As the FDA tries to clarify its intent for former FDA Commissioner Marty Makary’s plausible mechanism framework for bespoke therapies, experts emphasize the importance of expanding its scope to encompass rare diseases that affect more than just one or a few individuals.
Last month, the FDA held a workshop to discuss implementing its plausible mechanism pathway for individualized therapies, first introduced in November 2025 by Commissioner Marty Makary and Center for Biologics Evaluation and Research Director Vinay Prasad. Days before the May meeting, Prasad departed the FDA; a week later, Makary was also gone. Now, the status of all his initiatives is up in the air.
“I would imagine there would have to be some sort of delay while they are seeking more permanent leadership,” Stacey Frisk, then executive director of the Rare Disease Company Coalition (RDCC), told BioSpace about the program prior to leaving her post on May 15.
Saol Therapeutics is developing SL1009 for an ultrarare pediatric disease called pyruvate dehydrogenase complex deficiency (PDCD). When asked whether he is concerned that the plausible mechanism pathway might disappear along with Makary, CEO Dave Penake told BioSpace he is “constantly worried about making sure we deliver for these kids.”
Penake is pragmatic about the FDA upheaval.
“Organizations change, and so what we have control over is doing the best we can to support the science and kind of move the ball forward each day,” he continued. “That’s really the approach that we’re taking.”
Since Makary and Prasad first published on the idea in The New England Journal of Medicine, the plausible mechanism pathway has been both celebrated and questioned. While the intentions behind it appear to be genuine, experts say that guidance from the FDA could be clearer.
The workshop—held May 4 and cohosted by the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER)—was intended to further elucidate the framework.
A key point of clarification, according to Anna Kwilas, Gene Therapy CMC branch chief at the FDA, is that it is indeed a framework for achieving approval of applicable products through existing pathways, rather than a new approval pathway itself. Another important fact, Kwilas said, is that the framework is focused on genome editing and RNA-based therapies, including antisense oligonucleotides (ASOs)—though the concepts may also apply to other types of individualized therapies.
But despite these key takeaways—and the issuance of draft guidance in February around the framework—experts say there is still a lack of clarity regarding which products may qualify.
Maybe that’s okay, Penake said. From his perspective, the FDA should aim to define the pathway enough that people attempt to try to use it, “but you don’t want to over-define it so you exclude important technologies.”
“They have clarity of intent. I think the spirit of the program is great,” he said. “The devil’s in the details.”
Clarity needed on external controls
The plausible mechanism framework was modeled on the case of KJ Muldoon, a little boy with an ultrarare and potentially fatal genetic disorder called CSP1 deficiency. Last year, at nine months old, Baby KJ received the world’s first bespoke CRISPR-based gene therapy. So far, the treatment has been “very successful,” former acting CDER director Tracy Beth Høeg said during the workshop.
The framework is centered on seven pillars, according to slides presented at the workshop.
- A well-characterized disease abnormality
- A severely debilitating or life-threatening disease or condition occurring in a population too small to conduct a randomized trial
- Clinical evidence from such a population that demonstrates effectiveness and safety
- A well-characterized natural history in an untreated population
- Therapeutic targeting of the underlying abnormality, a proximal pathogenic pathway or a well-characterized downstream or compensatory mechanism with a clear mechanistic rationale
- Confirmation the target was successfully drugged, edited or both
- Demonstrated improvement in outcomes
“In practice, because these are so specific, the mechanisms of these therapies are actually a bit stronger than just plausible,” FDA Office of Neuroscience Director Teresa Buracchio said, according to Pink Sheet. “They’re actually very plausible, or maybe even probable.”
One question for the program’s implementation, however, is the use of external controls. Under Makary, the FDA issued guidance supporting the use of innovative trial designs, including externally controlled studies that use historical or real-world data (RWD), but several high profile rejections or rebuffs of rare disease applications supported by such controls have confused the industry.
“That doesn’t seem to be translating down well into the review staff,” Linda Marbán, CEO of Capricor Therapeutics, said during a BioSpace webinar earlier this year.
For Frisk, this is the crux of the plausible mechanism framework.
“The plausible mechanism framework really should be positioning about how evidence is generated and evaluated in settings where traditional evidence generation approaches aren’t necessarily feasible,” she said.
The FDA should clarify that the feasibility of generating traditional, controlled evidence “may be significantly limited in certain contexts,” Frisk continued, adding that the agency “should fully utilize its tools to expedite development of rare disease products, especially when it comes to use of alternatives to traditional controls, such as the use of single arm studies, external controls, natural history, real world data.”
It appears the FDA is taking further steps toward that end. On May 19, Motiur Rahman, a senior epidemiologist and policy advisor within CDER’s Office of Medical Policy, spoke at the Regulatory Education for Industry meeting, providing three case studies showing how drug sponsors can effectively use RWD to win approval of their products. The three case studies were Astellas’ Prograf for lung transplant and Bristol Myers Squibb’s Orencia to prevent acute graft-versus-host disease in 2021 and Novartis’ Zolgensma in 2019, Regulatory Focus reported.
Broader scope, better biopharma fit
Baby KJ stands as the shining example supporting the original conceit of the program. But the reality is that not many companies are developing N of 1 therapies. Rather, biotechs are often working on drugs for conditions afflicting very small patient populations. PDCD, for instance, affects fewer than 1,000 people in the U.S., Penake told BioSpace last December.
Frisk, and the RDCC, say the principles that underpin the plausible mechanism framework “should be applied more broadly across rare disease where scientifically appropriate, rather than very small patient populations or N of 1 individualized therapies.”
In fact, the FDA has continuously alluded to a broader application of the framework, including during the May workshop. But which therapies and indications will ultimately qualify remains unknown.
“It’s easy to start with the bite size of like a baby KJ, [a] single base pair change that can have a dramatic outcome,” Penake said. PDCD is caused by more than one base pair change or genetic problem, he explained.
“What we’re trying to understand is how do you broaden [the plausible mechanism pathway], and where’s the line that they draw, and how do you strengthen the mechanistic evidence and natural history evidence to support broadening the population that they would consider,” he said. “That’s not clear to us.”
However it happens, industry experts agree that the program won’t be useful if it is indeed only applied to N of 1 situations. The economics of such a model just aren’t there.
“Small patient populations mean lower peak revenue potential per indication, and that changes the whole risk-return calculus for traditional VCs,” Craig Martin, founder and CEO of the Orphan Therapeutics Accelerator (OTXL), told BioSpace in February.
Another barrier lies in the manufacturing of such treatments, according to Deanna Portero, OTXL’s vice president of Partnerships and Innovation, who viewed the workshop.
“The most important observation I made is that there continues to be a disconnect with the FDA regarding the resources available for the development of these individualized therapy programs, and the feasibility of the proposed standards given limited resources, especially on the genome editing applications where the FDA’s proposed approach in the guidance is to begin clinical trials with a level of CMC maturity that is at or near BLA standards,” Portero told BioSpace in an email.
She said that while the FDA indicated that the framework might be commercially developed to justify the upfront investments, industry leaders at the workshop continued to emphasize that the commercial pre-viability of these programs is not there, and that “academics are not able to meet the standards outlined in the guidance.”
Portero emphasized the importance of clarifying this point. “We want FDA to feel the pressure of this obvious and critical disconnect.”
