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How can HTA’s in Asia respond to Increased Clinical Uncertainty: the potential for PBRSAs

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Adrian Towse presentation at HTAi, Toyko - May 2016

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How can HTA’s in Asia respond to Increased Clinical Uncertainty: the potential for PBRSAs

  1. 1. Adrian Towse Director of the Office of Health Economics Visiting Professor London School of Economics HTAi Tokyo May 2016 How can HTA’s in Asia respond to Increased Clinical Uncertainty: the potential for PBRSAs
  2. 2. HTAi Tokyo May 2016 Abstract for the panel (extract) This panel will discuss the clinical implications of expedited review and consequent clinical uncertainty and will explore whether outcomes-based risk sharing might be an appropriate solution. In this regards the panel will focus on how to implement risk sharing in the region, will examine case studies and international best practice and will identify and address barriers and opportunities.
  3. 3. HTAi Tokyo May 2016 Agenda • What is happening in the US and Europe? • The demand for CER / RE as well as expedited access • Changes in drug development paradigm? • The EU adaptive pathway • When does the evidence appear? • The potential and reality of performance based risk sharing • Implications for Asia •
  4. 4. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. www.imi.europa.eu Background RWE on disease, treatments, care pathways, unmet need etc Post Launch RWE on: use of new medicine, relative effectiveness, longer term outcomes Potential Value Confirm Value Comparative Trials. Pragmatic Trials, giving information on effectiveness More Focussed Context for current care and outcomes to inform initial assessments Evidence Synthesis to combine all sources of information: RCT + PCT + OBS Predict Value of new Medicine How much can be done Pre-Launch? Or should we get to Post-Launch sooner? Before Phase3 During Phase3 After Launch
  5. 5. Futurescapes: expectations in Europe for relative effectiveness evidence for drugs in 2020: http://www.futuremedicine.com/doi/pdf/10.2217/cer.15.7 Futurescapes: evidence expectations in the USA for comparative effectiveness research for drugs in 2020: http://www.futuremedicine.com/doi/pdf/10.2217/cer.15.6 The future of comparative effectiveness and relative efficacy of drugs: an international perspective: http://www.futuremedicine.com/doi/pdf/10.2217/cer.15.8
  6. 6. NEW DRUG DEVELOPMENT PARADIGM FOR 2020: MOST LIKELY SCENARIO FOR CER/RE New Seamless Framework Exploratory Research Confirmatory Trials Patient/Payer Engagement Approval Key Features • Patient/payer engagement early to ensure outcomes reflect those of importance to them • Smaller targeted trial brings drug to market earlier • Bayesian/adaptive designs to improve efficiency of trial development throughout the life cycle with clear decision points after each round of evidence development • Second trial in broader population is large simple trial with focused question • EMA requirements for post-authorization efficacy studies can be built into the second trial • Sequential cohort studies initially used to track off-label use; data used to design second trial Modeling, simulation , Proof of concept trials Enrichment, Adaptive Designs Sponsor Activities Partnerships RCT Biomarker+ Reimbursement LST Population 2 Pivotal Trials Archetype 1: Breakthrough drug studied only in small population with biomarker Sequential Cohort Studies Open Label
  7. 7. HTAi Tokyo May 2016 Agenda • What is happening in the US and Europe? • The demand for CER / RE as well as expedited access • Changes in drug development paradigm? • The EU adaptive pathway • When does the evidence appear? • The potential and reality of performance based risk sharing • Implications for Asia •
