A rare disease advocacy group is petitioning FDA to fundamentally rethink how it evaluates therapies for small patient populations, submitting a formal petition that urges a more context-driven approach to evidence generation that acknowledges randomized controlled trials may not always be a suitable approach, even as agency officials say the push toward patient-centered endpoints is introducing new challenges around data availability and comparability.
More than 160 rare disease advocacy groups have signed onto the petition, along with national organizations including the National Organization for Rare Disorders and Friends of Cancer Research. The breadth of support reflects growing concern among stakeholders that existing evidentiary standards — particularly reliance on traditional randomized trials — do not adequately capture the complexities of rare disease research.
The petition from the Haystack Project seeks to amend the Code of Federal Regulations to specify that whether a trial is “adequate and well-controlled,” the standard FDA uses to determine whether evidence meets standards for approval, much be determined based on the context of the specific disease, and must be informed by patients and disease-specific experts.
The proposed framework would align study design, endpoints and analytical methods with disease characteristics and treatment context, while also formalizing the role of disease-specific expertise in regulatory decision-making. Advocates argue such expertise is critical in rare diseases, where patient populations are often small and heterogeneous, making traditional trial designs difficult to implement or interpret.
“This petition is the culmination of years of engagement with patients, clinicians, researchers and policymakers,” Kara Berasi, CEO of Haystack Project, said in the press release Wednesday. Berasi, who is also the parent of a child with a rare disease, said the proposal is intended to ensure that treatments for rare conditions are developed with the same level of scientific rigor as those for more common diseases, while accounting for real-world constraints.
FDA has often demonstrated a willingness to exercise flexibility in rare disease drug development, including through programs like the Rare Disease Endpoint Advancement (RDEA) pilot and the plausible mechanism guidance. But FDA Commissioner Marty Makary is also facing bipartisan scrutiny on Capitol Hill over his handling of gene therapies.
Saira Sultan, president and CEO of the rare disease consulting firm Connect 4 Strategies and consultant to Haystack, told Inside Health Policy the petition aims to offer the agency a clearer framework to ensure its decisions are “consistent, transparent, and scientifically grounded,” rather than fragmented across multiple initiatives.
Several high-profile rejections of rare disease therapies have called for deeper scrutiny of FDA-approved products and tighter evidentiary standards. Right-to-try proponents, including right-wing activist Laura Loomer, argue the agency should move more quickly to make investigational therapies available to patients with few alternatives.
Makary is in a difficult position under the Trump administration, navigating pressure from Kennedy’s MAHA base and President Donald Trump’s MAGA supporters.
Sultan said stakeholders do not view FDA’s recent actions as intentionally divisive, but rather as incremental steps toward a more comprehensive approach. “We don’t think FDA wants to continue doing initiatives that fragment the rare community,” she said.
However, unpredictability from FDA has had a clear negative impact on development of rare disease therapeutics. Sultan pointed to a recent multi-stakeholder letter from Rare Disease Advocacy, Biotechnology, and Investor Coalition to HHS, FDA and CMS leaders citing investor concerns, noting that 84% of biotech investors had “decreased, paused, or exited rare disease investments due to regulatory uncertainty.” That pullback represents “billions” in lost capital, she said, with direct implications for patients awaiting new treatments.
FDA officials say the growing push to incorporate patient-centered endpoints into rare disease trials is creating new methodological challenges, particularly around data availability and comparability. “You have to focus on the data source,” Amy Comstock Rick, associate director for rare disease strategy at FDA said at a Friends of Cancer Research event Tuesday (April 7), noting that in rare diseases it is critical to achieve a close match between external data and trial participants.
Comstock Rick said there is increasing “interest and pressure” to move toward endpoints that better reflect patient preferences, rather than relying solely on traditional clinical measures. However, she cautioned that many of these newer outcomes may not have been consistently captured in historical datasets, complicating efforts to use them in regulatory decision-making.
“There is a tension between being innovative in the moment and having the historical presence of those outcomes in the data,” Comstock Rick said, highlighting the challenges FDA faces in balancing methodological rigor with evolving expectations around patient-focused drug development.
