FDA-regulated drug and biologic development programs intended to diagnose, treat, or prevent a serious disease or condition where there is an unmet medical need may have accelerated clinical development timelines, including designation for the breakthrough therapy, accelerated and advanced regenerative medicine therapy (RMAT) programs. Yet applications to market products in these programs must still meet FDA approval standards, including manufacturing facility compliance with current Good Manufacturing Practices (CGMP). Products with accelerated clinical development activities may experience difficulty in accelerating CMC development activities to align with accelerated clinical timelines. Successful acceleration of CMC preparation may require additional interactions with the FDA during product development and, where appropriate, justify the use of science-based and risk-based regulatory approaches that allow streamlining of development activities of the CMC, so that the clinical benefits of early patient access to these products can be realized.
Due to the accelerated review timelines established for expedited programs for drugs and biologics intended to address unmet medical needs for serious conditions, CMC and GMP issues have often become limiting factors that have resulted in to complete response letters and prevented the FDA from approving drugs that are important advances in public health and that patients urgently need. The CMC and GMP challenges have been particularly important for complex biological products. To some extent, the Breakthrough and RMAT programs were intended to address these challenges, but FDA and industry have recognized that additional FDA interactions and assistance are needed to expedite the resolution of CMC issues. and GMP earlier in the application review cycle associated with accelerated program designation(s).
In response to these concerns and as described in the Prescription Drug User Fee Act (PDUFA) VII Commitment letter, the FDA is implementing this pilot program to facilitate the preparation of CMC for certain products regulated by the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) with accelerated clinical development timelines. For sponsors participating in the pilot, the FDA will provide product-specific CMC guidance during product development, to include two additional CMC-focused Type B meetings, as well as a limited number of additional CMC-focused discussions, based on readiness and defined CMC milestones. .
Who is eligible for the program?
Participants in the CDRP pilot program must have an active commercial IND clinical program that has not yet reached the end of Phase 2, to allow the pilot sufficient time to impact CMC readiness (for example, 2 years from the planned filing of the marketing application). However, in extenuating circumstances, requests for exceptions may be considered, where development programs would still benefit from the pilot.
When selecting INDs for the pilot program, the FDA intends to consider factors such as:
(1) the expected clinical benefits of facilitating earlier patient access to the product,
(2) product novelty,
(3) the complexity of the product or its manufacturing process, including technology,
(4) Sponsor’s overall manufacturing experience, as well as
(5) Sponsor’s experience with the particular product type, class or type of manufacturing process.
The FDA may also give additional consideration to less experienced sponsors.
What must a participation request contain?
Prospective applicants to the pilot program should describe in their “Application for Participation” as a modification to their IND:
(1) the current state of development of the CMC, including all ongoing activities not already included in the IND.
(2) an expected schedule for product development that aligns with the planned clinical development schedule, showing CMC tasks and activities intended to produce comprehensive CMC data and information for inclusion in the marketing application. This part of the plan should cover the following areas related to the CMC:
- Characterization of available product and preliminary identification of critical quality attributes.
- Description of the drug substance and drug product’s current manufacturing process and control strategy (including identification and development of assays), and a description and plan of the manufacturing and control strategy proposed commercial scale, including any necessary microbial control strategies.
- Identification of manufacturing facilities, including all contracted facilities, as well as recent facility inspection history (including foreign regulatory inspections, if applicable).
- Plans to ensure product availability for commercial launch.
- Drug Substance and Drug Product Stability Evaluation Plan.
- Overall process validation plan.
(3) potential challenges in completing CMC activities within the time frame that is typically required during CMC development.
The CMC development plan should also include the proposed schedule for the two additional CMC-specific Type B meetings offered by the pilot, as well as any other planned meetings and discussions.
Beginning April 1, 2023, the FDA will accept applications to participate in the CDRP program. Although the first year of the pilot is limited to nine applications (6 designated for CBER products), the FDA will continue the program for three additional years, and the number of participants for those years has not yet been disclosed. During this CDRP program, sponsors will have the opportunity to discuss their product development strategies and goals with FDA review staff in predefined Type B meetings and a limited number of additional discussions focused on the CMC. The FDA also said it may hold a public workshop and release a strategy document incorporating lessons from the CDRP. In addition, the CDER/OPQ has published a new Manual of Policies and Procedures (MAPP 5015.13) effective December 7, 2022, which provides additional details on how CDER will support and implement the pilot program, as well as the use of regulatory flexibilities under 21 CFR 314.105(c). As further described in PDUFA VII Commitment Letter, no later than April 30, 2026, FDA will release a strategic document outlining the agency’s plans for developing guidance and process documents to integrate lessons learned from the pilot project and related experience with accelerated clinical development timelines.
Similarly, CBER’s Office of Tissue and Advanced Therapies (OTAT) has announcement a virtual town hall on December 7, 2022 to answer questions from stakeholders related to cell therapy CMC issues, including for OTAT-regulated tissue-engineered medicinal products.
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