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Quality Risk Management and Submission Strategies for Breakthrough Therapies

IFPAC/Washington DCJanuary 22, 2014

Sarah Pope Miksinski, Ph.D.Acting Director, Division of New Drug Quality Assessment 2

ONDQA/OPS/CDER/FDA

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Outline• Background

– Quality– 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• Expedited programs for serious conditions– Draft guidance– Manufacturing and product quality considerations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

A Conversation of Risk…

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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

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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

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Linking Process - Product - Patient

Product

Patient

Process

Quality TargetProduct Profile

Critical QualityAttributes

Material Attributes &Process Parameters

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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

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• 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

Guidance for Industry (Draft)

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf

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• 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

Challenges for Expedited Reviews

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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.

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The Risk/Benefit Balance…

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Availability to patients Risks to Quality

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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

A Conversation of Risk…

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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

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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

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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

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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

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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

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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

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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

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FDA Innovative Drug Approvals• FY 2011-2012 Innovative Drug Approvals• Many were expedited reviews

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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)

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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

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Thank you!

Questions, comments, concerns:NewDrugCMC@fda.hhs.gov