The petition builds on several prior initiatives led by the Haystack Project, including work tied to the HEART Act in 2022, a scientific workshop convened last year that brought together patient groups and researchers, and a subsequent white paper outlining “fit-for-purpose” trial designs for rare disease therapies.
Supporters say the proposal also aligns with recent FDA efforts that have incorporated more contextual considerations into rare disease guidance, particularly in cases where the agency has acknowledged that randomized controlled trials may not be appropriate.
Kari Rosbeck, president and CEO of the TSC Alliance, said the framework addresses a “systemic challenge” across the rare disease community and could help accelerate development of new therapies.
Similarly, Jeff Allen, president and CEO of Friends of Cancer Research, said the proposed regulatory changes would clarify how FDA evaluates scientific data supporting new drug approvals, particularly as advances in science produce therapies that do not fit a “one-size-fits-all” development model.
If adopted, proponents say the framework would provide a more transparent and durable pathway for evaluating rare disease treatments. Advocates say the changes could reduce regulatory uncertainty for developers while preserving FDA’s standards for safety and effectiveness.
Concerns from rare disease stakeholders about the U.S. losing its edge in drug development are “real — and increasingly visible,” according to Sultan, who said the country is no longer the “unquestioned center” of innovation as investment, clinical trials and even first-mover regulatory activity shift abroad. What was once a near-monopoly has now become a “shrinking plurality,” Sultan added, underscoring growing anxiety that global competitors are gaining ground in rare disease research and approvals.
Sultan told IHP that the recent coalition letter highlighting reduced regulatory flexibility captures only part of the problem, arguing that the deeper issue is the lack of a “coherent, disease-informed evidentiary framework.” Without such a foundation, she warned, flexibility becomes “inconsistent, unpredictable, and ultimately unsustainable,” contributing to what stakeholders increasingly describe as regulatory “whiplash” in how FDA evaluates therapies for small or heterogeneous patient populations.
That inconsistency is particularly evident in how the agency deploys tools such as external controls, real-world evidence and surrogate endpoints, Sultan said. These approaches are often treated as “scientific compromises or exceptions” rather than fit-for-purpose methods, largely because they are applied without a unifying framework that prioritizes the right evidentiary tool based on disease context and treatment characteristics.
At the same time, Sultan noted FDA faces its own constraints when attempting to formalize alternative pathways through guidance. Efforts to outline clearer non-randomized trial approaches often come with pressure to narrowly define eligibility, ensuring such pathways are not used where randomized controlled trials would still be appropriate. She emphasized that a context-based approach, as reflected in recent proposals, is consistent with the kind of framework stakeholders are calling for.
Berasi told IHP the group’s petition seeks to address these structural shortcomings by pushing FDA to rethink how it defines and evaluates evidence in rare diseases. The agency should start by asking “what data to collect, how to collect it, and how to analyze it given the very rare circumstance and context in front of them,” rather than relying on standards developed for more common conditions, she said.
Applying ill-fitting frameworks risks distorting trial outcomes, Berasi added, warning that forcing methodologies designed for other diseases can produce “false positives and negatives,” leaving developers uncertain whether a failed study reflects the drug’s efficacy or flaws in trial design.
“We need endpoints, studies and statistical analysis for interpretable evidence in the context of the disease,” Berasi said. “We can do this without lowering evidentiary standards — by aligning study design with scientific reality. I don’t want my child or anyone else’s to have treatments approved with a lower standard.”
“This proposal does not weaken scientific standards — it strengthens them,” Andrea Gropman, pediatric neurologist at St. Jude Children’s Research Hospital, who argued that grounding clinical investigations in disease context would produce evidence that is more “interpretable and meaningful to clinicians, patients, and FDA.”
Gropman told IHP tailoring evidentiary approaches to the nuances of individual rare diseases would improve the reliability of trial outcomes and better support regulatory decision-making, particularly in small or heterogeneous patient populations where traditional models often fall short.
FDA is also asking Congress to permanently reauthorize the pediatric rare disease priority review voucher (PRV) program in its 2027 budget proposal, hoping to avoid a reauthorization cycle every four years that led to the program’s expiration in 2024 before it was later renewed.