ene therapy offers hope for patients suffering from rare genetic diseases long considered untreatable beyond symptom management. The therapy involves using genetic material to treat diseases by functionally repairing or replacing missing or damaged genes. Several gene therapies have gained Food and Drug Administration (FDA) approval in recent years, with a wave of new therapies predicted in the coming years. As of early 2025, the FDA has approved over 30 cell and gene therapies, and industry experts anticipate 30-50 additional cell and gene therapy approvals by 2030.

Peter Marks, the former director of the Center for Biologics Evaluation and Research (CBER) at FDA, vocally supported the expedited development of gene therapies. Part of that support included backing the increased use of the Accelerated Approval program. Regarding accelerated approval, Marks commented at various industry and regulatory meetings that there would be “increasing receptivity,” that CBER was “leaning in,” and that “Accelerated Approval would be the norm for a lot of our initial approvals of gene therapies.”

However, there has been controversy surrounding accelerated approvals. Accelerated Approval was implemented in 1992 in response to the HIV/AIDS crisis. It is a regulatory mechanism through which drugs for serious and life-threatening illnesses that address an unmet medical need can be approved by the FDA based on a surrogate endpoint or an intermediate clinical endpoint with a reasonable probability of predicting clinical benefit. Critics of the program argue that it often results in higher drug prices, delayed confirmatory trials, and uncertain clinical benefits, as well as limited enforcement action by FDA to remove ineffective drugs from the market. In response to these concerns, Congress included provisions in the Consolidated Appropriations Act of 2023, which created additional requirements and gave the FDA more authority related to accelerated approvals. The law requires the FDA to set conditions for confirmatory trials and create clear procedures for withdrawing products from the market that do not show clinical benefit.

As a result, the FDA recently issued two new draft guidance documents on accelerated approval: one on Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics in December 2024 and another one on Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway in January 2025. These draft guidance documents, when finalized, will reflect FDA’s commitment to ensuring that sponsors of drugs that are granted accelerated approval deliver on confirmatory studies and that the approval process remains accountable and transparent, while continuing to address significant unmet patient needs as efficiently as possible.

Accelerated Approval in Rare Disease and Gene Therapy

Drugs to treat rare diseases are often prime candidates for the Accelerated Approval pathway because of the high unmet need, limited endpoint development, and small number of patients affected by any given rare disease. These factors can make it difficult to establish robust study designs that are feasible to enroll. Rare diseases are typically also ideal candidates for gene therapy, as approximately 80% result from a single genetic mutation. By correcting or compensating for this mutation, gene therapy has the potential to provide long-term, curative treatment often with a single administration.

Many of the initial gene therapy approvals for nononcology rare diseases were full approvals. This was, in part, due to the historical reluctance of the agency to accept surrogate endpoints that were not already validated in the design of pivotal trials. However, the FDA has become more open to using surrogate endpoints in recent years, particularly for gene therapies. For example, Sarepta’s Elevidys was approved for Duchenne muscular dystrophy in June of 2023. This approval was somewhat unique in that the drug failed to meet its primary clinical endpoint, and the review office did not recommend approval. However, Dr. Marks chose to override the review division’s recommendation and grant accelerated approval based on transgene expression.

More recently, we have seen examples of FDA agreeing in principle to surrogate endpoints prior to filing and even prior to the initiation of clinical trials. Examples include Rocket Pharmaceuticals’ trial for Danon Disease and Regenexbio’s and Ultragenyx’s trials for MPS II and MPS IIIA, respectively. We believe that these newer precedents demonstrate a significant shift in agency thinking and confirm that CBER is leaning into accelerated approval.

According to the FDA, in the CBER guidance agenda of 2025, CBER plans to issue gene therapy-specific guidance on accelerated approval later this year. We believe the new guidance will build on and explain the growing number of precedents where CBER has agreed to a reasonably likely surrogate endpoint as a measure of clinical efficacy to support accelerated approval.

Global Implications

While the FDA embraces the regulatory flexibility of accelerated approval, the question arises as to whether the European Medicines Agency (EMA) and other global regulatory agencies will follow suit.

While EMA does not have accelerated approval, its conditional marketing authorization supports development of medicines that address unmet medical needs. Unlike the FDA, the EMA has not yet shown that it will “lean in” to increased use of conditional marketing authorization for gene therapies, as evidenced by the fact that gene therapy products granted accelerated approval in the US, such as Skysona and Elevidys, are still not approved in the EU. In contrast, gene therapy products granted full approval in the US, such as Beqvez, Hemgenix, Roctavian, and Zolgensma, are approved in the EU.

This leaves drug developers with questions around whether the expectations for accelerated approval will differ among different health authorities. Regardless, we believe that increased FDA accelerated approval in the US is still a major win for patients who are seeking access to treatments for rare and devastating diseases.

Conclusion

Recent events, including the resignation of Peter Marks as the director of CBER, have created some feelings of uncertainty about the future direction of the agency regarding accelerated approval for gene therapies. However, the cultural changes are already in full motion, and other leaders like Nicole Verdun, director of the Office of Therapeutic Products, have shown that they are already fully engaged. Therefore, FDA Accelerated Approval is not only here to stay, but its use will likely continue to expand in the gene therapy space. FDA has shown increasing understanding of how important regulatory flexibility is to patients who suffer from rare diseases and is actively engaged in efforts to enable more efficient development of potentially transformative therapies. We applaud the FDA for improving and leaning into, rather than shying away from or abandoning, the Accelerated Approval program.

To learn more about this topic, plan to attend DIA’s Cell and Gene Therapy Summit.