FDA Proposes New Evidence Playbook For Individualized Therapies

On February 23, 2026, the US Food and Drug Administration (FDA) released draft guidance outlining a new "plausible mechanism framework" that offers sponsors of certain individualized rare disease treatments an alternative way to demonstrate safety and effectiveness when the unique nature of the individualized therapies (such as genome editing and RNA-based treatments) make traditional randomized controlled trials (RCTs) potentially infeasible.

The draft guidance emphasizes that the FDA is not creating a new approval pathway and that sponsors must still satisfy existing statutory standards for approval or licensure. However, the FDA indicates that in some cases substantial evidence of effectiveness could potentially be established through a single adequate and well-controlled clinical investigation with confirmatory evidence. Tracy Beth Høeg, acting director of the FDA's Center for Drug Evaluation and Research, stated that the FDA believes this guidance will "inspire [the] industry to place increased focus on individualized therapies" and "driv[e] innovation" for treatments of ultra-rare diseases.

Background

In recent months, the FDA has focused significant attention on initiatives designed to reduce regulatory barriers and facilitate the development of novel therapies for rare diseases. For example, the FDA took steps in January 2026 to offer cell and gene therapy manufacturers certain regulatory flexibilities related to chemistry, manufacturing, and control (CMC) requirements. The agency also recently issued guidance addressing the use of alternative statistical methods in the context of small clinical studies.

One common point of friction in the development of rare disease therapies is that, as suggested by their name, affected patient populations tend to be extremely limited, which often makes it difficult for sponsors to use the gold standard method of RCTs and other traditional study designs to evaluate effectiveness. These difficulties are exacerbated in the case of individualized treatments for rare, severely debilitating or life-threatening diseases (SDLTs), where the disease may progress rapidly, patients may be one of only a few individuals with their specific condition, and the therapy may rely on a patient specific mechanism of action. In many cases, the highly individualized nature of these treatments may also mean that the first-in-human study must simultaneously serve as the pivotal trial underlying an eventual application for marketing approval. These challenges have increased pressures on regulators to identify development pathways for therapies targeting extremely small patient populations.

In part to address these challenges, the FDA recently published guidance titled "Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause." The "plausible mechanism framework" outlined in the guidance is designed to allow sponsors to demonstrate the safety and effectiveness of individualized treatments for SDLTs where RCTs prove unworkable. Although the guidance contains specific recommendations related to genome editing and RNA-based therapies for SDLTs, the FDA has suggested that the concepts described in the guidance may be generally applicable to other categories of individualized therapies.

In Depth

The plausible mechanism framework does not establish a new regulatory approval pathway for sponsors of individualized therapies. Instead, the framework describes how sponsors may be able to assemble evidence from focused clinical trials, mechanistic analysis, and natural history to support the safety and effectiveness of individualized therapies where traditional trial designs are infeasible.

The FDA identified the following actions as core tenets that should be demonstrated to support development under the plausible mechanism framework:

• Identifying a specific genetic, cellular, or molecular abnormality with a clear connection between specific alteration and disease indication
• Developing a therapy that targets the underlying or proximate pathogenic biological alterations
• Relying on a well-characterized natural history of the disease in an untreated population
• Confirming that the target was successfully drugged or edited or both
• Demonstrating improvement in clinical outcomes or course

In illustrating how the framework might be applied, the FDA provided specific recommendations for the structure of both nonclinical and clinical programs, as well as CMC considerations, in the context of genome editing and RNA-based therapies.

In the case of nonclinical programs, the FDA emphasized that studies should be aimed at generating enough evidence to support initiation of a first-in-human study by, for example, showing that the route of administration works as intended and gathering safety-related data to identify potential risks to participating patients. The FDA encouraged early engagement with the agency to ensure that nonclinical programs are effective, efficient, and properly structured and suggested that sponsors leverage new approach methodologies, such as organs-on-chips and artificial intelligence predictive models, where applicable. The FDA also encouraged sponsors relying on the plausible mechanism framework to initiate observational protocols while conducting nonclinical activities to gather data that can be used to support an eventual pivotal trial.

For clinical programs, the FDA noted that sponsors relying on the plausible mechanism framework would have to provide sufficient justification for the proposed trial design, including a discussion of why an RCT would not be feasible. In cases where the plausible mechanism framework is determined to be appropriate, sponsors may incorporate nontraditional trial design elements, such as relying on natural history data as an external control or altering follow-up periods to reflect the episodic nature of a disease. The FDA made clear, however, that even when utilizing the plausible mechanism framework to design a clinical study, other standard regulatory requirements are still applicable. For example, if the study is both the first-in-human and pivotal study, it must be designed to be adequate and well controlled. Moreover, the sponsor is still subject to regulatory requirements related to the submission of an investigational new drug application and must properly obtain participants' informed consent.

With regard to CMC considerations, the FDA emphasized that manufacturing for individualized therapies must still comply with applicable current good manufacturing practice requirements, and that CMC development should evolve in parallel with what may be a condensed research and submission timeline. To maximize efficient CMC development, sponsors are encouraged to leverage prior manufacturing and analytical knowledge to define and control critical quality attributes, validate processes and assays appropriately, and minimize manufacturing changes that could otherwise trigger extensive comparability assessments.

The FDA indicated that, as with other rare diseases, its ultimate assessment of whether substantial evidence exists to establish an individualized therapy's effectiveness will rely on factors such as the clinical context of use, the existence of unmet patient need, and potential recruitment challenges for corresponding clinical trials. Given the potential limitations of data gathered from pivotal trials relying on the plausible mechanism framework and small patient populations, the FDA suggested that it will likely require or request that sponsors conduct additional studies after approval.

Next steps

Sponsors developing therapies for extremely small patient populations may wish to consider how the principles described in the draft guidance could inform early development planning and engagement with the FDA.

The McDermott difference

McDermott Will & Schulte will continue to monitor the FDA's implementation of the plausible mechanism framework and its broader efforts to reduce regulatory barriers for rare disease therapies. If you have questions about how these developments may affect your business, please contact a member of our Food, Drug & Medical Device Group.

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