Dr. Earl Dye CMC/GMP Considerations for Expedited Development Programs

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1 Dr. Earl Dye CMC/GMP Considerations for Expedited Development Programs Earl Dye is Director of Technical Regulatory Policy in Genentech s Washington, DC Regulatory Affairs Office, and is the FDA Liaison for a Roche Global Technical Regulatory Policy Group. He has been at Genentech for ten years and is responsible for evaluating proposed biotechnology/biologic CMC regulations, guidelines, policies and practices of US FDA and other federal government agencies. Prior to joining Genentech Dr. Dye was the Director of the Division of Application Review and Policy in CDER s ODE 6, and was responsible for managing the review of BLA s, supplements, and IND s for therapeutic biologic proteins. He joined the FDA in 1992, and became a regulatory expert for therapeutic biologics, participated in foreign and domestic inspections of licensed manufacturers, and was actively involved in developing policy for review of therapeutic proteins. Dr. Dye graduated from Ohio State University with a PhD in Medical Microbiology in 1978, and was a staff scientist at the Trudeau Institute where he directed a laboratory investigating cellular mechanisms of antitumor resistance.

2 CMC/GMP Considerations for Expedited Development Programs Earl S. Dye, PhD 2015 AAPS Annual Meeting October 27, 2015

3 Outline Expedited Development Programs US FDA Other Countries Changes in Clinical Development Paradigms Compressed Clinical Timelines will put CMC/GMP Issues on Critical Path CMC/GMP Strategy for Breakthrough Therapy Programs CMC/GMP Considerations for Developing Breakthrough Products Balancing Risk of Less CMC Data at Time of Filing vs Patient Benefit Summary and Conclusion

4 Expedited Programs for Serious Conditions US FDA FDA final guidance issued in March 2014 defines each program, requirements, and benefits Accelerated Approval Fast Track Priority Review Breakthrough Therapy

5 FDA s Expedited Pathways Accelerated Approval Fast-track Designation Priority Review When Appropriate Drugs with the potential to fill an unmet need for serious or life-threatening diseases, and whose activity can be assessed using a qualified surrogate endpoint Drugs intended to fill an unmet need for serious diseases Drugs with potential to provide major advance over existing therapies How it Helps Makes potentially useful new agents rapidly available to patients Enables more efficient development through frequent communication between FDA and sponsor Shortens FDA review time by 4 months Limitations Requires additional randomization of patients in confirmatory trials Does not condense or abbreviate clinical development Does not condense or abbreviate clinical development

6 Breakthrough Therapy Program in US Advancing Breakthrough Therapies for Patients Act, 2012: Specifies that a new drug may be designated as a Breakthrough Therapy if it is intended to treat a serious or lifethreatening disease, and preliminary clinical evidence suggests that it provides a substantial improvement over existing therapies As of Oct 2015, FDA has rendered decisions on 337 BTDRs since the programs inception, granting 104 requests mostly through CDER CDER received 282 requests and granted 89 (31%) CBER received 55 requests and granted 15 (27%) 16 BT designated projects have been approved with an average of 5.7 months from submission of the BLA/NDA This year 4 Breakthrough Therapy Designations (BTD) rescinded because they no longer met criteria of substantial benefit over existing therapies

7 Medicines Adaptive Pathways to Patients Initiative (MAPPs) in EU EMA and CHMP have been discussing Progressive License approach Announced a Pilot Phase of adaptive licensing in March 2014 Since renamed pathways and referred to as Medicines Adaptive Pathways for Patients (MAPPs) The aim of the pilot phase is to discuss with various stakeholders the earliest possible point at which patients can be given access to innovative medicines Initial approval may be on a small sub-set of population Further submission and expansion of populations thereafter Gain experience in a safe harbour context with regulatory authorities and experts, health technology assessment bodies, and patient groups in discussion of specific requirements for the benefit-risk assessment in early authorizations of these medicines Several companies have already initiated pilot projects; a recent EMA report indicated that 58 products have been submitted to the pilot, and 16 accepted

