Quality Risk Management and Submission Strategies for Breakthrough Therapies

Transcription

1 Quality Risk Management and Submission Strategies for Breakthrough Therapies IFPAC/Washington DC January 22, 2014 Sarah Pope Miksinski, Ph.D. Acting Director, Division of New Drug Quality Assessment 2 ONDQA/OPS/CDER/FDA 1

2 Background Quality Outline FDASIA Breakthrough therapies Expedited programs for serious conditions Draft guidance Manufacturing and product quality considerations Risk to quality CMC challenges for expedited submissions Best practices and submission strategies 2

3 A Conversation of Risk 3

4 Expectations for Quality Patients and caregivers assume that their drugs: Are safe Are efficacious Have the correct identity Deliver the same performance as described in the label Perform consistently over their shelf life Are made in a manner that ensures quality Will be available when needed 4

5 What is Pharmaceutical Quality? The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength and purity (ICH Q6A) The degree to which a set of inherent properties of a product, system or process fulfills requirements (ICH Q9) Patient & Product Product & Process 5

6 Linking Process - Product - Patient Patient Quality Target Product Profile Product Critical Quality Attributes Process Material Attributes & Process Parameters 6

7 FDASIA (2012) Section 901 Fast Track Drug Products Facilitate development and expedite the review of drugs for the treatment of a serious or life-threatening disease or condition that demonstrates the potential to address unmet medical need Section 902 Breakthrough Therapy Drugs Expedite the development and review of a drug for serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies Provide timely advice and interactive communication with the sponsor regarding the development of the drug Provide a collaborative cross disciplinary review utilizing senior managers and experienced review staff, as appropriate Section 905 Risk Benefit Framework Implement a structured risk-benefit assessment framework in the new drug approval process and regulatory decision making 7

8 Guidance for Industry (Draft) Expedited Programs for Serious Conditions Drugs and Biologics (2012) Communication is critical May involve a more rapid manufacturing development program to accommodate the accelerated pace of the clinical program Focus on early communication to ensure that the manufacturing development programs and timing of submissions meet the Agency s expectations for licensure or marketing approval Proposal of a commercial manufacturing program that will ensure availability of quality product at the time of approval 8

9 Challenges for Expedited Reviews Alignment of CMC development timelines with clinical development Consideration of manufacturing scale Coordination with contract manufacturers, as needed Early availability of manufacturing sites for inspection Accelerated manufacturing development likely with less information than typically available May warrant a risk-benefit assessment regarding risk of less CMC information vs. patient benefit 9

10 Considerations for Expedited Reviews Limited data available and/or submitted Manufacturing batch data Stability data Data available at time of submission Review timing constraints Frequent communication often needed Supply/availability considerations All rest on the overall risk to quality as well as potential mitigation strategies

11 The Risk/Benefit Balance Availability to patients Risks to Quality 11

12 Communications IND stage preind, EOP1, EOP2, prenda Additional meetings upon request CMC-specific meetings are an option Formal information requests NDA stage Formal information requests PDUFA V interactions (e.g. LCM) Teleconferences during review clock, as needed 12 12

13 A Conversation of Risk 13

14 Risk-Based Discussions Focus on identified risks and potential unidentified risks to quality Should happen at appropriate times during IND and NDA review Most effective when discussions are transparent and proactive (vs retroactive or reactive) Can be initiated by Applicant or Agency Proactively incorporate elements of risk mitigation Propose risk mitigation strategies as soon as possible Highly collaborative in nature Proactive conversations with all key players present 14 14

15 Expedited Reviews Best Practices General Discuss NDA submission strategy/timing as soon as possible Early assignment of CMC review team Proactive communication between review and inspection staff Early submission of manufacturing site information Submit with expanded access submission Submit with first piece of rolling review 15 15

16 Expedited Reviews Best Practices General Early discussion of stability data package Strategy Amount of data Early discussion of application-specific aspects New technologies Significant QbD aspects Use of post-marketing CMC commitments/requirements to mitigate risks 16 16

17 Expedited Reviews Best Practices IND/Pre-NDA discussions NDA submission strategy/timing Planned amendments Clinical/commercial comparability Strategy Supporting data Stability data package to be submitted Amount of stability data in original NDA Manufacturing sites 17 17

18 Expedited Reviews Best Practices IND/Pre-NDA discussions Significant Quality by Design elements Proposed regulatory flexibility Possible post-marketing CMC commitments/requirements Risks that may need postapproval mitigation strategies Availability of drug for commercial launch Plans for treatment protocols/expanded access submissions Other opportunities for early submission of certain CMC information 18 18

19 Expedited Reviews Best Practices During the NDA review Teleconferences as needed for clarification Agency- and Applicant-initiated Preceding/following information requests or inquiries Information Requests Staggered as necessary Responses submitted as available Early discussions of possible PMCs/PMRs 19 19

20 Expedited Reviews Best Practices During the NDA review Discussion of launch challenges Quick response times to Agency requests Proactive communication regarding incoming submissions Discussions based on risk and link to the patient Early discussions of CMC labeling Container/carton labeling 20 20

21 FDA Innovative Drug Approvals FY Innovative Drug Approvals Many were expedited reviews 21 21

22 Proposed Office of Pharmaceutical Quality Combines components of current CDER Office of Pharmaceutical Sciences and CDER Office of Compliance Intended to provide better alignment between all quality functions (review, inspection, research) Focus areas for new office: Integrated approaches for review and inspection Risk based approaches to review and inspection Efficiency and risk-based work prioritization Modern regulatory science approaches (e.g., clinically relevant specifications, statistical sampling) 22

23 Conclusions Patient/caregiver expectations of quality Safe, effective, high quality, correct identity, perform as labelled, available Pharmaceutical quality Expectations the same regardless of submission strategy Challenges with expedited/breakthrough therapies Alignment of CMC and clinical development Often warrant a risk/benefit assessment regarding risk of less CMC information vs. patient benefit Proactive communications regarding risk management encouraged during development and review Best practices focus on the identification of opportunities for early submission and/or dialog, as well as effective communication of risk to quality FDASIA and CDER s restructuring of quality functions hold promise for moving forward 23

24 Thank you! Questions, comments, concerns: 24