FDA Leadership Unveils New Plausible Mechanism Pathway

Rare Daily Staff

U.S. Food and Drug Administration officials outlined a new pathway for bespoke, personalized therapies.

The creation of the pathway comes in response to calls from patients, advocates, clinicians, and drug developers for such an approach in the wake of the case of Baby K.J., an infant with a deadly genetic metabolic condition who was successfully treated with a bespoke gene-editing therapy.

U.S. Food and Drug Administration Commissioner Martin Makary and Center for Biologics Evaluation and Research Director Vinay Prasad, writing in the New England Journal of Medicine, point to the case of Baby K.J. to define what they call a “plausible mechanism” pathway.

They said the agency will reserve the use of this pathway for diseases for which the biological cause is known, rather than for conditions defined by a constellation of clinical findings or unclear genome-wide associations. The medical product must target the biological alteration, and the care team must rely on a well-characterized natural history of the disease in the untreated population.

In addition, the FDA must have confirmation that the target was successfully drugged or edited. Finally, the agency will seek evidence of improvement in clinical outcomes. In conditions marked by progressive deterioration, consistent improvements will be considered.

“The case of Baby K.J. highlights the potential of individualized therapies designed specifically for an individual person’s mutation to generate critical clinical safety and efficacy data and thereby inform development of a product that could be modified to address multiple genetic mutations,” they wrote. “Once a manufacturer has demonstrated success with several consecutive patients with different bespoke therapies, the FDA will move toward granting marketing authorization for the product. Manufacturers will then be able to leverage platform data from such personalized products to gain marketing approval for similar products in additional conditions.”

Sponsors will be required to collect real-world evidence after approval to confirm efficacy, verify that no off-target edits occurred, study the effect of early treatment on childhood growth and developmental milestones, and detect unexpected safety signals.

Photo: U.S. Food and Drug Administration Commissioner Martin Makary