8 SAKIGAKE Process in Japan Principles are broadly similar to US FDA Breakthrough Designation Process Speed review of innovative new drugs Sakigake products receive priority review with a target of six months from submission to approval (versus 12 month review for standard products) Waiting time for consultations with the regulator before the start of clinical trials cut from the standard 2 months to one month PMDA will assign a consistent concierge contact to shepherd Sakigake products through the regulatory process from consultations to approval Rolling submissions allowed to start reviews on available data before full submission of pivotal clinical results; may result in enhanced requirements for post-marketing surveillance and lengthened re-examination period

9 New Approaches to Clinical Development Compress Timelines by Combining Phases Standard Drug Development Paradigm: 8-10 years FIH POC Registrational Alternative Development Paradigms: 3-5 years FIH=POC Registrational FIH POC=Registrational FIH=POC=Registrational

10 Expedited Clinical Development Programs will put CMC/GMP Issues on Critical Path Clinical development timelines may be reduced from 7-10 years to 3-5 years necessitating new approaches to product & process development, commercial readiness, launch and regulatory filings Will need effective interface with clinical to identify potential candidates early Resource intensive; will need to be selective Requires collaborative cross functional approach between development, commercial and regulatory operations Does not mean you can do less, will need to start some activities sooner Focus on reliable supply of quality product at launch, not process optimization Front-load critical product and process characterization activities earlier Develop manufacturing readiness plan to address timeline for development of the manufacturing capabilities with goals aligned to clinical development program Perform risk assessment regarding availability of less CMC information at the time of filing and product launch versus patient benefit; discuss mitigation approaches with Health Authorities Ensure adequate supply of safe and effective product at time of launch

11 Modeling CMC Development Timelines for Breakthrough Products Cross functional technical team modeled accelerated timelines for large and small molecule products based on traditional phase dependent CMC/GMP activities Assumed 5 year clinical development program from initiation of phase l to launch based on: Breakthrough designation granted after phase l studies, with pivotal study becoming expanded phase lb or ll 1-2 years for sufficient preliminary clinical data to qualify for breakthrough therapy designation 2-3 years to complete the pivotal study, file an application and launch the product Under this scenario some phase lll activities will be on critical path and need to be accelerated; sufficient time to complete PC/PV activities available unless phase lll timelines reduced Each breakthrough development programs will vary depending on: complexity of the product; timing of designation; how soon accelerated CMC development activities begin; availability of platform technology and relevant prior knowledge

12 Perspective on Breakthrough Process Chemistry, Manufacturing and Control--Typical Clinical Timeline BTD Interim Data R&D Non- Clinical Phase 1 Phase 2 File Approve Life Cycle Phase Management 3 File Approve Life Cycle Management Non-clinical Studies Studies Clinical Studies Clinical Studies Define TPP pcqas Establish Analytical Profile & Methods Profile & Methods CMC on Critical Path to BTD Launch Product Release Product w Release w Commercial Method Commercial Method Product Release Product w Release w Qualified Methods Qualified Methods Transfer & Validation Transfer & Validation Validated Methods Validated Methods Cell Line Selection Clinical Site DS/DP Clinical Site Qual Lots DS/DP Commercial Qual Site Commercial Site Lots Compress CMC Ph 3 Activities Process Characterization & Validation Product & Process Monitoring Stability studies

13 Breakthrough Therapy CMC/GMP Considerations for Developing Breakthrough Products

14 General Manufacturing Considerations Leverage prior knowledge, platform data, and use of comparability protocols Prioritize development efforts on process reliability over yield and cost of goods. Optimize process and formulation post-approval, if no impact on patient safety or product availability Ensure fit of candidate molecules into manufacturer s platform for DS and DP and related processes to improve speed and robustness Front load activities to address non-platform behavior and / or unusual product and process characteristics Assess CQAs earlier and front load method validation for them Identify launch sites for drug substance (DS) and drug product (DP) early

