MEB experience: Adaptive Pathways & PRIME

1. MEB experience: Adaptive Pathways & PRIME Andre Elferink Dutch Medicines Evaluation Board Member ScientificAdviceWorking Party / PRIME oversightgroup Thanks for slides by StiinaAarum, Anna F. Cerrata , B. Hiemstra, BIO Holland, P. Mol, H. Ovelgonne

2. Early assessment tools PRIME Adaptive Pathways Major public health interest, unmet medical need. Dedicated and reinforced support. Enable accelerated assessment. Better use of existing regulatory & procedural tools. Scientific concept of development and data generation. Iterative development with use of real-life data. Engagement with other healthcare-decision makers. Accelerated Assessment Conditional MA Unmet medical need, seriously debilitating or life-threatening disease, a rare disease or use in emergency situations. Early approval of a medicine on the basis of less complete clinical data. Major public health interest, unmet medical need. Reduce assessment time to 150 days. 20171010-AE

3. ‘Precursors’ • Conditional Marketing Authorization • New Pharmacovigilancelegislation • Risk Management Plans • Periodic Safety Update Reports • Five-year renewal MAA Reproduced from Eichler et al. Clin. Pharm. Ther. 2012; 91(3): 426-437 20171010-AE

4. Adaptive pathways Aim: To get good medicines to the patient as soon as possible Support the selection of pathway of product development and (potential) earlier access to medicines through early dialogue involving all stakeholders (regulators, HTAs, payers, patients, learned societies.…) 20171010-AE

5. Adaptive pathways concept ”Widening of the indication" Time Final target indication in green, patient group with highest need in red 1st approval 2nd approval the sponsor could follow two strategies 1st approval 20171010-AE

6. Conditions • Prospective agreements on data requirements • Including data collection after registration • Including usage data, registry data • Between industry, HTA and regulator • Aligning HTA and licensing requirements • Post licensing data to • Reduce uncertainties • Widen the indication • Adaptive reimbursement to enforce collection of further evidence 20171010-AE

7. HTA/payers perspective • Viability of introducing adaptive licensing depends on the assessments by HTA bodies and decision by payers • Regulatory requirements for evidence need to be better harmonized with HTA requirements • Allowance of - Reimbursement to rise from a initial lower level - Decreasing uncertainties of B/R - Conditions to be met - Conditions to be fulfilled 20171010-AE

8. Initial experience • 39 products submitted as candidates • 11 selected for in-depth discussion with company • 4 SMEs • 5 are Orphan drugs • 2 are ATMP (Advanced Therapy Medicinal Products) • Main reasons for rejection were: • Development too advanced • Limited learning potential for a pilot 20171010-AE

9. Criteria for selection • Unmet medical need • An iterative development plan (start in a well-defined subpopulation and expand, or have a Conditional Marketing Authorisation, may be surrogate endpoints and confirm) • Real World Data (safety and efficacy) can be acquired to supplement Clinical Trials - RCTs / PAES / PASS / Registies / Large Data basis / Off-label use • Input / commitment of all stakeholders likely 20171010-AE

10. Rules of the game • Demonstration of a positive Benefit/Risk required. Involve all stakeholders to discuss how to demonstrate, and how to optimise requirements. • Embedded within existing regulatory tools Not a new procedure, not a new approval route. • A request for parallel EMA/HTA advice is expected to discuss science and requirements in depth i.e. a formal Scientific Advice letter • Acceptance/rejection in the AL pilot has no inference about approval potential 20171010-AE

11. Challenges • HTA and EMA requirementsnotalways well aligned. • After marketing authorisationreimbursementmay take manyyears • Delayingpatient access • HTAs do not form a homogeneous groups - Not all HTAs are interested in a scenario where reimbursements rise form am initial lower level - Some HTA’sreluctanttoengage in earlierreimbursements - Whenuncertainties are still large - Subsidizing drug development - No chance tonegotiatelowerprices? - Paymentby performance 20171010-AE

12. Challenges • Companies mayalsobereluctanttoengage in earlyreimbursement - Less control - Risk of low initialreimbursement - Remainingtobecomethefinalreimbursement • Implementation of commitment togenerate of additional data • Confirmativeefficacy data maybeneeded • Confirmativeefficacy data needtobegenerated • Safety data willneedtobegenerated • After marketing authorisationthere is limiteduse of real world data, fromuse of the product 20171010-AE

13. Solutions • Talk earlier: HTA involvement at earlier stage recommended - Scientific Advice optimises resource use - Parallel HTA / EMA adviceextremelyhelpful • Confidence in the regulation increase when commitments are fulfilled 20171010-AE

