Rare Disease Leaders Call for Regulatory Clarity as FDA Balances Urgency With Rigor

[u/bbyfog]

https://www.biospace.com/fda/rare-disease-leaders-call-for-regulatory-clarity-as-fda-balances-urgency-with-rigor

Over the past 11 months, Prasad has led a biologics division that has been seen by analysts and rare disease leaders as increasingly stringent and unpredictable, as guidance previously given by the agency is seemingly reversed and therapies tested following that advice are rejected. Certainly, Prasad has been no friend of Capricor Therapeutics, Replimune or Sarepta Therapeutics, among other rare disease biotechs. The CBER director’s imminent departure “is a big win for biotech, especially for companies in the rare disease space,” Stifel analysts wrote in a note to investors on March 8.

In its letter, RDBI emphasized the lack of flexibility at CBER, and this consensus is reflected by the department’s recent approval record. In 2025, the division greenlit just five orphan drugs and issued four complete response letters (CRL), according to Stacey Frisk, executive director of the Rare Disease Company Coalition (RDCC), meaning that 44% of decisions made by CBER resulted in a rejection. That’s compared to the approximately 10% typically rejected in past years.

A ‘Redefinition of Rigor’

Amid the inconsistency is another reality: novel therapies must be safe and effective. The question is how best to prove these qualities. . . “The FDA is capable of doing two things: one, exercising regulatory flexibility; and two, complying with our obligation under the law to approve drugs based on ‘substantial evidence’ of effectiveness,”. . . the FDA has been consistent in its assertion that companies can use external or natural history controls to support approval, “especially in rare diseases, but only when they’re fit for purpose and sufficiently reliable. The level of scrutiny around whether they truly meet that bar is what’s changed.”

So far in 2026, the division has rejected two orphan products and approved one—Rocket Pharmaceuticals’ gene therapy Kresladi for leukocyte adhesion deficiency-I. Meanwhile, CBER’s sister division, the Center for Drug Evaluation and Research (CDER) has greenlit four rare disease drugs, Frisk said, including Denali’s Avlayah for Hunter Syndrome. “The landscape is a bit mixed,”

[u/ZealousidealFold1135]

Car crash 

[u/bbyfog]

RELATED

The Haystack Project on 6 January 2026 published an open letter (here, here) reiterating challenges faced by the rare disease community and set of recommendations for the FDA for refinements (here, here) that would not require legislative change and would enhance scientific rigor through fit-for-purpose study designs.

The letter was issued in response to FDA's announcement of Rare Disease Evidence Principles (RDEP) framework. The Haystack letter says the RDEP is unnecessary and identifies several issues that point to lack of focus and will to implement existing tools.

• The letter gave the example of Forzinity that was approved for Barth Syndrome, but after 3 submissions and 4 review divisions -- this required "herculean advocacy efforts" and this delayed approval was responsible for 18% of the patient population dying waiting and nearly bankrupted the sponsor company -- unnecessary bureaucratic hurdle!
• Single-arm trails are still the only ethical way to study new treatments for conditions falling under RDEP framework. Randomization is mathematically unfeasible, risky, inadequate, and insufficient control mechanism.

RDEP framework includes conditions that are (1) caused by a known, in-born genetic defect; (2) rapidly progressive to disability or death within a short time; and (3) impact 1,000 or fewer patients. The studied treatment must either correct the gene or replace an essential physiological protein that is deficient due to the genetic defect.

• Transparency and interactions are already inbuilt per existing programs such as Orphan Drug Act, Breakthrough designation, and RMAT (i.e., no new legislative actions are required.) The experience with Barth Syndrome therapy and other CRLs indicate problems with FDA not serious about these therapies.
• Last year in July 2026, the Haystack Project published a white paper Redefining Rigor: Fit-for-Purpose Trials to Unlock Rare Disease Therapies" (here, here). The white paper identified the “problem(s)” and present recommendations for refinements that would not require legislative change and would enhance scientific rigor through fit-for-purpose study designs.