Track 2: Regulatory Submission, Assessment and Inspection

Breakthrough Therapy – CMC Challenges Moderators: Ganapathy Mohan, Merck and Margaret Caulk, FDA

Background

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• FDASIA (2012): Section 901 Fast Track Drug Products, Section 902 Breakthrough Therapy Drugs, Section 903 Risk Benefit Framework

• Breakthrough Therapy Designation (BTD): granted for the benefit of the American Public, not for industry or FDA; drugs for serious and life-threatening conditions

1. Preliminary clinical evidence risk-based approach (Phase 1/Phase 2) 2. Reduced manufacturing, R&D, processing timelines, but no reduction

in CMC quality requirements from the Agency 3. Significant increase in communications between sponsor and FDA

• Timelines: dramatic reductions, especially compressed CMC development and review novel approaches used in BTD • Rolling submissions; supplements; PMCs/PMRs; less stability data, etc • Huge time invest from both industry and FDA

• MaPPs and Guidance: MaPP 6025.6, MaPP 6025.7, Guidance: Expedited Programs from Serious Conditions-Drugs and Biologics (2014)

CMC Challenges • CMC quality expectations for BTD drug is the same as fully developed

product • Quicker filing and review is challenging for both sides

• FDA: less available CMC data (safety, stability, processing, manufacturing); additional amendments during lifecycle; early submissions for facilities; treatment protocols/expanded access submissions; increased PMCs/PMRs to cover residual risk

• Industry: high clinical demands; product lifecycle planning; pre-approval inspection (PAI) readiness; establishing meaningful specifications; develop robust manufacturing processes

• Developing open lines of communication will assist in addressing many of these challenges for industry and the Agency

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Increased Communications • Various formal and informal communications between sponsor and

FDA are critical on decreased timelines • Sponsor informs Agency early of potential risks or issues • Agency tries to anticipate problem areas during lifecycle of BTD

• Key to mitigating risks and solving unexpected issues is early, open and increased communications between sponsor and Agency

• Industry has found that timely and meaningful communications with the Agency to be vital and game-changing when issues arise • FDA and sponsor collaboratively are able to explore, troubleshoot and

resolve unexpected issues throughout the lifecycle of BT drugs • FDA is able to adopt novel strategies to assess quality of BT therapies

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Conclusions • BT therapies provide expedited availability of life-saving drugs to the

American public • Shorter timelines result in challenges for industry and FDA, especially

for CMC • FDA is exploring and utilizing novel approaches to assess the quality

of BT therapies • Increased communications between industry and FDA is essential to

facilitate timely approval of BT drugs • Additional informal communications have the potential to:

• Mitigate development and processing issues, risks associated with BT drugs and IR’s for the submission

• Assist in leveraging comparability protocols, collaborative acceptance of provisional specifications and PAI site readiness/inspection timelines in accordance with lifecycle of BT drugs

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Pre-Approval and Surveillance Inspection Moderators: Mary Oates, Pfizer and Brian Hasselbalch, FDA

Pre-Approval and Surveillance Inspections

Pre-Approval Inspection Recommendations •Inspection team include reviewer with investigator •Same team inspects all facilities •Coordinate inspections with other regulators •Address findings through application review •Provide questions/issues in advance of inspection

Pre-Approval and Surveillance Inspections

Surveillance Inspection Recommendations •Promote/encourage highly functioning facilities •Collaborate on identifying risks; focus on “real risks” •Use metrics wisely; promote voluntary reports •Evaluate each facility on its own merits and whether it is improving against it’s plan

Risk-based Regulatory Assessment Moderators: G.K. Raju, Light Pharma and Ramesh Sood, FDA

Risk Based Regulatory Assessment 1. What is the Desired State?

• Quality • More open dialogue is desired from both industry and

Agency • Additional Transparency from industry regarding:

• Risk Uncertainty, Robustness, Consistency, Balance, Quality Control Strategies

• Incentives • Don’t penalize firms for transparency and sharing risk

assessment • Focus on Risk • Empowered Consumers • Quality vs. Compliance

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Risk Based Regulatory Assessment 2. What is the Current State?