15 Process and Formulation Development Considerations In general: Phase lll and commercial process and formulation optimization could be truncated due to accelerated clinical development timelines. Prioritize development efforts on process reliability over yield and cost of goods. Optimize process and formulation post-approval, if no impact on patient safety or product availability Consider straight through processing and scheduling of intermediates to avoid need for intermediate hold time studies Biologic drugs focus on: Cell line lock at Phase I Launch with Phase I/II formulation and optimize post-approval Small molecule drugs focus on: API and excipient attributes impacting formulation and DP manufacturability DP process impacting PK and patient safety If possible, lock clinical formulation to avoid BE studies prior to launch

16 Process Validation Considerations Likely to have limited manufacturing experience at commercial scale Leverage process and product platform knowledge (e.g., for monoclonal antibodies) with appropriate justification to speed development Consider whether clinical DS could be used to validate commercial DP process Consider life-cycle validation principles, continued verification Use development experience/smaller scale batches in PPQ strategy Some PC/PV studies could be deferred, such as linkage studies Consider concurrent validation approach to allow for product distribution concurrent with release of each conformance batch (batch specific release option). Dependent on ability to demonstrate manufacturing consistency of clinical process material Provide validation protocol and at least one executed batch record at time of filing Robust Quality Systems able to identify deviations and correct PC/PV studies impacting patient safety must be complete prior to filing

17 Analytical Development Considerations Analytical method development Partial or complete front-loading of analytical understanding to balance more limited process robustness and support future comparability exercises Focus on high priority assays early, such as potency for biologics; and content, impurities and dissolution for small molecules to ensure suitability for control system Involve commercial QC in assay design during development and co-validate if possible Use partially validated methods for internal release and stability testing of qualification lots and complete validation before commercial release This approach presents a business risk if problems arise in validating a method and should be accompanied with a backup plan requiring retesting lots and or implementing alternative methods. Launch from clinical site and transfer to commercial site post-launch

18 Control Strategy Considerations Control strategy based on limited manufacturing experience but ensuring patient safety and efficacy. Launch with provisional control system that ensures consistent product, and upgrade the control system post-approval after more manufacturing experience and completion of process validation, i.e., Filing with an expanded monitoring program with more tests initially, more assay controls, and justify elimination of some tests post-approval as more knowledge is accumulated Filing with broader IPC and product specification acceptance criteria at launch and reevaluating post-approval for specifications that are linked to process consistency Filing with preliminary CPPs and CQAs Utilize enhanced modeling techniques where possible to support conclusions Manage second generation processes through a life-cycle approach in post-approval lifecycle management plan

19 Manufacturing Scale and Launch Site Considerations In general: Determine as soon as possible launch sites for DS and DP (clinical vs commercial) Clinical manufacturing facilities used for launch would need to meet the same quality expectations as commercial manufacturing facilities. Key differences for consideration are: Cleaning verification versus cleaning validation Multi-product manufacturing, including investigational compounds with limited safety data Use of dedicated product contact equipment and or use of disposables to assist in cleaning validation issues If using a contract manufacturing organization (CMO) for DS/DP need to ensure that they have the capacity for rapid scale up to support commercial volumes For Biologic drugs: Pivotal clinical studies could be performed with material from different scale and/or site than is intended for long term commercial production (e.g., Phase II study becomes pivotal) Scale-up Phase lll clinical lots to commercial scale for launch with bridging comparability study

20 Stability Data Considerations Accelerated development timelines will limit availability of real time stability data Launch with reduced real time stability for commercial material Leverage stability from early development and clinical batches when formulation remains unchanged and product comparability demonstrated Use forced degradation and stress studies to provide additional supporting and comparability data Provide stability protocol for commercial material Gain Health Authority concurrence and commit to provide more real time confirmatory data during review and post-approval

