FDA Touts Continued Commitment To Cell And Gene Therapy Products Through Trio Of Guidances

In late September, the U.S. Food & Drug Administration ("FDA") issued three draft guidances related to cell and gene therapy ("CGT") products: (1) Innovative Designs for Clinical Trials of CGT Products in Small Populations (the "Innovative Designs Guidance"), (2) Postapproval Methods to Capture Safety and Efficacy Data for CGT Products (the "Postapproval Methods Guidance"), and (3) Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (the "Expedited Programs Guidance") (each, a "Guidance"). Although none of these Guidances appear to significantly alter the existing landscape for CGT products, they do reflect a willingness on behalf of FDA to get creative about how to bring these products to market, especially where they are intended to address rare diseases and/or small populations – an area where traditional drug development paradigms are strained.

A. Guidance Overview

The Innovative Designs Guidance provides FDA's recommendations on how to design clinical trials for CGT products in small populations to produce the evidence needed for regulatory approval. It expands on existing FDA guidance,¹ but focuses specifically on how to adapt the general principles when populations are small and conventional trial designs may be infeasible or inefficient. The Guidance includes a list of potential solutions for designing clinical trials of such products, including single-arm trials using patients as their own controls, externally controlled studies, adaptive designs, Bayesian designs, master protocols (i.e., protocols designed with multiple sub-studies), and disease-progression modeling. It also discusses the potential use of surrogate or intermediate endpoints.

The Postapproval Methods Guidance suggests that post-approval proof of safety/efficacy may be especially appropriate for CGT products, as most provide long-term effects not easily measurable in pre-approval studies involving a limited number of subjects treated during limited timeframes. Accordingly, FDA suggests that pre-approval data may be balanced by robust post-marketing evidence, especially in cases where pre-approval evidence is inherently constrained. To this end, the Guidance recommends less traditional trial approaches, such as the use of real-world evidence ("RWE") (e.g., from electronic health records, claims, vital statistics, registries) and decentralized data collection.

The Expedited Programs Guidance provides outlines potential pathways for expedited development and review of regenerative medicine therapies² for serious or life-threatening conditions, and updates draft guidance of the same title from February 2019. Per the Guidance, these sponsors may be able to leverage information and relevant prior knowledge, when scientifically justified and legally permissible, outside of FDA's Platform Technology Designation Program,³ through pathways such as fast track designation, accelerated approval, breakthrough therapy designation, priority review designation, and/or regenerative medicine advanced therapy ("RMAT") designation.⁴ The Guidance provides detailed information on each of these pathways and encourages "flexibility in clinical trial design" (e.g., adaptive designs, enrichment strategies, novel endpoints, common and/or historical controls, sharing data among multiple sites, etc.).

B. Takeaway

As noted above, the Guidances do not present any shiny new options for CGT sponsors in terms of development and/or market access; however, they do represent FDA's continued acknowledgement that a novel approach is needed to address CGT development, regulatory review, and continued access, especially with respect to CGTs intended for rare diseases and/or small populations. This is the type of creative regulatory intervention needed, as CGT investment has seen a devastating decline over the past several years.⁵

Interestingly, however, the Guidances do not directly address the new "plausible mechanism" pathway – teased by FDA Commissioner, Dr. Marty Makary, in April,⁶ and supposedly expected to be more fully outlined in the New England Journal of Medicine soon⁷ – which will allegedly customize the approval process for CGTs intended to address ultra-rare conditions based on "a plausible mechanism on sort of a conditional basis."⁸ Although the proposed "plausible mechanism" pathway shares key concepts with some of the other expedited pathways discussed in the Guidances (e.g., permitting conditional market approval based on evidence that a certain therapy may be safe/effective), it appears to further lower the evidentiary standard for conditional approval of ultra-rare CGT products beyond what is set forth in this recent trio of Guidances.

Perhaps these Guidances are intended to drum up conversation around the need for additional expedited pathways for CGT products ahead of FDA's forthcoming "plausible mechanism" pathway announcement? Or perhaps these Guidances subtly indicate that the "plausible mechanism" pathway won't be getting the green light – and that the pathways described in these Guidances represent the lowest evidentiary standard that FDA is willing to establish for conditional approval of CGT products, regardless of population size? Ultimately, CGT sponsors should rely on this recent trio of Guidances, as it does represent FDA's current thinking on the matter, while sponsors of CGT therapies for ultra-rare conditions may remain cautiously optimistic for an even more permissive pathway in the near future. Either way, it appears that FDA is willing to work with sponsors on creative ways to bring safe and effective CGTs to market, which, at least for now, is a needed "win" for both sponsors and patients in the CGT space.

Footnotes

1. See Rare Diseases: Considerations for the Development of Drugs and Biological Products; Guidance for Industry (Dec. 2023); Rare Diseases: Natural History Studies for Drug Development; Draft Guidance for Industry (March 2019).

2. Section 3033 of the 21st Century Cures Act and Section 506(g) of the Food, Drug, and Cosmetics Act ("FDCA") define "regenerative medicine therapies" as including allogenic and autologous cell therapies, therapeutic tissue engineering products, human cell and tissue products ("HCT/Ps"), and combination products using any such therapies or products, except for those HCT/Ps solely regulated under Section 361 of the Public Health & Safety Act and 21 CFR Part 1271.

3. See Platform Technology Designation Program for Drug Development; Draft Guidance for Industry (May 2024).

4. According to the Expedited Programs Guidance, FDA plans to administer the RMAT designation program "in a manner that is consistent with the other expedited programs, where applicable."

5. According to data analysis from DealForma for Reuters, venture capital funding for gene therapies and gene-editing products decreased from $8.2 billion in 2021 to just $1.4 billion last year. See Gene Therapy Investment Declines Amidst Successes and Economic Headwinds, PackGene (Mar. 21, 2025).

6. See Marty Makary Interview (Apr. 17, 2025).

7. See New FDA approval pathway for n-of-1 therapies coming soon, Prasad says, Endpoints News (Sept. 8, 2025).

8. See Makary Interview, supra FN 6.

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