FDA Proposes New, Faster Approval Process for Ultra-Rare Disease Therapies

The FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) have jointly proposed the Rare Disease Evidence Principles (RDEP), a new framework to facilitate the approval of therapies for exceptionally rare diseases. This formalizes a process that had been under development, notably during the tenure of former CBER Director Peter Marks.

Key components of the RDEP framework:

• Evidence for Approval: For therapies targeting a known genetic defect in a population of fewer than 1,000 Americans, the FDA would permit a single-arm study to serve as the primary evidence for effectiveness, provided it is supported by other robust data. This is a departure from the traditional requirement of two well-controlled clinical investigations.
• Eligibility Criteria: The RDEP process is designed for therapies treating diseases with a known genetic defect that result in “significant disability or death,” and for which no adequate alternative therapies exist.
• Pre-Pivotal Trial Submission: Sponsors must submit their request to be considered under RDEP before starting a pivotal trial.
• Initial Engagement: Accepted companies will have an initial meeting with the FDA’s review team to define the necessary data for demonstrating safety and effectiveness. The FDA encourages the use of patient experience data, including “patient listening sessions,” to inform this process.
• Supportive Data: The single-arm study can be supplemented by various forms of confirmatory evidence, including: Data on the drug’s effect on the disease’s pathophysiology; Evidence from non-clinical models; Relevant clinical pharmacodynamic data; Other clinical data, such as case reports and expanded access data.
• Consistency and Oversight: To ensure a consistent approach between CDER and CBER, all decisions to accept a drug for review under RDEP will be made in consultation with the Rare Disease Policy and Portfolio Council (RDPPC).
• Post-Marketing Requirements: Drugs approved through this pathway may be subject to additional post-marketing requirements.

The initiative, which FDA Commissioner Marty Makary had previously discussed, builds upon the work of Peter Marks, who was a champion for accelerated approvals for rare disease gene therapies. It also parallels legislative efforts, such as the “Promising Pathway Act”, which sought to create a provisional approval pathway for rare disease drugs showing early evidence of safety and efficacy.