Summary:
- Cell & gene developers may unlock a new FDA pathway to approval without the need for RCTs, under strict conditions
- Initial focus is on bespoke therapies for rare conditions, but principles may be applied to other situations in the future
- Condition seemingly must be well-understood, from both a diagnostic and treatment perspective
- FDA leadership views current regulations as “onerous” and “stifles innovation”
I’ve reported many times that this year, the FDA has been sending several smoke signals that it may change how it regulates regenerative medicine. It’s speculation on my part, but to name a few:
- Before taking office, RFK tweeted he’ll end the “aggressive suppression” of stem cell therapies.
- Dr. Peter Marks (former CBER head) mentioned they were reevaluating the HCT/P framework (the regulatory framework for stem cells and similar biologics) just before being ousted.
- Dr. Marty Makary (current FDA commissioner) went on Megyn Kelly’s podcast in April 2025 and mentioned they were looking at a pathway based on “plausible mechanisms.”
Regarding the latter, Dr. Makary told Megyn, “We’re going to be rolling out a new pathway for drugs,” adding, “If there’s a rare condition or a condition that’s incurable that affects a small number of people, we may be approving drugs based on a plausible mechanism, on sort of a conditional basis.”
We finally received details on how that might work, in a new article titled “FDA’s New Plausible Mechanism Pathway” published in the New England Journal of Medicine, authored by Dr. Marty Makary and Dr. Vinay Prasad (new CBER head).
It seems rooted in the idea that if biological plausibility is strong enough, you may not need a traditional RCT to get therapies to market, particularly for rare, well-defined conditions.
The article mostly focused on bespoke therapies for rare, fatal genetic diseases where conventional trials may not be feasible, but also notes that these principles may be applied in other situations.
The Proposal:
As a proof-of-concept, the article uses the case of “Baby K.J.,” a neonate with an ultra-rare genetic disorder called carbamoyl-phosphate synthetase 1 (CPS1) deficiency. Early infancy mortality for this is estimated to be about 50%.
For K.J., the clinical team rapidly obtained a single-patient expanded-access IND, designed an mRNA-based editing therapy targeted to the child’s mutation, and reported improved protein tolerance and reduced need for nitrogen-scavenger drugs, along with clinical improvement relative to the typical course of CPS1 deficiency.
Single-patient expanded-access INDs aren’t new; what’s novel is that FDA leaders outlined this N=1 case as a template where very small patient series could be enough to support approval, if those cases meet five key pillars:
- Diagnosis must be very specific – It must be based on an understood cellular/molecular abnormality, rather than a “broad consensus diagnostic criteria”. Diagnoses based on a “constellation of clinical findings or dozens of unclear genomewide associations” would not qualify, to “safeguard against misapplication”.
- Must target that specific abnormality – The example used in the article is corticosteroids, which would fail to qualify, given the “distance of the therapy from the inciting pathophysiologic aberration.”. In short, must treat the root cause.
- The natural progression of the condition must be well understood – Regulators need a clear picture of how the disease typically behaves in untreated patients, so improvement can be meaningfully interpreted. CPS1 deficiency has a documented natural history of early hyperammonemia and neurological decline, so when K.J. improved, clinicians could compare that outcome against what would normally be expected and gain confidence that the intervention played a role.
- Evidence that the intended target was actually engaged – There should be confirmation that the therapy successfully drugged, edited, or otherwise acted on the specific biological target. In Baby K.J.’s case, while mouse models demonstrated successful liver editing, confirming this in the child would have required an invasive biopsy. The FDA notes that target confirmation is supportive when feasible, but recognizes it may not always be possible depending on the tissue involved and will embrace non-animal models. In select situations, evidence from a subset of patients, or even a first-in-class case, may be acceptable.
- Demonstrated clinical improvement – The therapy must produce a meaningful change in the patient’s clinical course. It appears that for progressive disorders, sustained improvement is viewed favorably, while in fluctuating conditions, longer periods of remission matter more. The FDA may compare the patient to their own prior history, but the data must be strong enough to rule out normal variation or regression to the mean.
For cell & gene therapy developers, a new, simpler path to market approval could be a big upside. If a manufacturer is successful with multiple bespoke therapies, the FDA will “move toward granting market authorization” and leverage this data to support approval of similar products in additional conditions.
They also mention that the priority will be rare, fatal conditions that affect children, and that a pathway will be available for common diseases without alternative treatments.
It continues by saying, “An appropriately designed study with a small sample size can support licensure of a product for which pharmacologic effect is aligned with biologic plausibility and congruent with observed clinical outcomes. That philosophy, in essence, embodies the plausible mechanism pathway.”
The last two quotes that stuck out were, “We see no reason that such principles will not also extend to other drugs over time.” and the big one: “the FDA has heard from patients, parents, researchers, clinicians, and developers that current regulations are onerous and unnecessarily demanding, provide unclear patient protection, and stifle innovation. We share this view.“
The fear, in my mind and many others’, is that the bar of science may be lowered, putting patients at risk. But, importantly, Dr. Makary and Dr. Prasad seem to acknowledge the trade-offs here. They note that lower pre-approval evidence means greater pressure on post-marketing surveillance.
Tailwinds for Other Therapies?
An adjacent situation looms over the FDA: NurOwn. If you’ve never heard of that saga, here’s the short version:
ALS (Lou Gehrig’s disease) has a 100% fatality rate, and the road to that end is horrible, with no curative and only modestly effective treatments. An Israeli biotech company, BrainStorm Cell Therapeutics, developed NurOwn, which is an autologous bone-marrow-derived MSC therapy with upregulated neurotrophic factors, administered via a series of intrathecal injections to treat ALS. Phases 1 and 2 looked very promising; trial patients on Facebook/Reddit posted videos finally using their limbs again, the stock exploded, and the ALS community had its heart set… until the recent Phase 3 flop, which missed its primary endpoints.
The disappointment split the ALS community. One side is extremely upset with the FDA’s strictness; a Facebook patient group titled “No More Excuses! ALS Watch Dog Group” has over 15K members, and the topic is often anger about the NurOwn situation. I spoke with the group’s founder, Mike, who seems to share this sentiment. I can’t fathom exactly what they’re going through, but I feel their side.
Mike and I talked for about an hour, and he mentioned many sad stories. One example was an ALS patient who was well-liked in the group, who passed away because his home caught on fire and he wasn’t able to get out. That’s a harrowing image.
Other ALS patients and advocates respect the FDA’s decision, including the ALS Association (a major beneficiary of the Ice Bucket Challenge).
However, the pro NurOwn side made a new move this summer. In June, BrainStorm released data from its expanded access program, stating that 90% of ALS patients survived beyond five years, well beyond the often-cited average five-year survival rate of 10%. Just a few weeks later, ALS advocates and patients submitted what’s known as a citizens’ petition to the FDA, asking the agency to approve it given the lack of effective treatments and some evidence of efficacy.
A citizens’ petition is actually a formal regulatory pathway, in which the FDA is typically supposed to respond within 180 days. The petition was submitted on July 3, 2025, so we may hear by the end of the year.
It’s important to understand that the response doesn’t require a yay or nay; it’s just a response, which could be “we’re looking into it”. However, I can’t imagine more tailwind than the above smoke signals and paper being published just weeks before.
Stay tuned, we’ll keep you updated.
Prasad V, Makary MA. FDA’s New Plausible Mechanism Pathway. N Engl J Med. 2025;393:2235-43. doi:10.1056/NEJMsb2512695.
