Development programs for FDA-regulated drugs and biologics intended to diagnose, treat, or prevent a serious disease or condition in which there is an unmet medical need may have accelerated clinical development timelines, including designation for Breakthrough Therapy, Fast Track and Regenerative Medicine Advance Therapy (RMAT) programs. However, marketing applications for products in these programs have yet to meet FDA approval standards, including compliance of manufacturing facilities with current Good Manufacturing Practices (CGMP). Products with accelerated clinical development activities may experience challenges expediting CMC development activities to align with accelerated clinical timelines. Successfully accelerating CMC readiness may require additional interactions with the FDA during product development and, if applicable, justify the use of science- and risk-based regulatory approaches that enable streamlining of CMC development activities, so that the clinical benefits of early patient access to these products can be realised.
As a result of accelerated review times established for accelerated programs targeting drugs and biologics intended to address unmet medical needs for serious conditions, CMC and GMP issues have often become limiting factors resulting in comprehensive response letters and prevented FDA from the approval of medicines that represent important advances in public health and that patients urgently need. The CMC and GMP challenges have been particularly significant for complex organic products. To some extent, the Breakthrough and RMAT programs were intended to address these challenges, but the FDA and industry have recognized that additional interactions and assistance from the FDA are needed to expedite resolution of early-stage CMC and GMP issues. of the review cycle for applications 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 CMC preparation for select Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) regulated products with accelerated clinical development timelines. For sponsors participating in the pilot, the FDA will provide product-specific CMC advice 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 on defined CMC milestones.
Who is eligible for the program?
Participants in the CDRP pilot 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 instance, 2 years from the advance submission of the marketing application). However, under extenuating circumstances, requests for exceptions may be considered where development programs would still benefit from the pilot.
In selecting INDs for the pilot program, the FDA intends to consider factors such as:
(1) anticipated clinical benefits in facilitating early patient access to the product,
(2) product novelty,
(3) complexity of the product or its manufacturing process, including technology,
(4) sponsor’s overall production experience, as well
(5) Sponsor’s experience with the particular product type, class, or type of manufacturing process.
The FDA may also give additional consideration to inexperienced sponsors.
What must be included in the application form?
Potential pilot program applicants should describe in their “Application to Participate” as a change to their IND:
(1) the current state of development of the CMC, including any ongoing activities not already included in the IND.
(2) an anticipated product development timeline that aligns with the anticipated clinical development timeline, 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 CMC:
- Available product characterization and preliminary identification of critical quality attributes.
- Description of the drug substance and drug product’s current manufacturing process and control strategy (including assay identification and development), and a description and plan for the proposed commercial-scale manufacturing and control strategy, including any necessary microbial control strategies.
- Identification of manufacturing facilities, including any contracted facilities, along with history of recent facility inspections (including overseas regulatory inspections where applicable).
- Plans to ensure product availability for commercial launch.
- Stability evaluation plan of the drug substance and drug product.
- Master plan for process validation.
(3) potential challenges in completing CMC activities within the allotted time that is typically needed during CMC development.
The CMC development plan should also include the proposed timing for the two additional CMC-specific Type B meetings offered by the pilot, as well as any other planned meetings and discussions.
Effective April 1, 2023, the FDA will accept applications to participate in the CDRP program. Although the first year of the pilot will be limited to nine applications (6 designated for CBER products), the FDA will continue the program for another three 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 CMC-focused discussions. The FDA also said it could hold a public seminar and issue a policy document incorporating the CDRP’s lessons. Furthermore, CDER/OPQ has released a new Policy and Procedures Manual (MAP 5015.13) which will take effect 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 issue a strategy document outlining the agency’s plans for developing guidelines and process documents to incorporate lessons learned from the pilot and related experience with accelerated clinical development timelines.
On a related note, CBER’s Office of Tissue and Advanced Therapies (OTAT) has announced a virtual town hall meeting on December 7, 2022 to answer questions from stakeholders related to cell therapy CMC issues, including for tissue-engineered medical products regulated by OTAT.