With CBER director Vinay Prasad set to depart the agency at the end of the month, a coalition of patient groups and biotech executives penned a letter imploring the Trump administration to “restore regulatory clarity” for rare disease therapies. Experts on a BioSpace panel last week also acknowledged the challenges faced by a more stringent FDA.
Rare disease drug developers rejoiced last year when the FDA issued multiple guidances aimed at accelerating therapies for these conditions to the market. In actual practice, however, there appears to be a disconnect between intent and regulatory decisions as the agency walks a precarious tightrope between scientific rigor and meeting unmet needs.
“[It’s] become more explicit that regulatory flexibility is appropriate, but not a waiver of rigor,” Rahul Gupta, President, GATC Health, said of the current FDA during a webinar hosted by BioSpace last week.
This balancing act has created strain between the FDA and the patient groups and biotech companies working to advance rare disease therapies. A coalition of advocates and executives this week penned a letter to the Trump administration imploring it “to restore regulatory clarity as it considers new leadership at the U.S. Food and Drug Administration’s Center for Biologics Evaluation and Research,” according to reporting by Reuters on Wednesday.
The letter, written by the Rare Disease Advocacy, Biotechnology, and Investor Coalition (RDBI), was sent to President Donald Trump, Health Secretary Robert F. Kennedy Jr., FDA Commissioner Marty Makary and Medicare administrator Mehmet Oz.
The leadership transition referenced by the authors is presumably the one about to occur at the FDA’s Center for Biologics Evaluation and Research (CBER), which is largely responsible for regulating rare disease therapies. On March 6, news broke that Vinay Prasad—the controversial and embattled head of the division since last spring—will depart the agency at the end of April. Prasad took over as chief of biologics after the surprising departure of longtime and well-respected regulator Peter Marks that sent the XBI biotech stock index plummeting to its lowest point in years. This is just one of many leadership changes the agency has seen in the past year.
“I know that institutional transitions create policy ambiguity, even when the intent is aligned,” Gupta said during the BioSpace webinar. “But the challenge right now is translating that FDA daily direction into actual, predictable and operational guidance for sponsors.”
A More Stringent FDA
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, Frisk said during the webinar. 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,” she said.
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,” Makary noted in a March 25 press release announcing Avlayah’s approval.
Frisk lauded this statement, saying, “I think we’re seeing some encouraging signals.”
Gupta added that 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.”
For Matthew Winton, chief commercial and business officer at CervoMed, the FDA’s official pivot in February from a requirement of two pivotal trials to one for new drug applications represents a “redefinition of rigor,” putting more of an onus on the overall evidence package.
Instead of placing all the emphasis on one or two pivotal trials, regulators will be looking at “a package of data or totality of evidence to ensure that the drug is safe and efficacious for patients,” Winton said during the webinar. “I think it’s important to acknowledge this is one the FDA got right.”
Frisk noted that in this new paradigm, it is essential for rare disease–focused companies to have an early, continuous and iterative dialogue with the FDA. “In rare disease we have different challenges,” she said. “We need to have the understanding that the expectation for a single perfect trial is going to be too high of a bar for many rare diseases,” especially when considering novel endpoints and limited precedent and experience.
Capricor CEO Linda Marbán agreed, advocating for the use of external controls—those where a cohort of patients receiving the investigational drug is compared to a group of patients outside of the trial. In guidance issued last year, the FDA itself encouraged the use of external controls in cell and gene therapy trials.
“Leadership is talking about history, real world evidence, all of the abilities to use those data sets clearly to define the pathogenesis of a disease process as compared to some kind of a treatment paradigm,” Marbán said during the webinar. “That doesn’t seem to be translating down well into the review staff.”
Investors Crave Clarity
Rare disease drug development doesn’t fit the traditional biopharma investment model, representing another challenge for companies like Capricor, CervoMed and the drug developers represented by the RDCC.
About two-thirds of biotech companies surveyed by RDBI said the uncertainty at the FDA had made it harder to raise capital over the past 12 months.
In this context as well, the single pivotal trial policy can be beneficial, according to Marbán.
“There’s huge investment implications in one versus two pivotal trials,” she said. “I think that we as a biotech community and world have to acknowledge the fact that we are very dependent on investors.”
The old two pivotal trial format—which the panelists acknowledged was already being phased out, particularly in the rare disease space—required “a lot more investment and a lot more time that a company has to stay afloat,” Marbán continued.
The requirement for only one pivotal trial, she concluded, “really can give some great energy to the investment space if we have a total package that is based on rigor, but in addition to that, recognizing that there is an infusion of capital that’s necessary to move these programs forward.”