• Recalls & Drug Shortages • Not enough transparency from industry or Agency • FDA would like to know how industry performs risk assessments

• Level of expertise • Are there risk assessments formal? • Are changes systematic?

• Industry Concerns: • Inconsistencies in regulatory assessments/inspections • Global divergence • Better understanding of product quality • Control strategies to increase FDA confidence

• Lack on Consumer Empowerment • Compliance vs. Quality 12

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Risk Based Regulatory Assessment 3. Path from “Here” to “There” (10-20 years)? • Collaboration between industry and Agency • Transparency from both sides to increase confidence and trust • Utilize successful examples from other industries to

standardize risk assessments (examples from aviation industry) • Both sides need to have the same intentions: operations,

vision, creativity, quality standards, etc. • Focus on patient safety no side has to “outsmart” other side • Create robust assessment tools, systems and re-evaluate risk • Stay focused on the big picture to increase transparency and

ultimately increase trust • Harmonize

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Risk Based Regulatory Assessment 4A. Barriers?

• Culture • Incentives • Regulations? • Lack of standardization of tools, techniques, systems • Trust between Industry & Agency is not fully established • Lack of open communication • Lack of Mutual Recognition • Lack of Lifecycle Focus • Submission Formats

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Risk Based Regulatory Assessment 4B. Potential Next Steps (1-5 yrs)?

• Industry Regulator Workshop • Pilot Alternate Options • Continue to improve transparency on both sides by

• Providing clear expectations to industry • Ensure appropriate control strategies are in place • Distinguish risk and characterize uncertainty • Share risk assessment techniques so Agency can

trust data • Determine and confirm predictability

• Build Mutual Trust 15

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How Quality Risk Management can Enable a More Effective Pharmaceutical Quality System Resulting in Improved Product Quality Moderators: Dave Doleski, FDA and Martin VanTrieste, Amgen

Quality Risk Management

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• Risk management drives the focus of Quality Management Systems (QMS), help define level of effort of those activities, and supports risk based decisions of Quality Management • Integration of Risk Management into Quality Management Systems drives

efficiency and effectiveness, and reduces: injury rate, backlog, inventory, capital, and losses

• Prioritizes and focuses product development efforts • Help define requirements and level of effort for investigations

• Quality Management System: Development, Evaluation of Quality Defects, Auditing and Inspection, Periodic Product Reviews, Change Control

Quality Risk Management

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• Quality risk management is used to guide development of a robust control strategy which ensures critical quality attributes are established and attained (risk assessment).

• The capability of the process and robustness of the control strategy to reproducibly deliver quality product should be re-evaluated periodically to ensure continued suitability (risk review).

• Risk management is incorporated into Manufacturing Governance • Product, site and system to have orthogonal reviews to obtain

comprehensive assessment of risks; maintain a risk file; • Updated based on production (nonconformities, process changes,

supplier changes), market (complaints, adverse events, and customer inquiries) and the Industry and Regulatory (new requirements, information on similar marketed products)

Quality Risk Management • Incorporating Risk Management into Manufacturing Governance:

• Long term activities (business strategy, policy, portfolio, enterprise goals), mid-term (operational strategy, key objectives, global governance, performance targets) and short term (resource deployment, shop floor execution, process control, monitoring)

• management involvement, escalation, decision making, and auditing • QRM scope should include worst-case situations prospectively,

resulting in the generation of knowledge understand risks and/or implementation controls to mitigate risks • Leadership should focus on risks associated with human behavior • Better understand perspective of individuals manufacturing the product • Implement appropriate levels of authority, incentives, controls to mitigate

quality issues • Importance of QRM in remediation of compliance issues after

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Quality Risk Management • Integrate QRM design across all systems to ensure orthogonal

reviews of entire process • Setup every site the same to maintain same level of quality control • Reduce confusion and streamline functionality of QMS • Use common quality practices

• Continue to improve quality control strategies based on common deficiencies, OOS, etc.

