"New Approach for Rare Disease Approvals Unveiled by FDA: Lack of Presents, Focus on Wrappers"

The Food and Drug Administration (FDA) has announced a new initiative to streamline the approval of therapies for ultra-rare diseases. The Rare Disease Evidence Principles (RDEP) framework, unveiled on Wednesday by FDA Commissioner Marty Makary, aims to provide a more efficient pathway for companies developing treatments for rare conditions.

Under the RDEP, companies can file for approval under an investigational new drug (IND) application using a single-arm trial for diseases that affect a "very small, rare disease population... generally less than 1,000 persons in the United States." This approach could potentially expedite the development and approval of life-changing therapies for those suffering from these debilitating conditions.

A key example of a gene therapy in development with approval based on a single-arm study is ETX101 for treating Dravet syndrome. This treatment has received the FDA's Regenerative Medicine Advanced Therapy (RMAT) status, enabling accelerated approval processes based on promising clinical data reducing seizure frequency.

However, not all conditions are eligible for the RDEP. It applies to treatments for conditions that are genetically-based or progressive functional deterioration leading to disability or death. Moreover, it does not apply to conditions with adequate alternative therapies.

Analysts at Jefferies view the RDEP as a sign of a more "favorable" regulatory environment at the FDA regarding rare diseases. However, analysts at William Blair are uncertain about the tangible impact of the RDEP on the development process and approval timeline for gene therapies in development. Most therapies in development, according to the analysts at William Blair, will not be eligible to apply under the RDEP due to the restriction on patient population.

Experts have previously expressed skepticism about the FDA enacting changes to its rare disease review pathways without legislation. Paul Kim, advisor at the National Organization for Rare Disorders, stated in a LinkedIn post that the RDEP is "all wrapper and no gift" and is merely a restatement of current Agency practice. Daniel Kracov, a partner and chair of the Global Life Sciences Industry Practice at Arnold & Porter, shares similar sentiments, expressing skepticism about the FDA enacting changes without legislation.

Commissioner Marty Makary is also considering a new regulatory pathway for rare diseases based on a molecule's "plausible mechanism." However, Kracov insists that basing approvals on a drug's plausible mechanism is "about as low a standard as you could possibly get." If a drug "makes sense physiologically," according to Commissioner Makary, the FDA could consider approval "on a conditional basis."

Companies applying under the RDEP will have to provide supporting data, such as evidence of a treatment effect on the disease's pathophysiology and findings from relevant non-clinical models. The FDA emphasizes that the RDEP does not lower the bar for safety or efficacy, but rather aims to provide a more efficient pathway for life-saving treatments for those suffering from ultra-rare diseases.

The RDEP framework marks a significant step forward in the FDA's commitment to streamline rare disease drug approvals, as pledged by Commissioner Marty Makary in April during an appearance on The Megyn Kelly Show. While the impact and implications of the RDEP are still uncertain, it presents a promising opportunity for the development and approval of life-changing therapies for those suffering from ultra-rare diseases.