One of the biopharmaceutical industry’s most closely watched forthcoming regulatory developments is the FDA’s imminent reauthorization of the Prescription Drug User Fee Act (PDUFA). PDUFA VII, as the reauthorization is commonly known, will cover the fiscal years 2023-2027. Many of the advancements included in PDUFA VII are driven in large part by an increase in the development of innovative products such as cell and gene therapies. This blog post addresses those aspects of PDUFA VII that are expected to affect sponsors of cell and gene therapy products, as well as therapies designed to treat rare diseases. A separate blog post will address other important elements of PDUFA VII.

Beefing Up CBER

A key provision of PDUFA VII is a budget and staffing increase for the Center for Biologics Evaluation and Research (CBER). The increase is designed to strengthen CBER’s capacity and capabilities for regulating cell and gene therapies. The projected staff increases over the next five fiscal years are as follows:

• 2023: 132 staffers
• 2024: 48 staffers
• 2025: 29 staffers
• 2026: 15 staffers
• 2027: 4 staffers
• TOTAL: 228 staffers

Notably, these new additions to CBER’s staff will far outnumber the 123 new hires budgeted for the Center for Drugs Evaluation and Research (CDER) over the same period. Presumably, the difference reflects an anticipated higher volume of regulatory submissions from developers of cell and gene therapies, compared to conventional drug products.

Enhancing Product Quality Reviews

Enhanced product quality reviews conducted under PDUFA VII will focus on innovative manufacturing technologies like those used to produce cell and gene therapies, particularly products with accelerated clinical development timelines. The CMC Development and Readiness Pilot (CDRP) program is designed both to facilitate chemistry, manufacturing, and controls (CMC) processes for products with accelerated clinical development and to facilitate communication between FDA review staff and the industry. Ideally, the initiative will help the FDA and sponsors reach a mutual understanding regarding which CMC activities are to be completed and at what time points.

Another area of the product quality reviews that will be enhanced is information requests and responses. For handling CMC information requests and responses, PDUFA VII calls for use of the “four-part harmony” approach, which is the FDA’s term for the four essential components of these requests:

• What was provided (i.e., the applicant’s initial submission)
• What is the issue or deficiency
• What is needed
• Why it is needed

The FDA will provide further information on the four-part harmony approach in updates to the associated CDER Manual of Policies & Procedures (MAPP) and CBER Standard Operating Procedures and Policies (SOPP) on information requests. This is targeted for FY 2023.

In addition, the FDA will issue guidance documents and policies on the use of alternative tools to assess manufacturing facilities supporting pending applications. Such tools may include inspection reports obtained from other trusted foreign regulatory bodies through mutual recognition and confidentiality agreements. They may also include records and other information obtained from applicants or directly from facilities, as well as the use of advanced technologies to assess and inspect facilities.

Advancing Rare Disease Endpoints

Another highlight of PDUFA VII is the Rare Disease Endpoint Advancement (RDEA) pilot program, an important initiative for patients, as evidenced by public comments at the September 28, 2021, Public Meeting on PDUFA VII. The FDA recognizes that clinical trials in rare disease populations can be especially challenging because the endpoints are not as well understood as in more common diseases. The pilot will aim to advance rare disease drug development programs by providing a mechanism for sponsors to collaborate with the FDA throughout the endpoint development process.

Launching Other Pertinent Initiatives

To support the cell and gene therapy field, the FDA has announced plans for a series of public meetings, public-private partnerships, and additional guidance, including updates to “Guidance for Industry: Expedited Programs for Regenerative Medicine Therapies for Serious Conditions,” which was last updated in February 2019. The guidance updates are expected to provide additional input from the FDA on safety monitoring and long-term follow-up and on post-approval requirements, including the use of real-world evidence to confirm clinical benefit, for products advancing through the Accelerated Approval mechanism. The guidance may also reflect updated thinking on CMC approaches and processes, including considerations for determining sponsors’ CMC readiness to take advantage of the expedited programs.

---

All told, the proposed provisions of PDUFA VII are designed to increase support for CBER, particularly in terms of advancing innovative technologies such as cell and gene therapies. The initiative reflects the FDA’s recognition of this sector as a growing and increasingly important area of drug development.

For additional thoughts on other important aspects of PDUFA VII, stay tuned for an accompanying blog post.

Author:

Laura Kilgore, RAC
VP, Regulatory Affairs, CMC