• Create global standards to have more accountability • Governance is very important to success

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FDA Integrated Quality Assessment: Common Deficiencies/Information Requests

Moderators: Ashley Boam, FDA and Tony Tong, Teva Speakers: Sarah Pope Miksinski, FDA, Susan Rosencrance, FDA, Mike Saleh, Pfizer, Siva Vaithiyalingam, Teva, and Tony Mire-Sluris, Amgen

Integrated Quality Assessment (IQA)

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The Office of Pharmaceutical Quality (OPQ) will use a team-based Integrated Quality Assessment (IQA) approach to maximize each team member’s expertise and provide aligned patient-focused and risk-based drug product quality recommendations, inclusive of drug substance, drug product, manufacturing, and facilities. Patient-Centric Quality Review • OPQ teams are expected to work in a highly collaborative model • Teams are expected to work within PDUFA/GDUFA timelines • Communication/discussion of quality risk and link to the patient are critical • Incorporates a robust and broad dialog

• Clinical framework (e.g. urgency) • Regulatory framework (review deliverables) • Appropriately considers prior knowledge (lifecycle) • Lifecycle management considerations • Strong collaboration for common understanding

• Reviewers focus on quality risks as they relate to patient needs and communicate IRs in terms of risk to clinical performance

Team-Based IQA • NDAs – evolved from CMC pilot and team-based reviews on

breakthrough submissions • ANDAs – evolved as part of OPQ reorg and GDUFA along with use

of real-time communication (IRs) • All original NDAs and ANDAs (post 10/1/2014) use IQA approach • IQA Team = application technical lead (ATL), regulatory business

process manager (RBPM), discipline reviewers, and ORA investigators, plus other members (e.g., policy, research) as needed

• Proactive meeting frameworks to facilitate meeting PDUFA/GDUFA timelines

• Effective team leadership (RBPM and ATL) is critical to success One Quality Voice

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Integrated Quality Assessment: Industry Perspectives

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Overall: • The purpose and benefit of the FDA IQA are cleared understood and supported by the industry Pfizer (NDA): • Between 2011-2015, review of approved NDAs; common areas for deficiencies were process control and

specifications (together 60% of deficiencies) • Consistent drug product quality assessments has been observed • IRs equate to deficiencies in information provided in a submission, but do not necessarily reflect a

deficiency in firms’ development programs • Improved alignment in certain areas; opportunities for further dialog & clarity (e.g., Established Conditions) Teva (ANDA): • Observed increase in total number and diversity in questions (apparent questions generated by a team) • Questions: Fundamental in nature w.r.t both product & process • Very high expectation on mitigation strategy on all risks • QbD implementation for all ANDA product development Amgen (Biologics): • Developing a modern Quality Management System and Quality by Design principles reflected throughout

ICH Guidances (Q8-Q11) and FDA Process Validation guidance • Balance of information provided in dossier vs. on inspection – how much info to provide and where – e.g.,

Risk Assessments, Process Verification data, Process Characterization/DoE • CPV Plan will require the merger of GMP compliance, the QMS, and science-based requirements - Blurs

the line between reviewer and inspector • Knowledge Management and creating a learning organization are essential to modern Quality Management

Systems – but too much data without relevance or context has limitations for regulatory oversight

Key Takeaways on IQA

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Alignment that the goal for both FDA and industry is drug product quality on behalf of the ultimate stakeholder – the patient Expect to see more effective, transparent and risk-based communication linking quality to clinical performance More discussion needed around QMS information (also a topic of ICH Q12 discussions)

• how to make it transparent to the agency to build trust • how to manage blurred lines between reviewers and inspectors

Suggested improvements to IQA process so far (still a work in progress): • FDA communication through IRs/deficiencies should make clear the “why” behind the question

– what is the concern FDA is seeking to address? • ATLs should have a stronger role in consolidating questions and ensuring properly supported • Keep and expand on the dialogue between FDA and industry

• Can FDA provide best practices and/or expectations for risk assessments (how much information to provide and where to provide it)?

• Potential for F2F meeting shortly after starting submission review for NDAs? • Industry encouraged to ask for clarity regarding questions that are unclear, appear to be

unsupported, or might generate unexpectedly voluminous response