Industry suggests changes to FDA’s CMC readiness pilot

Officials from the US Food and Drug Administration (FDA) and representatives from the pharmaceutical industry shared insights on the agency’s Chemistry, Manufacturing, and Controls (CMC) Development and Readiness Pilot (CDRP) program. While industry members highlighted the benefits of the program, they also suggested ways in which it could be improved at a joint workshop held by FDA and the Duke-Margolis Institute for Health Policy on Wednesday.

The CDRP program began in April 2023 and covers new drug applications (NDAs) and new biologics license applications (BLAs) with expedited clinical development timeframes, including those that receive breakthrough therapy, fast track, and regenerative medicine advanced therapy designations. Sponsors must also have an active commercial IND in place, and such programs should not have reached the end of Phase 2 at the time of application. (RELATED: FDA announces CMC review pilot for drugs with expedited development, Regulatory Focus 1 November 2022)

“These CDRP programs have been quite effective in helping to bolster expedited development, but more work is still needed,” said Denise Gavin, director of the Office of Gene Therapy at the Center for Biologics Evaluation and Research (CBER).

Gavin pointed out that one of the challenges is that the rapid pace of clinical development can create a disconnect between the CMC element and the clinical development program. Often, while the clinical development program moves forward quickly, CMC development tends to lag behind.

During the workshop, FDA’s Ramjay Vatsan reported that the Center for Drug Evaluation and Research (CDER) received a total of 12 applications for the program, of which five were accepted. Meanwhile, the Center for Biologics Evaluation and Research (CBER) received seven applications and accepted four. Vatsan explained that the primary reason for rejecting applications was that they did not meet the minimum eligibility criteria.

Vatsan advised sponsors not to underestimate the resources required to participate in the CDRP program. Sponsors especially need to focus and invest their resources in conducting comparability studies, stability studies, process validation studies, developing potency assays, and preparing their manufacturing facilities.

Thomas Oliver, a chemist with the Office of New Drug Products at CDER, pointed out other areas of particular focus. He said it is important to ensure that the stability data in the applications conforms to the International Council on Harmonization’s (ICH) Q1A guidelines. He added that good communication is important to facilitate timely approval of the drug.

Oliver said that to help sponsors prepare for a successful CDRP experience, sponsors should prepare a comprehensive meeting package with specific directed questions, incorporate FDA’s recommendations in the meeting, and be prepared to discuss any follow-up questions.

Worth the effort

Isabella Palazzolo, the senior director of regulatory CMC for Intellia, said that participating in the pilot was worth the effort; the company’s CRISPR-based gene-editing therapy for hereditary angioedema (HAE), NTLA-2002, was accepted into the program in December 2023.

Some of the advantages of participating in the pilot are that the CMC dedicated meetings allowed more time for clinical and non-clinical discussions with FDA. The greatest benefit was achieved from unsolicited feedback and responses from informal questions, she said.

One of the challenges in participating in the program, Palazzolo said, stems from preparing for three CMC only Type B meetings in one year, which requires significant time and resources, all while maintaining support for other regulatory and CMC activities.

She said that in order to improve the program, FDA should provide additional clarity on its structure and consider an agreement to increase participation.

Palazzolo also suggested that the FDA be more flexible regarding the frequency and scope of meetings, indicating that frequent, focused meetings may be more effective than broad meetings held only twice.

Neil Ichiro Laruan from the Biotechnology Innovation Organization (BIO) mentioned that the group conducted a survey among its members to evaluate their responses to CDRP. Participants who decided not to take part provided several reasons for their choice: they felt the program would involve too much administrative burden, expressed concerns about confidentiality and disclosure, and were uncertain about the advantages compared to existing accelerated development programs.

Survey participants recommended that the FDA clarify its confidentiality guidelines and showcase the unique value of CDRP compared to FDA’s other expedited programs.

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Industry suggests changes to FDA’s CMC readiness pilot

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