  8. 8. AL Shifts Evidence Timing, Amount and Use May 2015 Trusheim: Adaptive Pathways: What’s in it for Payers? 8 Current scenario Adaptive licensing scenario (illustrative) Patients treated with no active surveillance Patients in observational studies / registries Patients in RCTs License Initial License Full License Time (yrs) Time (yrs) Adapted by EU HTA from Eichler et al (2012) Adaptive Licensing: Taking the Next Step in the Evolution of Drug Approval, CP&T 91: 426-437 Phase III = = Source: Mark Trusheim
  9. 9. Adaptive Pathways Misconceptions • MYTH: Evidence standards are lower » Actually increases evidence over time » Multiple decision points change timing of patient access » Quid pro quo for developers: Earlier market access in exchange for continued monitoring and label changes based on that monitoring • MYTH: Development is fast and at lower cost » ONLY to FIRST decision. May increase if ongoing monitoring does not leverage payer & clinical systems » Entire clinical development program through indication roll-out & surveillance AGREED early • MYTH: Patients gain unfettered early access » Early patients must likely participate in tracking, registries and observational studies with associated informed consent » REMS with ‘teeth’ May 2015 Trusheim: Adaptive Pathways: What’s in it for Payers? 9 Source: Mark Trusheim
  10. 10. MOVEMENT TOWARD GREATER EVIDENCE “HARMONIZATION” IN EUROPE Post-authorisation efficacy studies (PAES) implemented Greater HTA and EMA coordination pre-launch Disease registries in some countries , and progress in EHRs Coordination across HTA bodies in demand for P-L studies, often linked to CED, P4P schemes Collaborations across large registries Full use of EHRs Good progress in methods Public-private partnerships have a major role AP applied to a variety of drugs Joint HTA and EMA coordination for pre-and post- launch
  11. 11. HTAi Tokyo May 2016 Agenda • What is happening in the US and Europe? • The demand for CER / RE as well as expedited access • Changes in drug development paradigm? • The EU adaptive pathway • When does the evidence appear? • The potential and reality of performance based risk sharing • Implications for Asia •
  12. 12. 12 Source: UW PBRSA Database Total Schemes: 369
  13. 13. HTAi Tokyo May 2016 • MEAs are used to give access to new technologies where traditional reimbursement is deemed inappropriate. • Three different forms of MEAs have been identified: • management of uncertainty relating to clinical and/or cost- effectiveness; • management of utilization to optimize performance. • management of budget impact; • The rationale for using these approaches and their advantages and disadvantages differ. • All forms of MEA should take the form of a formal written agreement among stakeholders, clearly identifying the rationale for the agreement, aspects to be assessed, methods of data collection and review, and the criteria for ending the agreement. Role for Managed Entry Agreements?* *Klemp, Frønsdal and Facey on behalf of the HTAi Policy Forum (2011) IJTAHC 27: 77-83
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  15. 15. HTAi Tokyo May 2016 Performance based risk sharing arrangements To manage utilization in the real world To provide evidence regarding decision uncertainty - Outcomes guarantees - Money back guarantees - Conditional treatment continuation - Budget capping - Utilization capping - Discounts - Price/volume Coverage with evidence development Performance linked reimbursement Intermediate endpoint Clinical endpoint - Only with research - Only in research - Process of care Pre-specified agreement No pre-specified agreement Examples of PBRSA Schemes UK: MS RSS Aus: Bosentan UK: Votrient France: DPP4; risperidone US Medicare: LVRS, PET, PTAS Italy: oncology schemes UK: Velcade, Lucentis etc.
