FDA Leaders Propose New Regulatory Pathway for Bespoke Therapies

Leaders from the Food and Drug Administration proposed a new “plausible mechanism pathway” to support the development of bespoke therapies when traditional clinical trials are not feasible. Vinay Prasad, MD, MPH, FDA’s chief medical and scientific officer and director of the Center for Biologics Evaluation and Research; and Martin A. Makary, MD, MPH, FDA commissioner, described the pathway in a recent New England Journal of Medicine editorial and outlined its potential to accelerate individualized treatments for rare and severe conditions.

To illustrate how the pathway could work, Prasad and Makary highlighted a case in which a newborn with carbamoyl-phosphate synthetase 1 deficiency received a customized base-editing therapy after FDA processed a single-patient, expanded-access IND in approximately one week. Prasad and Makary noted that the newborn’s case reflects several core elements of the plausible mechanism pathway.

First, eligibility would depend on the identification of a specific molecular or cellular abnormality, rather than a broad set of consensus diagnostic criteria. Second, the pathway would be open only to products that act directly on the underlying or proximate biological alteration. Third, developers would need to rely on a well-characterized natural history of the disease. Fourth, FDA would look for confirmation that the target was successfully drugged or edited, when clinically feasible. Finally, FDA would look for consistent clinical improvement that cannot be explained by regression to the mean, with patients in some cases serving as their own control.

Prasad and Makary said the case study underscores the potential of individualized therapies designed for a specific mutation to generate clinical safety and efficacy data that could inform development of products targeting additional genetic alterations.

Once a manufacturer has demonstrated success with several consecutive bespoke therapies, FDA could move toward marketing authorization and allow manufacturers to leverage platform data to support similar products for additional mutations or conditions. Postmarketing commitments would focus on real-world evidence to confirm efficacy, monitor for off-target effects and assess long-term safety, with requirements tailored to feasibility and disease context.

While FDA would prioritize bespoke therapies for rare and pediatric diseases, Prasad and Makary noted that the pathway could also extend to common conditions with numerous causative mutations or considerable unmet need. They added that the same principles may also apply beyond cell and gene therapy to other drug classes over time.