The FDA has gained a reputation during the past year for being inconsistently flexible, particularly when it comes to rare diseases. Executives at Rezolute and CERo Therapeutics recently had positive interactions with the agency, in which they told BioSpace reviewers have been “collaborative” and “curious.
In March 2025, CERo Therapeutics kicked off a Phase 1 trial for its lead candidate, an autologous T cell therapy called CER-1236, focused on acute myeloid leukemia. In October, however, the company detected an unexpectedly positive response in a patient whose AML had progressed to myelodysplastic syndrome. Prior to treatment with CERo’s drug, this patient was burdened with frequent platelet transfusions. After four rounds of CER-1236, however, they started making their own platelets, said Robert Sikorski, chief medical officer at the Bay Area biotech.
“We hadn’t expected that,” Sikorski told BioSpace. “Obviously, when you see that . . . we made the decision to add more myelodysplastic syndrome patients to the trial.”
So, CERo went to the FDA with a proposal to amend the trial to include both indications. The request was approved within 30 days, enabling the company to “really quickly move into a new set of patient populations in an active trial without having any downtime,” Sikorski said. This was critical, he added, given the serious nature of the diseases, and the FDA seemed to understand that. The agency, he said, was “very responsive and collaborative.”
This feedback stands out from recent headlines. The FDA has been repeatedly criticized by politicians, patient advocates and biotech executives alike for a lack of flexibility—not to mention clarity—in its regulation, particularly of rare disease therapies. Earlier this month, the Rare Disease Advocacy, Biotechnology, and Investor Coalition penned a letter to the Trump administration in which it called on FDA and Department of Health and Human Services (HHS) leaders “to restore regulatory clarity” as they consider candidates to replace outgoing Center for Biologics Evaluation and Research (CBER) chief Vinay Prasad.
Certainly, myriad companies—including Capricor Therapeutics, Replimune and uniQure—have been thrown for a loop this past year as guidance given by previous FDA leaders was reversed and their rare disease candidates were either rejected or punted to further trials. Regulatory experts acknowledge that these reversals are frustrating but say they are not necessarily inappropriate.
FDA leadership is not obligated to follow previous guidance, Holly Fernandez Lynch, associate professor of Medical Ethics and Health Policy at the University of Pennsylvania School of Medicine, told BioSpace last month. “Just because the FDA said something doesn’t mean that future FDAs should not be able to say, ‘That was wrong. We have an obligation to not approve a drug that doesn’t work.’”
As for why some companies find themselves derailed at the final checkpoint, and others like CERo report positive feedback, Sikorski noted that some of the apparently reversed guidance was provided under the previous administration. That was the case for Capricor and uniQure, as guidance on the design of their registrational studies was given by agency leadership while Joe Biden was president and Robert Califf ran the FDA.
Moreover, Sikorski noted that the agency’s approach could differ between the FDA’s actions in early- and late-stage clinical trials. “I have not observed a lack of flexibility in recent early-stage trials and have found the agency’s technical staff to be constructive overall,” he said. The most publicized reversals of guidance primarily occurred either in late-stage meetings with the FDA or during the product’s review.
Sikorski additionally noted that his experience has been limited to that technical staff, which includes reviewers, medical officers and safety officers. In contrast, Prasad reportedly played a role in the review of Capricor’s deramiocel for Duchenne muscular dystrophy cardiomyopathy, and both Prasad and FDA Commissioner Marty Makary made comments to the press about uniQure’s Huntington’s disease gene therapy.
Positive resolutions for Rezolute
CERo is not alone in its praise for the FDA under Makary. Another company with a positive experience in the past year is Rezolute, which in August 2025 received the agency’s blessing to pivot from a randomized, placebo-controlled Phase 3 trial to a truncated single-arm, open-label study comprising as few as 16 patients. Rezolute’s lead candidate, ersodetug, had shown success in tumor hyperinsulinism (HI) in several patients treated through an expanded access program and onlookers questioned the rationale for conducting a randomized study in this indication, CEO Nevan Charles Elam told BioSpace.
The FDA appears to be on board with innovative trial designs—at least in theory. Last year, the agency issued draft guidance encouraging cell and gene therapy developers to use alternative trial designs including externally controlled trials and single-arm studies to streamline the development of these products. The FDA at the time cited the “urgent need for safe and effective” medicines to address severe conditions affecting “small populations.”
Recent decisions regarding products tested through these innovative trials, however, have led to confusion.
But according to Harpreet Singh, chief medical officer at Precision for Medicine and a former oncology regulator at the FDA, final acceptability of an external control “really can’t be determined until the review process is complete, or throughout the course of the review process.”
Nuance aside, these stories do indicate a nod toward flexibility at the FDA. Last month, the agency again extended flexibility to Rezolute when it acknowledged that a missed primary endpoint in another trial of ersodetug—this time for congenital hyperinsulinism—could have been caused partly by behavioral factors. The FDA requested more data from the trial.
“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,” CEO Nevan Charles Elam told BioSpace last month.
Notably, the FDA offers a number of pathways through which increased communication is possible, including Breakthrough Therapy and Fast Track designations. Most recently, in June 2025, the agency introduced the Commissioner’s National Priority Voucher program, which aims to expedite the timeline for decisions for products that align with certain national priorities from 10–12 months down to 1–2 months. Being in receipt of one of these vouchers also offers enhanced communication with the FDA.
And just this month, the FDA proposed a new “clinical trial notification pathway” that would offer an alternative to the current Investigational New Drug application system, which the agency in its 2027 budget document called “burdensome.” While details remain sparse, the program “would create an accelerated path to initiate U.S.-based Phase 1 clinical programs,” according to the proposal.
Given the evolving regulations, Singh recommends early and continuous interaction with the agency.
“From the leadership, we are seeing more enthusiasm, or perhaps more openness, to engage directly with industry,” Singh observed. Her advice to sponsors: “[It’s] that old adage; engage early and often.”
