FDA Takes Aim at Personalized Medicine in New Draft Guidance

Personalized medicine has long been the objective of the FDA and its regulated industries, and a new draft guidance from the FDA’s drug and biologics centers would seem to suggest that the era of truly personalized medicine is on the horizon for both pediatric patients and patients of all ages with rare diseases.

The FDA’s press release announcing the February 2026 draft guidance for the plausible mechanisms framework for individualized therapies states that the agency is committed to advancing therapies for rare diseases. FDA commissioner Marty Makary said the agency’s priorities include removing barriers and exercising regulatory flexibility to encourage scientific advances that result in treatments and cures for patients suffering from rare conditions.

The plausible mechanisms draft is one of several guidances published recently by the FDA that deal with novel therapies. In September 2025, the agency’s Center for Biologics Evaluation and Research (CBER) released a draft guidance for innovative clinical trial designs for cell and gene therapy products for small patient populations.

The innovative clinical trials guidance would allow sponsors to use study participants as their own controls, an approach the FDA does not typically allow. This would require that the sponsor collect data from the patient during a lead-in period, but this feature would likely be available only for conditions that are persistently progressive as opposed to diseases in which disease progression waxes and wanes.

Also in September 2025, CBER posted a draft guidance addressing expedited programs for regenerative medicine advanced therapies (RMATs). The scope of this draft guidance is limited to products for serious and life-threatening conditions and provides a fast-track designation. The fast-track designation would be contingent on demonstrations that the therapy may prove effective on the basis of in vitro or animal models, although RMAT products might qualify as breakthrough therapy products as well.

While the clinical trials and expedited review draft guidances were published solely by CBER, the Center for Drug Evaluation and Research (CDER) co-authored the plausible mechanisms draft with CBER. The plausible mechanism framework consists of several components, including the identification of a specific genetic, cellular or molecular abnormality when a clear connection between any of these features and a disease state is available. The sponsor can base the application on a well characterized natural disease history in untreated populations, and then demonstrate that the patient experienced an improvement in clinical outcomes or disease course.

The fact that any clinical trials enrolled under this guidance will be small in terms of enrollment requires that the trial demonstrate a robust therapeutic effect. This would alleviate any concerns that the findings errantly suggest effectiveness, but the guidance also indicates that the agency may require confirmatory evidence. This could include mechanistic or pharmacodynamic data along with confirmation of the therapy’s engagement with the target genetic, cellular or molecular abnormality.

In some instances, the FDA will require that a confirmatory trial be underway already prior to the agency’s approval of the therapy, as is characteristic of products reviewed under the accelerated drug approval program. The agency advised also that it intends to closely monitor adverse event reports for drugs and biologics that achieve market access via the plausible mechanism program.