The FDA is launching a Chemistry, Manufacturing, and Controls (CMC) Development and Readiness Pilot program to facilitate the expedited review of products with accelerated development timeframes.

New CMC pilot program for products with accelerated clinical timelines
The US Food and Drug Administration (FDA) is implementing a pilot program to facilitate chemistry, manufacturing and controls (CMC) readiness for selected investigational drugs with accelerated clinical development timelines that are regulated by the Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER). The pilot program, the Chemistry, Manufacturing, and Controls (CMC) Development and Readiness Pilot program, will begin April 1, 2023.

Products with accelerated clinical development times, include CDER- and CBER-regulated products, such as those receiving breakthrough therapy and fast-tracked designations by the FDA, as well as those receiving regenerative medicine advance therapy designations by the FDA. The FDA notes that such products may face challenges in expediting CMC development activities to align with the accelerated clinical timelines. It says that successfully expediting CMC readiness may require additional interactions with the FDA during product development and, if applicable, warrant the use of science- and risk-based regulatory approaches to allow the streamlining of CMC development activities, so that clinical benefits of earlier patient access to these products can be realized.

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 (i.e., routine meetings occurring at pre-defined endpoints between the FDA and a sponsor) as well as a limited number of additional CMC-focused discussions based on readiness and defined CMC milestones. The increased communication between the FDA review staff and sponsors is intended to ensure a mutual understanding of approaches to completing CMC activities, including what information should be provided at the appropriate timepoint (i.e., at the time of the submission of a new drug application or biologics license application, prior to the end of the review cycle, or post-approval), to ensure CMC readiness for a marketing application.

Participation in the CMC pilot program
Starting April 1, 2023, the FDA says it will accept requests to participate in the pilot program and select no more than nine proposals, with approximately two thirds being CBER-regulated products and one third CDER-regulated products. Taking into consideration lessons from the prior year, the FDA says it will publish in the Federal Register a notice to announce pilot programs for each of the three following fiscal years. Sponsors who are interested in participating in the pilot program should submit a request to participate as an amendment to their investigational new drug (IND) applications. Participation is voluntary and at the discretion of the sponsor.

The FDA says that in general, at the time of application to the pilot, the IND clinical program should not have yet reached the end of Phase II development in order to allow the pilot to have sufficient time to have an impact on CMC readiness (e.g., two years from anticipated marketing application submission). However, in extenuating circumstances, the FDA says that requests for exceptions may be considered where the development programs would still benefit from the pilot. Examples of what could constitute such circumstances include cases where the clinical development is following an innovative clinical trial design or the product is intended to treat a rare disease.

CMC development plan
To focus pilot resources where they should be most useful and have an impact on the timeliness with which CMC readiness is achieved, the FDA says that prospective applicants to the pilot program should include in their request to participate a description of their CMC development plan that includes a timeline for CMC development aligned with when the clinical development program is expected to be completed. The plan should describe the current state of CMC development, including any ongoing activities not already included in the IND. The plan should also include a projected timeline for product development that aligns with the anticipated clinical development timeline and show the CMC tasks and activities intended to yield complete CMC data and information to be included in the marketing application. The FDA says that the CMC plan should highlight certain key areas (see bulleted list below) and any additional CMC challenges that may require the FDA’s input in order to facilitate the FDA’s engagement on the types of supportive data and information that might be used to address these challenges. 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;
  
• A drug-substance and drug-product stability assessment plan; and
  
• An overall plan for process validation.

Selection process to participate in the CMC pilot
The FDA says it plans to review requests to participate in the pilot quarterly, or as may needed, and that it will notify each sponsor of its decision within 180 days of receipt of the request to participate. In selecting INDs for the pilot program, the FDA says it intends to consider the following factors: (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) a sponsor’s overall manufacturing experience; and (5) a sponsor’s experience with the particular product type, class, or the type of manufacturing process. The FDA says it may give additional consideration to less experienced sponsors. Overall, the FDA says it intends to seek balance and diversity in product types, sponsors, and therapeutic indications to obtain a variety of relevant experience and learnings from the pilot.

Lessons learned from the pilot
To promote innovation and understanding, lessons learned through the pilot may be presented by the FDA (e.g., in a public workshop) as case studies. The FDA says it intends to conduct a public workshop and issue a strategy document focused on the CMC aspects of expedited development incorporating lessons from the pilot. The general nature and extent of information that could be publicly shared will be discussed and agreed upon between the sponsor and the FDA during the course of the pilot program, and, where feasible, the FDA will notify a sponsor in advance when it plans to include some aspect of their program’s experience in a public discussion (e.g., a slide presentation or a white paper).