MEB experience: Adaptive Pathways & PRIME Andre Elferink Dutch Medicines Evaluation Board Member Scientific Advice Working Party / PRIME oversight group Thanks for slides by Stiina Aarum, Anna F. Cerrata , B. Hiemstra, BIO Holland, P. Mol, H. Ovelgonne

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 Major public health interest, unmet medical need. Reduce assessment time to 150 days. 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. 20171010-AE

‘Precursors’ Conditional Marketing Authorization New Pharmacovigilance legislation 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

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

Adaptive pathways concept 27 February 2019 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 Simplified concept is 1st approval 20171010-AE

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

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

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

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

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

Challenges HTA and EMA requirements not always well aligned. After marketing authorisation reimbursement may take many years Delaying patient 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’s reluctant to engage in earlier reimbursements - When uncertainties are still large - Subsidizing drug development - No chance to negotiate lower prices? - Payment by performance 20171010-AE

Challenges Companies may also be reluctant to engage in early reimbursement - Less control - Risk of low initial reimbursement - Remaining to become the final reimbursement Implementation of commitment to generate of additional data Confirmative efficacy data may be needed Confirmative efficacy data need to be generated Safety data will need to be generated After marketing authorisation there is limited use of real world data, from use of the product 20171010-AE

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

Eligibility to PRIME scheme 27 February 2019 Eligibility to PRIME scheme 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 No satisfactory method or if method exists, bring a major therapeutic advantage Introducing new methods or improving existing ones Meaningful improvement of efficacy (impact on onset, duration, improving morbidity, mortality) Scientific justification, based on: - Rational pharmacodynamy - MOA - Proof of concept nonclinical/clinical - Preliminary efficacy - Expexted magnitude and its relevance 20171010-AE

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

Experience one year of PRIME 27 February 2019 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

70% on oncology/haematology 34% of requests for ATMPs 27 February 2019 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

Eligibility criteria Unmet medical need: case by case basis 27 February 2019 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

Next steps Where are we now? 27 February 2019 Next steps Submissions Eligibility granted Kick-off mtgs Scientific advices Where are we now? Over 90 appl 19 13 8 products 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

Early Rapporteur appointment 27 February 2019 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

27 February 2019 Kick-off meeting 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. Multi disciplinary meeting with relevant experts from SAWP and CHMP and other committees; Introduction of product and development status by applicant; 20171010-AE

Enhanced scientific advice 27 February 2019 Enhanced scientific advice 7 products 11 SA requests following kick-off meetings 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-submission 3 adopted in 40 days 20171010-AE

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 enables early 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

Challenges Unmet medical need can not be defined unambiguously Cave: Disease slicing High expectations: PRIME is not a guarantee for success Cave: Regression to the mean Back to the ground : The work still has to be done Different expectations what should be in the clinical development plan – Clarify-Talk-Explain- future data 20171010-AE

Transparency Publication of monthly reports Broad characteristics 27 February 2019 Transparency Publication of monthly reports Broad characteristics Active substance (for eligible products only) High-level statistics 20171010-AE

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 Major public health interest, unmet medical need. Reduce assessment time to 150 days. 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. 20171010-AE

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