  16. 16. HTAi Tokyo May 2016 Key Dimensions of Taxonomies Non-Outcome-Based Outcome-Based Patient- Level · Utilization capitations · Discounted treatment initiation · Fixed cost per patient · Price linked to per patient outcome · Conditional treatment continuation · Money-back guarantee Population- Level · Market share · Price-volume · Expenditure/budget cap · Price change/discount · Only with research (coverage with evidence development) using observational study or RCT · Only in research (patients only get access if they agree to participate in a study)
  17. 17. HTAi Tokyo May 2016 An overview of practice • Overview of the US • Case studies from the UK • Could have used: • Sweden • Italy • Netherlands • Australia
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  20. 20. HTAi Tokyo May 2016 Recent Public Sector Interest in the U.S. CMS (2016) proposes to test new Medicare Part B prescription drug models to improve quality of care and deliver better value for Medicare beneficiaries: • Risk-sharing agreements based on outcomes. This proposed test would allow CMS to enter into voluntary agreements with drug manufacturers to link patient outcomes with price adjustments. • https://www.federalregister.gov/articles/2016/03/11/2 016-05459/medicare-program-part-b-drug-payment- model
  21. 21. HTAi Tokyo May 2016 Velcade for Multiple Myeloma in UK Performance-based scheme development: • Resubmission to NICE with performance- based scheme • Conditional treatment continuation (stopping rule after 4 cycles) and outcomes guarantee (rebate for non-responders) • ICER with rebate, stopping rule: £20,700/QALY  NICE approval • Handling uncertainty: Mitigate negative consequences of uncertainty about value 21
  22. 22. HTAi Tokyo May 2016 VELCADE® Response Scheme (VRS) for patients with Multiple Myeloma at 1st relapse within the NHS in England, Wales and N.Ireland- Process Flow Janssen-Cilag/Ortho BiotechCustomer JC Drug SafetyVRS Administrator Orders VELCADE Evaluate response after a maximum of 4 cycles (16 vials) Response Y/N Yes1 No2 Claim validated3 Y/N Order further vials of VELCADE Replacement product delivered or credit note/cash refund issued to customer Yes No JC advises and discusses with customer Instruction to despatch replacement stock, issue credit note or full cash refund VRS claim logged (Audit and Healthcare Compliance) Signs VRS agreement with JC VRS claim forms are sent to Customer upon receipt of signed VRS agreement Hospital completes VRS claim form for replacement stock, credit or full cash refund for 16 vials. Fax/Post to JC VRS Claim Form copied to JC Drug Safety Dept. Drug Safety allocates a specific UK/DS Number and writes to clinician requesting more details on the non- response event Notes: 1 Response defined as a patient, at first relapse, with a 50% or greater reduction in serum M-protein, within 4 cycles of treatment, compared to baseline level immediately prior to VELCADE treatment 2 Non-response or minor response defined as a patient, at first relapse, having less than a 50% reduction in serum M-protein, within 4 cycles of treatment, compared to baseline level immediately prior to VELCADE treatment NB: 15% - 20% of patients do not have measurable serum M-protein levels, and for this group Bence-Jones urine protein (urine free light chains) could be used. Response defined according to the standard EBMT (European Group for Blood and Marrow Transplantation) criteria, i.e. at least a 90% reduction, compared to baseline. This would be compared to baseline immediately prior to VELCADE treatment (and within 4 cycles). 3 Claim Validation to check: • VRS claim form completed in full and signed
  23. 23. HTAi Tokyo May 2016 Votrient (pazopanib) for Renal Cell Carcinoma in UK • 12.5% discount on Votrient 's list price • Price parity with Sutent (a monthly cost of just under GBP2,000 (US$3,085) per patient). • Future financial rebate if Votrient proves inferior to Sutent with regards to its efficacy, in ongoing head-to-head trials. • Exact scale of the potential rebate not disclosed • The results of the COMPARZ study reported in October 2012 and showed non-inferiority in PFS 23
  24. 24. HTAi Tokyo May 2016 UK Multiple Sclerosis Risk Sharing Scheme: The Context NICE reviewed MS drugs for relapsing-remitting multiple sclerosis in 2001 • Models: 5 year : £380K-£780K/QALY; 10: £190K-£425K; 20: £40K-£90K • “beta interferons and glatiramer acetate are not cost-effective” • Dependent on long-term outcomes: Only 2-years of follow up data • Used assumptions + historical control to estimate long-term outcomes • Sensitive to (i) impact of a relapse on quality of life (ii) time horizon • Performance-based scheme development • Detailed monitoring over 10 years of a cohort of patients to confirm the cost- effectiveness of the MS treatments: Avonex, Betaferon, Copaxone and Rebif – Treatments initiated by specialist MS centres based on ABN guidelines, no bar to clinicians prescribing for patients outside these guidelines – Outcome measure is Expanded Disability Status Score. (EDSS) – Actual outcomes reviewed every 2 years against standard MS disease (non- treated) progression model through the EDSS scale. – Price adjustment to maintain CE threshold at £36,000/QALY
