Rare disease drug developers and advocates are calling for clearer regulatory guidance from the U.S. Food and Drug Administration as the agency faces leadership changes, according to an April 2 webinar hosted by BioSpace.
The issue is significant because rare disease therapies often face unique challenges in clinical development, making predictable and flexible regulation crucial for companies seeking to bring new treatments to patients with unmet medical needs.
Rahul Gupta, President of GATC Health, said during the BioSpace webinar that it has "become more explicit that regulatory flexibility is appropriate, but not a waiver of rigor." He noted the challenge of translating FDA direction into "actual, predictable and operational guidance for sponsors." This comes as a coalition of advocates and executives sent a letter to President Donald Trump and other officials urging them "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.
Leadership transitions at the FDA have contributed to uncertainty. Vinay Prasad will depart his role as head of CBER at the end of April after a tenure marked by what some analysts described as increased stringency in rare disease drug approvals. Under Prasad's leadership, approval rates dropped; in 2025 CBER approved five orphan drugs but issued four complete response letters—meaning nearly half were rejected compared to about 10% in prior years. In contrast, CDER has approved several rare disease drugs this year.
Stacey Frisk, executive director of the Rare Disease Company Coalition (RDCC), said during the webinar that "the landscape is a bit mixed" regarding approvals. She emphasized that ongoing dialogue with regulators is vital: “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.”
Recent policy shifts include allowing approval based on one pivotal trial instead of two—a move described by Matthew Winton from CervoMed as a “redefinition of rigor,” focusing on total evidence rather than just trials. Capricor CEO Linda Marbán advocated using external controls in trials: “Leadership is talking about history, real world evidence...that doesn’t seem to be translating down well into the review staff.”
Uncertainty at FDA has also affected investment; two-thirds of biotech companies surveyed by RDBI found it harder to raise capital recently. Marbán noted investment implications: “There’s huge investment implications in one versus two pivotal trials...we are very dependent on investors.” She concluded that requiring only one pivotal trial could energize investment if combined with rigorous evidence.
