FDA proposes plausible mechanism framework to support approval of individualized therapies for ultra-rare diseases

The US Food and Drug Administration (FDA) has issued draft guidance describing how sponsors may generate substantial evidence of effectiveness and evidence of safety for individualized therapies that target specific genetic conditions with a known biological cause, particularly where randomized controlled trials (RCTs) are not feasible because only a very small number of patients can be studied.

The draft, developed by the Office of Therapeutic Products within the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER), sets out FDA’s current thinking on how existing approval pathways may be applied to highly targeted therapies for ultra-rare, severely debilitating, or life-threatening diseases. While conventional development programs may not be feasible, the agency states that it may still be possible to generate evidence sufficient to support approval.

The agency states that:

“The purpose of this guidance is to describe considerations for generating substantial evidence of effectiveness and evidence of safety for individualized therapies based on a plausible mechanism framework.”

This framework is described as “a set of recommendations to help developers of individualized therapies generate sufficient clinical safety and efficacy data” while also demonstrating that the product can be manufactured to regulatory quality standards.

Individualized therapies are described as those that “target a specific pathophysiologic abnormality serving as the root cause of a disease… in a small number of patients where a randomized controlled trial typically is not feasible.” Although the draft focuses on genome editing (GE) and RNA-based therapies such as antisense oligonucleotides (ASOs), it notes that “the general concepts may apply to other types of individualized therapies,” particularly when clinical evidence will be limited to a small patient population.

Application of the framework involves identifying “a specific genetic, cellular, or molecular abnormality” clearly linked to disease, developing a therapy that targets the underlying or proximate pathogenic pathway, relying on “a well-characterized natural history of the disease in an untreated population,” confirming that the intended target was successfully drugged or edited, and demonstrating improvement in clinical outcomes or disease course.

The FDA anticipates that the first-in-human study may often serve as the primary evidence base, noting that:

 “FDA anticipates that the first in human clinical investigation that will open an IND will also be the primary source of evidence to support approval; therefore, protocols should be designed to be adequate and well controlled.”

Sponsors are expected to justify why randomization is not feasible.

Although trials will involve small numbers of patients, the agency makes clear that evidentiary standards remain high. As it states:

“FDA recognizes that an adequate and well controlled clinical investigation in this context will include a small sample size, therefore, investigation results should be robust to exclude chance findings that may incorrectly suggest effectiveness.”

The agency further states that substantial evidence may be established through “a single adequate and well controlled clinical investigation with confirmatory evidence,” including mechanistic or pharmacodynamic data, confirmation of target engagement, and exposure response relationships.

To strengthen inference, the FDA recommends systematic baseline data collection, noting that “it is recommended that data be collected in an observational period prior to the initiation of the treatment” to establish a lead-in baseline. Where appropriate, “natural history data may serve as an external control” to help distinguish treatment effects from disease variability.

The draft also signals openness to master protocols evaluating therapies that target different genetic variants within the same disease. For certain GE products, a “highly supported plausible mechanism of action may then be used to support the addition of other such GE product variants” beyond those initially studied.

Given limited pre-approval exposure, post-marketing oversight will play a central role. The agency notes that “the amount of safety data available at the time of approval for the products described in this guidance will be limited,” and may require additional data collection after authorization. At the same time, it underscores the importance of proactive development planning, stating that:

“Early planning is critical to identify the potential sources of efficacy and safety data for the product to support a future marketing application.”

Why this matters for RWE

This draft guidance sits within what appears to be a broader structural shift in the FDA’s evidentiary framework. The agency has recently stated that one adequate and well-controlled clinical investigation, supported by confirmatory evidence, will generally be sufficient for marketing authorization, formally moving away from the long-standing expectation of two pivotal trials. In late 2025, it also confirmed that it will consider real-world evidence (RWE) derived from de-identified real-world data (RWD) sources, including patient registries, insurance claims data, and electronic health records. Viewed together, these developments signal a more integrated model of evidence generation in which regulatory-grade RWD are positioned not as ancillary, but as central to confirmatory evidence, external control development, and strengthened post-approval oversight, particularly in contexts where conventional trial designs are not feasible.