Background

Development programs for FDA-regulated drugs and biologics 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 Breakthrough Therapy, Fast Track, and Regenerative Medicine Advance Therapy (RMAT) programs . Yet marketing applications for products in these programs still need to meet FDA's approval standards, including manufacturing facility compliance with current good manufacturing practice (CGMP). Products with accelerated clinical development activities may face challenges in expediting CMC development activities to align with the accelerated clinical timelines. Successfully expediting CMC readiness may require additional interactions with FDA during product development and, if applicable, warrant the use of science- and risk-based regulatory approaches allowing streamlining of CMC development activities, so that clinical benefits of earlier patient access to these products can be realized.

As a result of the accelerated review timeframes established for expedited programs intended for drugs and biologics that are intended to address unmet medical needs for serious conditions, CMC and GMP issues have often become rate-limiting factors that have resulted in Complete Response Letters and prevented FDA from approving drugs that are important advancements in public health and urgently needed by patients. CMC and GMP challenges have been particularly significant for complex biological products. To some degree the Breakthrough and RMAT programs were intended to address these challenges, but FDA and industry have recognized that additional interactions with, and assistance from, FDA are necessary to accelerate resolution of CMC and GMP issues earlier in the review cycle for applications associated with expedited program designation(s).

In response to these concerns and as described in the Prescription Drug User Fee Act (PDUFA) VII Commitment letter, FDA is implementing this pilot program to facilitate CMC readiness for selected 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, 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 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 to have sufficient time to have an impact on CMC readiness (e.g., 2 years from anticipated marketing application submission). However, in extenuating circumstances, requests for exceptions may be considered, where the development programs would still benefit from the pilot.

In selecting INDs for the pilot program, FDA intends to consider factors such as:

(1) anticipated clinical benefits of facilitating earlier patient access to the product,

(2) novelty of the product,

(3) 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 the type of manufacturing process.

FDA may also give additional consideration to less experienced sponsors.

What should be included in a request to participate?

Prospective applicants to the pilot program should describe in their “Request to Participate” as an amendment to their IND:

(1) the current state of CMC development, including any ongoing activities not already included in the IND.

(2) a projected timeline for product development that aligns with the anticipated clinical development timeline, showing the CMC tasks and activities intended to yield complete CMC data and information to be included in the marketing application. This part of the plan should cover the following CMC-related areas:

• Available product characterization and preliminary identification of critical quality attributes.
• Description of the current drug substance and drug product manufacturing process and control strategy (including identification and development of assays), and a description of and plan for the proposed commercial scale manufacturing and control strategy, including any necessary microbial control strategy.
• Identification of manufacturing facilities, including any contract facilities, along with the facilities' recent inspection history (including foreign regulatory inspections, where applicable).
• Plans for ensuring product availability for commercial launch.
• Drug substance and drug product stability assessment plan.
• Overall plan for process validation.

(3) potential challenges in accomplishing CMC activities within the allotted time that is typically needed during CMC development.

The CMC Development Plan should also include proposed timing for the two additional CMC-specific Type B meetings afforded by the pilot, as well as any other meetings and discussions foreseen.

Next steps

Starting April 1, 2023, FDA will accept requests to participate in the CDRP program. Although the first year of the pilot will be limited to nine applications (6 designated for CBER products), FDA will continue the program for three additional years, and the number of participants for these years has not yet been disclosed. During this CDRP program, sponsors will have the ability to discuss their product development strategies and goals with FDA review staff during predesignated Type B meetings and a limited number of additional CMC-focused discussions. FDA also said it may hold a public workshop and issue a strategy document incorporating lessons from the CDRP. In addition, CDER/OPQ has released a new Manual of Policies and Procedures (MAPP 5015.13) that will become effective on 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 the PDUFA VII commitment letter, no later than April 30, 2026, FDA will issue a strategy document outlining the agency’s plans for developing guidance 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 stakeholder questions related to cell therapy CMC issues, including for tissue-engineered medical products regulated by OTAT.

If you may be interested in applying to the program, or have questions on Chemistry, Manufacturing, and Control issues more generally, feel free to contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.

Authored by David Horowitz and Ted Lis