1. 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

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
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. AE

3. ‘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): 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.…) AE

5. 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 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 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 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 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 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 AE

11. 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 AE

12. 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 AE

13. 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 AE

14. 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 AE

15. 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 AE

16. 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 AE

17. 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 AE

18. 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 AE

19. 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 AE

20. 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 AE

21. 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; AE

22. 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 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 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 AE

24. 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 AE

25. 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 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
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. AE

27. AE