14. No satisfactory method or if method exists, bring a major therapeutic advantage Introducing new methods or improving existing ones Medicinal products of major public health interest and in particular from the viewpoint of therapeutic innovation. • Potential to address to a significant extent an unmet medical need • Potential game changer Meaningful improvement of efficacy (impact on onset, duration, improving morbidity, mortality) Eligibility to PRIME scheme • Scientific justification, based on: - Rational pharmacodynamy - MOA - Proof of concept nonclinical/clinical - Preliminary efficacy - Expexted magnitude and its relevance 20171010-AE

15. Final recommendation Procedure Policy issues EMA & SAWP reviewers Oversightgroup CAT* appointed sponsor SAWP CHMP Short, lean process, involving multiple committees for robust assessment *For advanced therapies 20171010-AE

16. Experience one year of PRIME 108 requests received > 90 eligibility requests assessed > 50% from SMEs 20 granted* + Publication of report and list of products on EMA website 22% success rate 20171010-AE

17. Requests covering wide range of therapeutic areas and product type 70% on oncology/haematology 34% of requests for ATMPs Most in rare diseases Several area’s of priority: Alzheimer’s Disease Rare cancers 20171010-AE

18. Eligibility criteria • Unmet medical need: case by case basis • Epidemiological data about the disease • Justification of ‘Recognised Entity’: Diagnostic, Prevention,Treatment options, SOC • Justification why the medical need is not fulfilled • Life-threatening / Non-life-threatening • Potential to significantly address the unmet medical need • New pharmacological principle • Description of observed and predicted effects, clinical relevance, added value and impact on health system • Expected improvement over existing treatments if applicable • Non-clinical /clinical data available • Proof of principle, proof of concept non-clinical, clinical • Stage in development Too early / Too advanced • Further development plan for different stages of development 20171010-AE

19. Submissions Eligibility granted Kick-off mtgs • Scientific advices Next steps Where are we now? 8 products Over 90 appl 19 13 • Written confirmation of PRIME eligibility and potential for accelerated assessment; • Early CHMP Rapporteur appointment during development; • Kick off meeting with multidisciplinary expertise from EU network; • Enhanced scientific advice at key development milestones/decision points 20171010-AE

20. Early rapporteur appointment Early Rapporteur appointment Opportunity for knowledge gain on the product Identification of relevant expertise and build adequate team Opportunity to influence development • Very positive views on the kick-off meeting • Importance of preparation and tailored agenda • Facilitate interactions across committees and with EMA Timing of PRIME eligibility is critical for fruitful engagement Involvement in follow-up scientific advice and workload Need to improve follow-up communications/updates 20171010-AE

21. To take place shortly after eligibility confirmation, at EMA • Facilitate initial interaction between applicant and EU regulatory network; • Discuss the overall development plan and regulatory strategy; • Provide recommendation on milestones and topics for scientific advice. Kick-off meeting • Multi disciplinary meeting with relevant experts from SAWP and CHMP and other committees; • Introduction of product and development status by applicant; 20171010-AE

22. 7 products 11 SA requests following kick-off meetings Enhanced scientific advice Multi-stakeholder 1 EMA/HTA parallel advice 2 with patients involved All aspects covered Quality, nonclinical, clinical Scientific advice Rapporteur involvement through one of SAWP coordinator Flexibility Shorter pre-submission3 adopted in 40 days 20171010-AE

23. In summary, • Eligibility review: robust, short time, in writing • Quality of applications received is generally high • Kick-off meeting: excellent opportunity to initiate interaction and flag issues • Rapporteur appointment enablesearly identification of potential issues • Excellent collaboration across committees • Iterative scientific advices with opportunity for multi-stakeholders involvement • Scheme triggers discussions across product type / class 20171010-AE

24. Challenges • Unmet medical need can not be defined unambiguously Cave: Diseaseslicing • High expectations: PRIME is not a guarantee for success Cave: Regressiontothemean Back totheground : The workstill has tobedone • Different expectationswhatshouldbe in theclinical development plan – Clarify-Talk-Explain- future data 20171010-AE

25. Transparency • Publication of monthly reports • Broad characteristics • Active substance (for eligible products only) • High-level statistics 20171010-AE

26. Early assessment tools PRIME Adaptive Pathways Major public health interest, unmet medical need. Dedicated and reinforced support. Enable accelerated assessment. Better use of existing regulatory & procedural tools. Scientific concept of development and data generation. Iterative development with use of real-life data. Engagement with other healthcare-decision makers. Accelerated Assessment Conditional MA Unmet medical need, seriously debilitating or life-threatening disease, a rare disease or use in emergency situations. Early approval of a medicine on the basis of less complete clinical data. Major public health interest, unmet medical need. Reduce assessment time to 150 days. 20171010-AE

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