Emily Marden, JD

Emily Marden, Senior Counsel, Sidley Austin LLP

Gene therapies have been talked about for years as having the potential to treat and even cure a wide range of previously intractable diseases, including cystic fibrosis, hemophilia, diabetes and many forms of cancer. Yet, despite its promise and the significant investment in research and development, few such therapies have been approved by FDA to date. As a result, few patients have received the benefits of gene therapy.

This situation may be changing. Recently, FDA’s Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research (CBER), signaled that the agency intends to “lean in” to approvals of gene therapies and specifically rely on a flexible approach to accelerated approval pathway as a means of bringing therapies to patients sooner in the development process. Even more, Marks suggested that CBER intends to embrace an innovative approach in which FDA would rely on continued follow-up of subjects in a pivotal trial to provide the confirmatory evidence required for accelerated approvals, rather than the more typical approach of requiring that the sponsor conduct an additional clinical study. These developments have the potential to bring more gene therapies to patients, and to speed the timeline for doing so. In addition, this innovative approach to confirmatory studies could bolster confidence in the accelerated approval pathway, and could even finally open the door to incorporating real-world evidence (RWE), alleviating the significant challenges often associated with confirmatory clinical trials.

Accelerated approval allows for conditional approval of therapies for unmet medical conditions

FDA introduced the accelerated approval pathway in 1992, in large part to facilitate the availability of novel therapeutics to AIDS patients even before a sponsor had demonstrated safety and efficacy using standard clinical endpoints. Introduced first in regulations, the accelerated approval pathway was later added as Section 506 to the Food Drug and Cosmetic Act (FDCA) by Congress in 2012. Under the statute, FDA may grant accelerated approval based upon a surrogate or an intermediate clinical endpoint for drugs or biologic products for serious conditions that fill an unmet medical need. A surrogate endpoint, for purposes of accelerated approval, is a marker, e.g., a laboratory measurement, physical sign, or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit; an intermediate clinical endpoint, in turn, is a measure of therapeutic effect that is considered reasonably likely to predict clinical benefit.

FDA has made extensive use of the accelerated approval pathway since its introduction. To date, FDA has approved over 300 accelerated approval applications, including many cancer therapies and four gene therapies.

 In recent years, however, the agency and Congress have expressed frustration about shortcomings of using accelerated approval, including a perceived large number of so-called “dangling approvals” where confirmatory studies were not conducted, or did not show a favorable benefit-risk but the approval product was, nevertheless, not withdrawn from the market. FDA also struggled with the resource-intensive process required for withdrawal of approval of an accelerated approval drug under the statute.

In part in response to such issues, Congress approved changes to the statutory accelerated approval pathway in 2022 including, among other things, that FDA specify conditions for confirmatory trials prior to approval and the introduction of certain “expedited procedures” for withdrawal of accelerated approval where, for example, evidence subsequent to approval “demonstrates that the product is not shown to be safe or effective under the conditions of use.” These expedited procedures largely reduce the process of withdrawing an accelerated approval such that FDA needs only to open a Federal Register docket to publish its proposal to withdraw, open for public comments, followed by a meeting with FDA and, in limited circumstances, an advisory committee meeting. FDA has not yet published detailed guidance on this process, and has only recently initiated the first withdrawal under this process. 

Accelerated approval to facilitate availability of gene therapy products

In recent months, CBER’s expressed willingness to rely on—and even expand use of—the accelerated approval pathway has been reinvigorated, at least for gene therapy products. This renewed reliance holds out promise for significant impacts in the treatment and cure of disease. Specifically, CBER’S Marks has explicitly embraced accelerated approval as a means of ensuring a greater number of approvals of gene therapies in the near future, even opening the door to a more streamlined form of confirmatory data in a manner that seems to implicate reliance on real world evidence rather than just clinical data. 

CBER’s focus on accelerated approval for gene therapy products is particularly noteworthy for several reasons.

