ does not exist, ˗ exists but needs to be modified • The selection criteria for adequate measures/endpoints are very similar to those described by EUnetHTA European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 26
  • Global development for global registration? DIFFERENT • Regions: EU, USA, Japan, other regions • Regulatory requirements • Pricing and reimbursement criteria • Medical practices: patient management, hospital care, concomitant treatments, invasive procedures • Lifestyle: diet, tobacco, alcohol, sun exposure, compliance… Differences in intrinsic and extrinsic factors (ICH-E5) I: genetic polymorphism, age, weight E: environmental and cultural factors Differences in outcomes observed regionally WHATEVER THE TYPE OF OUTCOME (mortality, symptom scales) European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 27
  • Divergent regulatory outcomes in EU and USA Period: January 1995 to March 2009 • 31 products approved in the US but had negative outcome in Europe • 24 products approved in Europe but had negative outcome in the US Reasons for negative outcome: Clinical efficacy: EU neg: 19, Clinical safety: EU neg 14, Study design: EU neg 7, Comparators: EU neg 4, Further data needed: EU neg 12, US neg: 9 US neg 11 US neg 1 US neg 0 US neg 15 European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 28
  • Endpoints to show treatment benefit Links to make • With national assessments/requirements for pricing and reimbursement • With all stakeholders ˗With regulators • EMA: ongoing • FDA: road map to patient-focused outcome measurement in clinical trials ˗With developers ˗With payers European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 29
  • EUnetHTA early dialogue • Early Dialogue/scientific advice between HTA bodies and companies ˗Multi HTA Early dialogue ˗Supported by EC, Part of EUnetHTA JA2 (2012 – 2015) • Experience to get on ˗Consolidated/transparent/harmonised(?) views on the initial and additional evidence requirements ˗Assessment methodology requirements tested on real examples of product development ˗Help develop disease-specific guidelines • Develop sustainable collaboration ˗Among HTA bodies ˗With regulators ˗With national payers/other parties European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 30
  • Multi-HTA Early dialogue JA2 WP7 ED pilots • 10 in total, all on drugs • 2 pre-pilots (2012) and 8 pilots (2013) • Coordinated and hosted by HAS, France • HTA participants: AIFA, ASSR, IQWIG, GBA, NICE, HVB, CVZ, KCE/INAMI, GYEMSZI, TLV and HAS • EMA invited as observer • All documents remain confidential (unless explicit company’s request) • Various therapeutic fields • Small and big companies • One or 2-day FTF meeting (one product/day) • Successful experience: improvement of collaboration between partners and process efficiency European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 31
  • Additional ED (2014) EC Call for tender In addition to EUnetHTA ED • At least 10 EDs - 7 drugs and 3 MD/diagnostics/procedures • At least 10 HTA organisations. • Consortium HAS (lead) + 13 partners, selected by EC • SEED: Shaping European Early Dialogues • Regulators, payers, patient representatives as observers. • Sustainable process to put in place, including collaboration with EMA • Kick off meeting (D1): October 21, 2013 • Preliminary work : ˗procedures ˗Templates for BB (medicines, MD) • All ED in 2014, interim report after 5 ED • Model for permanent network at the end European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 32
  • Disease-specific guidelines for technology developers ˗CER on the Treatment of Chronic Wounds (CMTP) ˗Green Park Collaborative (CMTP): ˗Alzheimer’s disease ˗PRO in oncology ˗Diagnostics ˗EUnetHTA Disease specific guidelines: initial and additional evidence requirements to support effectiveness and cost-effectiveness 1st guideline: Osteoarthritis European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 33
  • ED and DSG integrate EUnetHTA reasoning on endpoints and methodology of assessment • ED example FOR DISCUSSION: ALL • Indication: locally advanced unresectable or metastatic pancreatic adenoK 1st line • XX+gemcitabine vs gemcitabine alone • Superiority trial • PE: OS European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 34
  • Acknowledgements EUnetHTA partners (guidelines), Eric Abadie (regulatiry input), Laurie Burke (FDA road map) European network for Health Technology Assessment | JA2 2012-2015 | www.eunethta.eu 35