While recent FDA guidance speaks to the agency’s support of innovative trial designs—including the use of external controls—the application of this flexibility appears to be inconsistent. One former regulator says the situation is more nuanced.
In 2024, the FDA agreed that data from a trial of uniQure’s Huntington’s disease gene therapy comparing treated patients to a natural history external control could serve as the primary basis for a regulatory application. Recent FDA guidance encourages this type of innovative trial design for testing rare disease therapies. But late last year, the agency reversed course, sending uniQure off to conduct a sham surgery–controlled study.
“Leadership is talking about history, real-world evidence, [encouraging companies] to use those datasets clearly to define the pathogenesis of a disease process as compared to some kind of a treatment paradigm,” Linda Marbán, CEO of Capricor Therapeutics, said during a recent BioSpace webinar. “That doesn’t seem to be translating down well into the review staff.”
This disconnect could have near-term implications for some biopharma companies, including Stoke Therapeutics, Denali Therapeutics and Praxis Medicines, Jefferies analyst Andrew Tsai told BioSpace.
Stoke is currently conducting a sham-controlled Phase 3 trial for zorevunersen in Dravet syndrome, a rare and severe form of epilepsy. However, the company has had discussions with the FDA about potential expedited regulatory pathways based on its Phase 1/2a and open-label extension studies, as well as data from a two-year natural history study, a company spokesperson told BioSpace.
Denali, meanwhile, is studying DNL126 in a Phase 1/2 trial for Sanfilippo syndrome type A, which is expected to wrap in August 2028. But the drug’s confirmatory trial is likely to be an open-label study compared to an external control, Tsai said. Denali plans to finalize the design of the study this year, according to a company spokesperson.
And in December, the FDA agreed that Praxis could convert its registrational study for elsunersen in epilepsy from a double-blind, sham-controlled design to a single-arm trial compared to baseline followed by an open-label extension (OLE).
Indeed, the FDA issued guidance last year indicating support for—and even encouraging—cell and gene therapy developers to use innovative clinical trial designs, including externally-controlled trials—those using historical or real-world data. This could be “rather than or in addition to enrolling a concurrent control arm within the same study protocol,” the agency said. But the devil is in the details, Harpreet Singh, chief medical officer at Precision for Medicine, who previously served as a division director of Oncology at the FDA, told BioSpace.
“It’s incredibly complex to determine whether an external control is appropriate.”
Capricor, UniQure and Biohaven Thwarted
The use of an externally controlled study, Marbán said, was “one of the major issues” raised in the July 2025 complete response letter for Capricor’s deramiocel, being developed for Duchenne muscular dystrophy cardiomyopathy.
Deramiocel’s Biologics License Application (BLA) was supported by data from the Phase 2 HOPE-2 trial, which featured an OLE study and natural history comparisons from FDA-funded datasets. But, as Marbán said, “that was not enough to support approval.”
The cell therapy is now back under review at the FDA, supported by data from Capricor’s successful Phase 3 HOPE-3 trial. A decision is expected by August 22.
When considering the use of external studies, “companies should engage early and often with regulators to align on the acceptability of external controls, trial endpoints and the proposed statistical framework—ideally well before a pivotal study is initiated,” Bruce Leuchter, president and CEO of Neurvati Neurosciences and GRIN Therapeutics, told BioSpace
Marbán believed Capricor had done just that. “We are surprised by this decision by the FDA,” she said in a statement at the time. “We have followed their guidance throughout the process.”
UniQure was similarly thrown for a loop in November 2025, revealing that the FDA “no longer agrees” with its own 2024 position that a Phase 1/2 study using a natural history external control could support a BLA for the Huntington’s gene therapy AMT-130. The sham surgery–controlled Phase 3 study the agency is now requiring only raises further questions for the company and Huntington’s patient community.
Leuchter said that external controls are most successful when used as “a complement to, not a substitute for, robust trial design and comprehensive evidence generation.”
But Biohaven struck out with this approach in a New Drug Application (NDA) for troriluzole in spinocerebellar ataxia, which was rejected by the FDA in November 2025. The regulatory package was supported by both a one-year placebo-controlled study and a three-year RWE study, which met its primary and secondary outcome efficacy endpoints.
In a complete response letter, the FDA cited issues “that can be inherent to real-world evidence and external control studies including potential bias, design flaws, lack of pre-specification and unmeasured confounding factors,” according to Biohaven’s press release at the time.
“I’d love to understand why these companies and sponsors have been turned down based on the real-world evidence data when it seems such a clear path forward,” Marbán said during the webinar.
Singh offered a regulator’s perspective.
“The FDA can give a lot of guidance and feedback as you’re creating the external control, or as the companies are thinking about the external control, but its final acceptability really can’t be determined until the review process is complete,” she said. “So the idea that FDA is shifting its position [on uniQure’s AMT-130] I think, really remains to be seen.”
Rahul Gupta, president of GATC Health, made a similar point during the BioSpace webinar. “It’s become more explicit that regulatory flexibility is appropriate,” he said, “but not a waiver of rigor.”
Flexibility Granted
Certainly, there are other cases over the past year in which the FDA has shown at least initial flexibility with the use of external controls.
In August 2025, the agency told Rezolute it would not be required to conduct a randomized, placebo-controlled trial for its lead candidate in hypoglycemia caused by tumor hyperinsulinism (HI). Onlookers had questioned the rationale for conducting a randomized study in this indication, CEO Nevan Charles Elam told BioSpace, “And sure enough, FDA said, ‘Guess what? You don’t need to.’” Instead, the FDA said, Rezolute could run a truncated open-label study of ersodetug in as few as 16 patients with tumor HI, according to a company announcement in September.
Rezolute was gifted more FDA flexibility last month when during a Type B meeting, the agency did not dismiss out of hand data from a Phase 3 trial of ersodetug in congenital hyperinsulinism, which failed both its primary and secondary endpoints. Instead, the FDA agreed that the missed endpoint, a reduction in hypoglycemia events, could have been confounded in part by behavioral factors. The agency encouraged Rezolute to submit study reports and analysis datasets for the agency to conduct its own analysis.
“For a division to say ‘We’re going to do our own analysis, if you give us the data set, because we’re curious’ . . . I haven’t seen that in years,” Elam said.
Another recent example of FDA flexibility is the recent approval of Denali Therapeutics’ Avlayah for Hunter syndrome. The nod was based on an open-label Phase 1/2 trial in which treatment with the enzyme replacement therapy led to a 91% reduction in levels of heparan sulfate in the cerebrospinal fluid, a key disease marker that is “reasonably likely to predict clinical benefit,” according to Denali’s approval announcement on March 25. Notably, REGENXBIO’s gene therapy for Hunter syndrome failed to receive approval earlier last month, with the FDA citing, among other sticking points, the company’s use of external controls, which it said “lack the comparability” with the trial patients, according to the complete response letter.
Ultimately, Gupta said, “FDA has consistently said that external or natural history controls can support approval, especially in rare diseases, but only when they’re fit for purpose and sufficiently reliable. What’s changed is the level of scrutiny around whether they truly meet that bar.”
