FDA Under Makary Eyes New Pathway for Rare Disease Drugs Amid Debate Over Feasibility and Safety
While the U.S. Food and Drug Administration (FDA) under new Health and Human Services (HHS) Secretary Robert F. Kennedy Jr. may seem a far cry from its 2024 counterpart, the agency appears to be maintaining a strong focus on expediting treatments for rare—and especially ultrarare—diseases.
Peter Marks, who led the FDA’s Center for Biologics Evaluation and Research (CBER) until his sudden resignation in March, was a vocal proponent of regulatory flexibility for rare disease therapies. In June 2024, Marks sparked controversy by granting full approval to Sarepta Therapeutics’ Duchenne muscular dystrophy gene therapy, Elevidys, overriding the FDA advisory committee’s recommendation.
Now, newly appointed FDA Commissioner Marty Makary seems poised to continue that legacy. In an April interview with former Fox News host Megyn Kelly, Makary introduced plans for a new regulatory pathway that would allow conditional approval of rare disease drugs based on a “scientifically plausible mechanism”—even without data from randomized, controlled clinical trials.
Makary said patients would be monitored via a surveillance system that would enable the FDA to assess efficacy and safety as data emerge. An HHS spokesperson confirmed the idea but did not offer further details.
A Potential Game-Changer for Biotech and Patients
If implemented, the proposal could be a major breakthrough for both rare disease patients and biotech firms. Small patient populations make conducting large-scale trials difficult and often financially unviable. Removing these barriers could revitalize investment in areas like cell and gene therapy.
“You can’t expect companies to do randomized, controlled trials; you’ll kill innovation,” Makary told Kelly.
Marks, too, had supported alternative trial designs, such as single-arm trials, for rare disease treatments. “The concept of trying to do a randomized trial [for ultrarare diseases] is very challenging at best and impossible at worst,” he told BioSpace in 2023.
Legal and Practical Hurdles
Despite its promise, the proposed pathway faces considerable challenges. Experts, including Arnold & Porter’s Daniel Kracov, argue that such a program would likely require new legislation.
“You can’t just do this by agency fiat,” Kracov said. He also warned that a mechanism-based approval standard may be too low to ensure safety and efficacy. “Approving drugs based on a plausible mechanism is about as low a standard as you could possibly get.”
Kracov noted that even the current accelerated approval pathway has created difficulties with payers, particularly when expensive therapies—sometimes costing over $1 million—lack robust clinical data.
Eva Temkin, also a partner at Arnold & Porter and a former FDA official, echoed this concern, likening the proposal to the Right to Try law enacted in 2018. However, she said the proposed pathway might offer even fewer protections for patients, since Right to Try requires the drug to have completed Phase I trials and be under clinical investigation.
Temkin added that without adequate safety data, it becomes very difficult to detect and analyze adverse events. “Separating signal from noise becomes very difficult when you don’t know much about the drug’s safety or efficacy.”
Advanced Surveillance and Industry Optimism
Some biotech leaders see potential in Makary’s vision. Rob Etherington, CEO of Clene, highlighted the value of modern postmarket surveillance using digital biomarkers, AI analytics, and electronic health records. With proper oversight and confirmatory trials, he said, these tools could help ensure patient safety and early insights into drug effectiveness.
He noted that for diseases like ALS—often categorized as rare despite broader impact—conditional approvals could allow therapies targeting underlying cellular dysfunctions to reach patients more quickly. “Commissioner Makary’s remarks suggest a willingness to move beyond rigid, disease-specific silos,” he said.
Yet, Temkin cautioned that assumptions about industry buy-in may be premature. Liability concerns and lack of reimbursement could discourage companies from participating.
Kracov added, “How do you take the drug off the market if it doesn’t prove out? Does the FDA have to litigate or convene an advisory committee?”
Divisions Within HHS?
While Makary appears enthusiastic about a conditional approval pathway, the newly appointed CBER head, Vinay Prasad, may be less supportive. Prasad has voiced concerns over the FDA’s accelerated approval process and the limited follow-through on confirmatory trials.
He and colleague Timothée Olivier criticized the approval of Elevidys last year, citing its high cost and uncertain clinical benefit.
In response to questions about differing viewpoints, an HHS spokesperson stated that both Makary and Prasad “are committed to ensuring patient safety through the Gold Standard of Science.”
Industry experts like Etherington see the differing perspectives as a potential strength rather than a source of conflict. “It’s more likely there will be a healthy and necessary tension,” he said.
A Long Road Ahead
Kracov noted that conditional approval is not a new idea. Former acting FDA Commissioner Janet Woodcock also championed a tailored pathway for ultrarare diseases. At a 2024 workshop, she emphasized the “mismatch” between current regulatory standards and the realities of ultrarare drug development.
However, she also warned against over-flexibility. “You can be flexible, flexible, flexible, and then pretty soon you’re going to break.”
Ultragenyx CEO Emil Kakkis suggested the existing accelerated approval pathway—using biomarkers or intermediate endpoints—remains a viable option in many cases. But he welcomed Makary’s willingness to explore alternatives for diseases with high unmet needs and impractical trial designs.
Still, challenges remain around legislation, payer acceptance, investor confidence, and legal liability. As Kracov put it, “There has to be a meaningful standard for approval in order for payers to be willing to pay—and for innovation to be sustainable.”