21 Ensure PQS Alignment with Acceleration and Deferral of CMC Activities PQS must provide flexibility to accommodate accelerated activities for BT product development and potential need to defer certain activities as documented in a manufacturing readiness plan The accelerated development PQS strategy for each product will be dependent on timing of BT designation, and available product and platform knowledge for the product Only PQS activities with no impact to patient safety or product supply can be deferred. A quality risk assessment must be applied to all activities that will be deferred, and the rationale, and controls needed to ensure deferred activities are completed documented All deferred activities must be addressed in comparability/bridging protocols and incorporated in a post approval lifecycle management (PALM) plan The manufacturing readiness plan can be used for developing internal filing and inspection readiness checklists to ensure all deferred activities are completed or addressed in a PALM; and serve as roadmap for discussions with FDA

22 Breakthrough Therapy Balancing Risk of Less CMC data at Time of Filing vs Patient Benefit

23 Addressing Technical Risks vs Patient Benefit (1/2) In spite of front-loading certain critical product and process characterization activities it may not be possible to complete all CMC/GMP activities at the time of filing and launch of a breakthrough product. Manufacturers should develop a manufacturing readiness plan which aligns the timeline for completing the manufacturing activities with those of the clinical development program. Plan should address: All manufacturing sites readiness to launch the breakthrough product; Status of critical characterization tools; Validation approach for process and methods; Stability data to support adequate expiration dating for the product;

24 Addressing Technical Risks vs Benefit to Patients (2/2) Where gaps exist in completing certain activities a risk assessment should be performed addressing the availability of less CMC information at the time of filing and product launch versus patient benefit. This should be coupled with a risk mitigation plan to address these risks either prior to launch or through the use of a post approval life-cycle management plan. This manufacturing readiness plan and risk assessment should form the basis for discussion and agreement with FDA prior to filing the marketing application.

25 CMC Activities that May be Incomplete at Launch Cannot Compromise Patient Safety or Product Supply Process validation (fewer than the standard number of full-scale manufacturing runs) Process characterization (e.g. long duration elements like resin reuse, validation of intermediate process hold times, or extending limit of in vitro cell age for lifecycle management of a biologic product) Available real time stability data on commercial product Validated transfer to commercial manufacturing site/scale, Provisional control system that ensures consistent product with need to upgrade postapproval Reliable process capable of meeting initial product demand with need to optimize process yield and performance post-approval Phase I-II formulation for launch with potential need to optimize post-approval

26 Risk Mitigation Approach for Less CMC Data PMCs & PMRs Well designed comparability protocols Post-approval lifecycle management plan Include as part of the filing to support completion of deferred CMC activities postapproval Provide detailed timelines, deliverables, and types of regulatory filings to complete activities Ensure appropriate flexibility in the Pharmaceutical Quality System to enable acceleration or deferral of certain manufacturing development activities for breakthrough drug development QC reviewed and approved Ensure PAI readiness

27 FDA Standards for Marketing Approval Substantial evidence of effectiveness, safety and product quality Expectation for pharmaceutical quality is the same for all drugs FDA regulations for orphan drugs allow for flexibility and scientific judgment in applying approval standards, in terms of Kind of data needed, and Amount needed for a particular drug to meet the statutory standards FDA final guidance on Expedited Programs for Serious Diseases: FDA may exercise some flexibility on the type and extent of manufacturing information that is expected at the time of submission and approval for certain components (e.g., stability updates, validation strategies, inspection planning, manufacturing scale-up). Need open and transparent discussions with FDA on balancing risk of less CMC information at the time of filing vs patient benefit; and means to mitigate risk

28 Summary Breakthrough Therapies offer significant patient benefits, but the reduced timelines introduce significant CMC challenges for product development Each case will have different risks and constraints so the specific CMC approaches will vary by product Key areas of opportunity include: Leveraging prior knowledge and platform data, Use of comparability protocols Use of initial product supply from a clinical process or site; Delaying certain process validation requirements not directly related to patient safety Expect these programs to generate significant post-approval CMC efforts and Phase IV commitments Key to success is open and transparent discussions with FDA 28

29 Doing now what patients need next