Flexible approach to evidence required for approval

First, Marks has indicated that accelerated approval for gene therapy can be flexible, including by taking a flexible approach to the relevant surrogate or intermediate clinical endpoint, depending on the disease state and available measurements. In an interview with Fierce Biotech, Marks stated “[w]e've [got] a better idea over time over the nature of the data that we want to see that can help us feel that there is a compelling case that a given intervention will potentially be associated with a positive clinical outcome.”

 Marks has further used the metaphor of a rubber band, suggesting that the agency can use flexibility in accelerated approvals to the maximum possible level, up to a finite point where the rubber band breaks.

 In this context, Marks has explained that FDA does not “have to get to 100% certainty between an accelerated approval endpoint and a clinical endpoint” and that “[i]If that were the case, there wouldn't be a difference, then we wouldn't have accelerated approval."

Continued follow-up as confirmatory evidence

. Second, Marks has suggested that confirmatory evidence can come from continued follow-up of subjects, rather than a separate confirmatory study. To this end, at a recent meeting of the American Society of Gene & Cell Therapy (ASGCT) Marks stated, “[w]ith gene therapy under the regenerative medicine advanced therapy designation, a confirmatory trial could simply be following the cohort you have enrolled in your registration trial.”

 This suggestion is consistent with reliance on intermediate clinical endpoints, and alleviates one of the main challenges to accelerated approval—namely enrolling a confirmatory study once a drug has been approved. It also provides a manner of ensuring that further data on the clinical endpoints will be gathered in a timely manner. Marks appears to be open to such data confirming benefit in a broad sense, rather than pursuant to a narrow understanding of the intermediate clinical endpoint.

Taken together, these approaches recapture the sense of urgency that gave rise to accelerated approval in the 1990s, and have the potential to reinvigorate use of the pathway for gene therapy, and perhaps more broadly. FDA and sponsors have long struggled with the challenges of enrolling confirmatory trials once a drug has been approved, with some sponsors proposing the use of RWE as an avenue for further insight into the safety and efficacy. Marks’ indication that FDA would consider continued follow-up of clinical subjects as confirmatory evidence, could be seen as a first step in incorporating RWE into the accelerated approval pathway. Such a move would be highly significant for sponsors.

It is worth noting that FDA has indicated that it is fostering approval of gene therapies in other ways as well. For example, FDA and sponsors have long acknowledged that manufacturing is a key challenge for the approval and widespread availability of gene therapies. Manufacturing changes in the development of a biological product, and particularly gene therapies, pose challenges because of the potential impact on the safety and efficacy of the therapeutic product. FDA is now tackling this issue head on for gene therapy products with the publication of a recent draft guidance, “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products.”

 In that guidance, FDA makes clear that it that it is open to innovative approaches in manufacturing gene therapies and that it acknowledges that manufacturing processes may be subject to modification even after approval. The new draft guidance focuses on establishing “a robust framework” for managing these manufacturing changes, including attention to risk management, product stability, and comparability studies.

Marks’ high-profile commitment to greater use of the accelerated approval pathway and this recent focus on gene therapy manufacturing issues are a welcome and positive sign that FDA is committed to approving additional gene therapy products. These developments also promise renewed interest and flexibility in using the accelerated approval process to bring promising products to patients.

, JD, is senior counsel at Sidley Austin LLP

FDA, Accelerated Approval Program. May 30, 2023 

https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program#:~:text=The%20FDA%20instituted%20its%20Accelerated,based%20on%20a%20surrogate%20endpoint.%22

The Future of Accelerated Approval for FDA's Marks? More Rare Disease Drugs and No 'Hanging Chads.' Fierce Biotech. July 28, 2023. 

https://www.fiercebiotech.com/biotech/peter-marks-says-fda-now-has-better-sense-rare-disease-biomarkers-will-more-accelerated

Cell/Gene Therapies: US FDA Wants ‘Quantitative Correlation' Between Surrogate and Clinical Outcome, Former Reviewer Says. Pink Sheet. July 10, 203.

FDA 'Leans In' to Accelerated Approval for Rare Disease Drugs. Pharma & Healthcare Monitor Worldwide. May 22, 2023.

FDA, Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products: Draft Guidance for Industry (July 2023). 

https://www.fda.gov/media/170198/download

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