In February 2026, FDA issued the following draft guidance, “Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause” This is a very interesting guidance as it provides a roadmap for the development of individualized therapies in ultra-rare diseases where, due to prevalence alone, it would not be feasible to conduct a controlled clinical trial. Following issuance of this guideline, a workshop sponsored by CERSI and FDA entitled, “Advancing Novel Surrogate Endpoints for Rare Disease Development,” was held on May 18, 2026.
There are many very important take home messages from this guidance as well as from the presentations at the workshop. I think one of the main practices that those of us in drug development need to keep in mind is that our development programs must follow good science. When there are new developments in the underlying science, we should be prepared to pivot, adjust, and integrate them into our programs. A second consideration relates to “how good are the data.” The smaller the number of patients included in a program, the more important the magnitude of the effect will be. An effect size that is convincing in a large study may not be substantial enough when one has a small sample size. In addition, all the endpoints need to point in the same direction, providing further corroboration that the effect is real. The smaller the sample size, the more critical this becomes. Finally, the mechanism by which the disease occurs and how the therapy works must be well characterized, including the natural course of the disease. This last piece becomes a challenge as natural history data of a rare disease may be scant.
For a therapy to be considered an individualized therapy, the therapy must target a specific abnormality that is the root cause of the disease, the disease must be severely debilitating or life-threatening, and the prevalence of the condition must be so small that a typical randomized controlled trail is not feasible.
Demonstrating that the patient population is too small for a randomized controlled study is the Sponsor’s responsibility and is the differentiating feature from the guidance outlined in the FDA final Clinical Pharmacology guidance, “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease” issued in October 2018.
What is required to develop individualized therapies based in a plausible mechanism framework?
- A specific genetic, cellular, or molecular abnormality for which there is a clear connection between this alteration and the disease
- A therapy that targets this or a proximate pathologic alteration(s). While this mechanism fits with gene editing and RNA-based therapies, it is not limited to these therapies.
- A well-characterized natural history of the disease in the untreated population
- Demonstration that the therapy had a direct effect on the target
- Demonstration of improvements in the clinical course of the disease in treated patients
The first two items listed above are what we routinely do in drug development, and, with a well-defined target, our scientists are happy to work on agents that will be directed at that target. The third bullet point is very important and, in some cases, one for which Sponsors may underestimate the value. Because of the small number of patients with these ultra-rare diseases, the course of the disease over time may not be well characterized, or with remissions and flares have an inconsistent progression. This may become an issue in demonstrating efficacy as required in the last two bullets. One of the suggestions at the Rare Disease Workshop referenced above (Presentation by Eli Brimble MSc, MS, CGC From community to clinic: Patient- centered evidence accelerates therapeutic development in rare disease), was to start the natural history study early by collecting real world data (RWD) in patients with the disease at the same time that IND-enabling activities are underway. Thus, at the start of the clinical study, one has data to demonstrate the course of the disease over time, which can be used as an external control or, if the same patients are entered into the study, can be used as intrinsic controls.
The last two items listed relate to efficacy and for this we need to remember that while this “plausible pathway” provides a mechanism for approval of individualized therapies, it does not lessen the requirements for “substantial evidence of activity,” or confirmatory evidence if one clinical study is conducted. Very important here is the benefit/risk relationship: the strength of the evidence provided to support efficacy, compared with the safety of the therapy in the intended patient(s). This will be weighed against the variable expression, seriousness, and rarity of the disease, and availability of alternate therapies.
There are multiple opportunities to interact with FDA during development, starting in early development. The key to success is frequent interactions with regulators, a good understanding of the disease pathway, routine review of the data generated during development, and re-assessment of whether changes in the development pathway are necessary. We must always remember that drug development is not linear and what we learn in each phase will inform the next.
When pursuing any development pathway, including the plausible mechanism pathway, data should be reviewed on a routine basis and shared with regulatory authorities so that there is consensus on the development pathway. Frequent communications and adjusting the plan based on emerging data, with the results supported by high quality science, should help to bring clarity to the development process. We in industry also need to ask the difficult questions and listen carefully to the advice and recommendations of the regulators.
At PROMETRIKA, we have extensive experience with rare disease clinical studies and assist our clients with natural history, study design, study execution, and regulatory interactions.