  25. 25. HTAi Tokyo May 2016 UK Multiple Sclerosis Risk Sharing Scheme: Two Year Results
  26. 26. HTAi Tokyo May 2016 UK Multiple Sclerosis Risk Sharing Scheme: Six Year Results1 Outcome of the year-6 analysis of the UK Risk-Sharing Scheme for interferon-beta and glatiramer acetate in multiple sclerosis. “The primary analysis of the scheme shows that, on aggregate, the drugs perform beyond target at 6 years, with both models showing a 42% reduction in the predicted progression of utility” 1. Duddy M, Palace J. Pract Neurol 2016;16:1 4-6
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  28. 28. HTAi Tokyo May 2016 Evidence from the literature Pueg-Peiro et al. (2011) conducted a systematic literature review to identify existing knowledge about the costs and benefits, assessed either quantitatively or qualitatively, of PBRSAs. Found little quantitative evidence. Neumann et al. (2011) reviewed five PBRSAs in the US and UK and conclude that they are hard to implement in practice. The results from Italy and other EU countries are also unclear and the schemes are in evolution. Overall, the literature suggests there is an important gap in structured ex post evaluation of PBRSAs. Utilisation schemes appear to have been more successful to date than CED schemes. However, the evidence is limited, mixed, qualitative, and partial.
  29. 29. HTAi Tokyo May 2016 Is risk-sharing feasible? First Bottom-line: Cost and practicality of evidence collection are critical factors in deciding whether to set up a performance-based risk- sharing agreement 1. Transaction costs are key. 2. Evidence collection costs are the main part of transaction costs. 3. It only makes sense to incur these costs if the uncertainties that can be “resolved” by the evidence are important (e.g. surrogates may take a long time) 4. If evidence collection is to occur, then (arguably) it makes sense to do this in a pre-agreed risk-sharing framework.
  30. 30. HTAi Tokyo May 2016 Is risk sharing feasible? (2) Second Bottom-line: Prices need to vary with Outcomes. Can prices ever go up? 1. Withdrawal of discount may be easier than change in list price 2. Other ways to change effective revenue, e.g. expansion of approved sub-groups for use
  31. 31. HTAi Tokyo May 2016 Agenda • What is happening in the US and Europe? • The demand for CER / RE as well as expedited access • Changes in drug development paradigm? • The EU adaptive pathway • When does the evidence appear? • The potential and reality of performance based risk sharing • Implications for Asia •
  32. 32. HTAi Tokyo May 2016 Alternatives to outcomes-based risk sharing: Options for payers at launch • Adopt now with no further evidence collection • Get it right at launch. But increasingly hard to resolve all uncertainties • Coverage with evidence development with no agreement • Renegotiation with additional information (e.g. France) but – No commitment to information collection – No commitment how new evidence will be used • Delay adoption and collect further information – Lose benefits of access -
  33. 33. HTAi Tokyo May 2016 In the short run the rate of MEA /PBRSAs may fall: • Realisation of complexity (and lack of preparedness of most health care systems to collect data and monitor patients) • Pressure of austerity for immediate savings not sophisticated schemes However, in the medium and long run it will become a routine tool for use in some cases: • Adaptive pathways in the EU and early access - it takes time to resolve uncertainty • Option of non-adoption of promising therapies is not credible • Key issues of information, management and exit will be tackled What will happen in the US and Europe
  34. 34. HTAi Tokyo May 2016 Implications for Asia • Need institutional flexibility • Need to build post launch data collection capability both registries and pragmatic trials • Focus on transferability of “coverage with evidence development” studies • Watch the EU Adaptive Pathways evolution and do it better and faster
  35. 35. Adrian Towse The Office of Health Economics Registered address Southside, 7th Floor, 105 Victoria Street, London SW1E 6QT Website: www.ohe.org Blog: http://news.ohe.org Email: atowse@ohe.org THANK YOU FOR YOUR ATTENTION

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