The U.S. Food and Drug Administration has recently reversed several decisions regarding the use of external controls in clinical trials for rare disease therapies, leading to confusion among drug developers, according to an April 6 report by BioSpace.
The issue centers on whether data from studies using natural history or real-world evidence as external controls can serve as the primary basis for regulatory approval. While recent FDA guidance encourages innovative trial designs, including externally controlled trials for rare diseases, some companies have faced setbacks when these approaches were later deemed insufficient during the review process.
Linda Marbán, CEO of Capricor Therapeutics, said during a BioSpace webinar that there is a disconnect between leadership encouraging the use of real-world datasets and how review staff interpret this guidance. "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," Marbán said. "That doesn’t seem to be translating down well into the review staff." This situation has affected companies such as Stoke Therapeutics, Denali Therapeutics and Praxis Medicines.
Capricor’s cell therapy deramiocel was rejected due to concerns over its reliance on externally controlled studies but is now back under FDA review with new Phase 3 data. UniQure also experienced an FDA reversal regarding its Huntington’s gene therapy AMT-130; after initially agreeing that external control data would suffice for approval consideration in 2024, the agency later required a sham surgery–controlled study instead.
Harpreet Singh, chief medical officer at Precision for Medicine and former division director at the FDA, explained: “It’s incredibly complex to determine whether an external control is appropriate.” She added that while guidance can be given early in development, “its final acceptability really can’t be determined until the review process is complete.”
Rahul Gupta, president of GATC Health, commented that regulatory flexibility should not mean lowering standards: “It’s become more explicit that regulatory flexibility is appropriate,” he said during the webinar,“but not a waiver of rigor.”
Despite these challenges, there have been instances where FDA showed initial flexibility with external controls. For example, Rezolute was allowed by the agency in August 2025 to conduct an open-label study rather than a randomized trial for its hypoglycemia drug candidate after concerns about feasibility were raised. The agency also accepted additional analysis following missed endpoints due partly to behavioral confounders.
Denali Therapeutics received approval for Avlayah based on open-label trial results showing significant biomarker improvement; however REGENXBIO's similar approach did not receive approval due partly to lack of comparability between trial patients and historical controls.
Gupta summarized: “FDA has consistently said that external or natural history controls can support approval... 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.”
