New FDA approval process promotes development of rare disease gene therapies

On Wednesday, FDA announced a new process called “Rare Disease Evidence Principles” (RDEP), which is intended to facilitate the approval of drugs and biological products:

1. to treat rare diseases with very small patient populations,
2. where patients have a significant unmet medical need,
3. and for which a genetic defect is known to be the major driver of the pathophysiology.

What are the benefits of RDEP?

For drugs and biologics meeting RDEP’s eligibility criteria, FDA said it expects that “substantial evidence of effectiveness” may generally be established “based on one adequate and well-controlled study that may be a single arm trial,” together with “robust data that provides strong confirmatory evidence of the drug’s treatment effect.” FDA will also consider confirmatory evidence provided through the appropriate selection of external controls or natural history studies.

FDA has already provided a series of draft guidances (in September 2023; December 2019, and May 1998) on other circumstances where a determination of “substantial evidence of effectiveness” may be “based upon one adequate and well-controlled study with confirmatory evidence,” as we previously analyzed here.

FDA stated that the RDEP process will provide sponsors of drugs or biologics that meet the eligibility criteria:

• an initial meeting with the appropriate FDA review team to determine what data could be used to demonstrate “substantial evidence of effectiveness.”
• assurance that FDA’s review will encompass additional supportive data, “including by leveraging separate patient listening sessions where appropriate.”

However, drugs and biologics approved after participation in RDEP may be subject to additional postmarketing requirements, FDA says.

Who is eligible for RDEP?

FDA explained that drug or biologic sponsors may apply for RDEP at any time prior to the launch of a pivotal trial, if all of the following conditions apply:

1. the investigational therapy is specific to the correction of the genetic defect in question (i.e., either correcting the gene or is a replacement of an essential physiological protein that is otherwise deficient due to the gene defect);
2. the drug is for a very small, rare disease population or subpopulation (e.g., generally less than 1,000 persons in the U.S.);
3. the drug is intended to treat a known, in-born genetic defect that is the major driver of the pathophysiology;
4. the clinical course of the disease is progressive deterioration in function leading to rapid and/or significant disability or death in a relatively short period of time; and,
5. there are no adequate alternative therapies that alter the course of the disease.

FDA says drug review teams will consult with the CDER/CBER Rare Disease Policy and Portfolio Council (RDPPC) in the decision to accept a drug for review under this process. The agency also clarifies that sponsor requests for RDEP review are separate from requests for orphan-drug designation. Sponsors will therefore still need to seek orphan-drug designations for eligible products.

Next steps

The announcement of the RDEP process came Wednesday at an FDA/Duke Margolis Institute for Health Policy rare diseases meeting, where FDA Commissioner Marty Makary and CBER Director Vinay Prasad previewed a forthcoming FDA "plausible mechanism of action" approval pathway that will be limited to bespoke therapies for very rare diseases. They said that pathway would be explained soon in a New England Journal of Medicine (NEJM) article that they would co-author. The meeting was the first “Rare disease Innovation, Science and Exploration” (RISE) workshop convened under the FDA Rare Disease Hub's FY-2025 strategic plan.

On a policy level, we note that the RDEP process comes after U.S. legislators in 2024 proposed the “Promising Pathway Act,” which sought to create a conditional FDA approval pathway for rare disease drugs (and which would have required the drugs to be reimbursed without cost-sharing). We see the RDEP program as an extension of FDA's trend toward using its regulatory flexibility and recognizing the challenges in the development of drugs and biologics for rare diseases, unmet need, and regenerative medicines, as we previously discussed online here and here.

This trend also mirrors efforts of other regulators around the globe. For example, the European Medicines Agency offers protocol assistance to developers of designated rare disease products or “orphan medicinal products” on the basis of Article 6 of EU Regulation (EC) 141/2000 on Orphan Medicinal Products. This protocol assistance consists of answers to questions relating to the criteria for authorization, including clinical aspects and exploratory or confirmatory safety and efficacy studies.

As noted above, this new process does not alter the statutory “substantial evidence” standard for approval. Even so, it is clear the agency is focused on being more explicit that it will consider a range of evidence that may be used to establish substantial evidence and will communicate that to sponsors earlier in development. Moreover, this new process may offer additional flexibility to sponsors when designing their pivotal clinical trials. As such, we recommend that sponsors of early-phase products to treat ultra-rare diseases should actively consider how this new process may impact their pivotal study programs, and whether this process may offer a faster and more efficient pathway to generating the data needed for an NDA or BLA.

FDA stated that a request for participation in RDEP should be accompanied by a formal meeting request appropriate for the sponsor's stage in the drug development process. If you may be interested in applying for the RDEP process, or if you have questions on planning clinical trials for rare diseases, please contact the Hogan Lovells with whom you generally work or one of the authors of this alert.

Authored by Lynn Mehler, Mike Druckman, Robert Church, Komal Nigam, Bryan Walsh, and Julia Mischie