After the FDA’s first-ever public listening meeting on data-sharing in the cell and gene therapy space, new draft guidance aims to standardize the practice. But recent decisions call into question whether shared evidence and prior knowledge will accelerate development in rare diseases.
The FDA is moving to formalize greater data sharing across the cell and gene therapy sector through new draft guidance outlining a “plausible mechanism” review pathway for individualized genetic medicines targeting rare diseases. But recent regulatory decisions have raised questions about how consistently this regulatory flexibility will be applied in practice.
Specifically, the draft guidance encourages sponsors to leverage shared datasets, natural history evidence and prior program knowledge. But just in the last month, the FDA declined to grant accelerated approval to REGENXBIO’S Hunter syndrome gene therapy, citing insufficient evidence, and told uniQure that its Huntington’s therapy would not be eligible for review on the basis of a Phase 1/2 trial supported by natural history external controls. Rather, the agency will require a new trial controlled by a sham surgery group, raising logistical and ethical questions.
“While we were pleased to see the FDA’s guidance for the plausible mechanism framework, and will be submitting comments on the draft, this meaningful step cannot distract from recent FDA regulatory surprises in which the agency reversed course on previous commitments for rare disease programs that could help thousands of patients right now,” Robin Muthig, senior director at the Alliance for Regenerative Medicine (ARM), said in a prepared statement.
Regulators Look To Set the Stage
The FDA has made clear its intention to streamline the development and review of CGT. Last fall, the agency released three draft guidance documents aimed toward this goal, particularly for products targeting small or rare patient populations. The guidance encouraged flexible trial designs and greater use of real-world evidence, while maintaining appropriate quality controls and post-approval data collection.
The plausible mechanism pathway, previewed in The New England Journal of Medicine last November, further supports this mission of greater regulatory flexibility in part by encouraging sponsors to leverage existing data to advance ultra-rare genome editing and RNA therapies when traditional randomized trials are not feasible.
The FDA emphasized the importance of data-sharing for FDA reviewers to exercise the proposed regulatory flexibilities. “Sponsors should seek early feedback on their nonclinical development plans to discuss data leveraging opportunities specific to their program,” the agency wrote in the latest draft guidance. “Shared learning through appropriate data sharing is one opportunity to facilitate continued research.”
Adoption of the proposed pathway will also depend on industry’s ability to adapt. Last July, BioSpace uncovered the lack of data-sharing in the CGT space. Developers’ data hoarding is fueled by misconceptions like hindering a competitive edge, industry experts said.
“There is little to no data sharing occurring today,” Trenchant Bio CEO Jon Ellis previously told BioSpace.
Changing that will require clear data collection and sharing standards plus consistent regulatory implementation, noted David Barrett, CEO of the American Society of Gene and Cell Therapy (ASGCT). “You can’t share what you can’t capture.” And data that are shared must be comparable.
Despite increasing harmonization efforts, inconsistencies in submitted data persist. According to a February 2025 study, only four of 20 trials (20%) reported the same clinical evidence to both the FDA and EMA, and nearly 70% showed discrepancies in reported efficacy outcomes.
During the FDA’s first-ever public listening meeting on the issue last fall, industry leaders and patient advocates warned that fragmented data and repeated development failures are delaying access to potentially life-saving therapies while accelerating capital burn and program shutdowns.
Cody Powers, principal at ZS Associates, stressed that industry must embrace a multi-stakeholder, data-sharing and standardization-focused approach to ensure the long-term viability and growth of CGT. The current lack of data-sharing explains why payers “aren’t necessarily convinced” of the “one-and-done model” for CGT reimbursement, he said.
Several framed the issue as both an economic and moral imperative, arguing that continued siloed development ultimately harms patients.
“Sadly, over the last few months, several gene therapy programs have been paused or stopped altogether,” patient advocate Kelly Brazzo, cofounder and CEO of advocacy group The CureLGMD2i Foundation whose daughter has a rare form of muscular dystrophy, said at the September meeting. “Sharing of data—on data collection processes, on trial designs, on manufacturing, on any serious adverse events—reduces duplication and can ultimately save time and muscle for our patients.”
New Pathway Embeds Data-Sharing Into Development
Under the draft guidance, the FDA encourages sponsors to leverage shared natural history datasets, prior program knowledge and master protocol designs, such as basket, umbrella or platform trials, to pool evidence across programs and make smaller studies interpretable.
“Master protocols have the potential to streamline processes and allow for larger scale data collection and sharing to advance science,” the draft guidance notes. “The use of prior knowledge can be leveraged to support process validation” of the manufacturing process.
Still, implementation of the plausible mechanism pathway remains an open question. Stephen Majors, VP of global communications and investor relations at ARM, said it is unclear how broadly the pathway will apply or whether regulators will consistently accept natural history evidence in place of randomized trials, pointing to recent FDA requests for controlled studies.
“It’s not clear from the guidance whether” the proposed pathway “applies only to individualized therapies or potentially therapies that affect” larger patient populations, Majors told BioSpace.
And the uncertainty in the FDA’s messaging is playing out in real time. The FDA’s decision on the data for uniQure’s Huntington’s gene therapy AMT-130 surprised the company and some industry observers, particularly given earlier discussions suggesting the existing data could support accelerated approval of the therapy’s biologics license application.
“The biggest issue is that there now seems to be a huge disconnect or divergence in [FDA regulatory decision-making] approaches between the Plausible Mechanism Framework and recent regulatory decisions that affect thousands,” Majors added.
Similarly, Barrett described the proposed pathway as a “good sign from the FDA” and part of its broader push to make greater use of shared data in regulatory decision-making, but said industry is watching closely to see how the policy aligns with recent agency decisions. “We’re eager to understand more completely how this will benefit patients,” he said.
The FDA will accept public comments on the draft guidance until April 27.
