On February 23, 2026, FDA issued a highly anticipated draft guidance entitled “Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause” (“Draft Guidance”). The Draft Guidance details a new regulatory approach—the plausible mechanism framework (“PM Framework”)—for the development of individualized therapies and follows a November 2025 article that FDA officials published in the New England Journal of Medicine (“NEJM Article”) (discussed in a previous Ropes & Gray Alert).
This Alert examines key takeaways from the Draft Guidance and identifies significant questions that remain for biopharmaceutical companies and investors interested in the development of personalized therapies.
Overview of the Draft Guidance
After the publication of the NEJM Article, which outlined five key characteristics that define eligibility for what the article referred to as a new “pathway,” the biopharmaceutical industry had been eagerly awaiting further details from FDA. The newly released Draft Guidance reaffirms the five characteristics set out in the NEJM Article and confirms that the PM Framework applies to therapies that target a specific pathophysiologic abnormality that is the root cause of the disease in question, like a specific pathogenic genetic variant. Although the Draft Guidance focuses primarily on genome-editing and RNA-based therapies, FDA anticipates the PM Framework may also be applicable to other types of individualized therapies.
The Draft Guidance addresses bespoke, personalized therapies for patients with severely debilitating or life-threatening diseases or conditions affecting such small patient populations that randomized clinical trials are typically not feasible. Organized into five sections, the Draft Guidance provides detailed recommendations for establishing substantial evidence of effectiveness and describes the circumstances under which data generated from individualized therapies may be sufficient to support FDA approval of a new drug or licensure of a new biologic. The recommendations span the full product lifecycle—from development through post-approval—and address, among other things, clinical and nonclinical evidence considerations, post-marketing efficacy and safety data collection, ethical and human subject protection considerations, and chemistry, manufacturing, and controls (“CMC”) expectations. The Draft Guidance heavily cross-references other existing FDA guidances related to rare disease product development and other issues and repeatedly encourages early engagement with FDA on key development issues.
Key Takeaways
PM Framework Is Intended to Align with Existing Statutory and Regulatory Standards. The Draft Guidance makes clear that FDA does not view the PM Framework as establishing a new standard for review of novel products; rather, it is intended to operate within the existing evidentiary framework under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and the Public Health Service Act. To obtain FDA approval, a New Drug Application, for example, must demonstrate to FDA’s satisfaction that the drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling; that the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are adequate to preserve its identity, strength, quality, and purity; and that there is substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling. 21 U.S.C. § 355(d). The “substantial evidence” standard for effectiveness requires at least one adequate, well-controlled clinical investigation plus confirmatory evidence. The difference between the PM Framework and the traditional drug approval process lies in how FDA intends to evaluate whether the evidentiary requirements for safety and efficacy have been met. Specifically, the Draft Guidance explains that, under the PM Framework, FDA anticipates that the first-in-human clinical investigation will serve as the “primary source of evidence to support approval,” which has the potential to significantly shorten the clinical development process compared with more traditional development plans that typically require multiple clinical studies (e.g., Phase 1 and 2 trials) before a pivotal trial can begin. The Draft Guidance further explains that the investigations under the PM Framework will include a small sample size and, when assessing whether individualized therapies satisfy the substantial evidence standard, FDA will consider “the clinical context for the disease, the level of unmet medical need, and the challenges involved in enrolling participants in a clinical investigation.”
Current Good Manufacturing Practice (“cGMP”) Compliance and CMC Expectations. The Draft Guidance emphasizes the importance of cGMP compliance when manufacturing products approved via, or under investigation pursuant to, the PM Framework. Additionally, because of the shorter clinical investigations and the limited number of subjects that will be treated during these clinical investigations, FDA explains that having well-defined and validated CMC processes will be critical to obtaining approval. The Draft Guidance summarizes manufacturing-related requirements and provides several notable recommendations, including:
- Manufacturing of both investigational and approved drugs and biologics is subject to the statutory cGMP obligation set forth in section 501(a)(2)(B) of the FDCA. While the Draft Guidance acknowledges, consistent with 21 C.F.R. § 210.2(c), that production of investigational drugs for use in Phase 1 clinical trials is typically exempt from FDA’s cGMP regulations in 21 C.F.R. Part 211, the Draft Guidance states that this exemption “generally applies to studies that are designed to establish basic safety, rather than efficacy of the drug product.”
- Because of how rapidly CMC development will occur for products utilizing the PM Framework, the sequence, structures (e.g., various modifications), stereochemistry, and other physicochemical characteristics that are critical to a product’s performance should be well-defined, confirmed, and controlled to ensure consistency.
- The manufacturing process to support a New Drug Application or Biologics License Application must be appropriately validated.
- All assays used in release and stability testing must satisfy applicable application-related and cGMP requirements.
- Given the limited number of batches expected to be manufactured for an individualized therapy, sponsors should develop a shelf-life strategy early in development. This includes collecting stability data for all batches.
- FDA notes in multiple contexts that a developer’s prior manufacturing and development knowledge or experience may be leveraged to support CMC development (e.g., process performance qualification from one product may be used to support manufacturing process validation of a similar product using the same manufacturing process at the same manufacturing site).
Scope of PM Framework. The NEJM Article introduced the PM Framework through the lens of cell and gene therapies (“CGTs”) intended for ultra-rare diseases but suggested its scope could be expanded in the future to cover, for example, small molecules, antibodies, and therapies for non-rare diseases. Similarly, although the Draft Guidance focuses on genome-editing and RNA-based therapies, FDA notes that “the general concepts may apply to other types of individualized therapies.” Further cementing this point, in FDA’s public remarks announcing the Draft Guidance, Center for Drug Evaluation and Research (“CDER”) Acting Director Tracy Beth Høeg stated that FDA was “very careful to leave [the PM Framework] open-ended to not limit this to ultra-rare diseases” because it “could really apply to any diseases, even common, if they meet the criteria for the plausible mechanism pathway.”
Open Questions About the Implementation of the PM Framework
As the PM Framework transitions from concept towards implementation, FDA may soon face important questions that the Draft Guidance leaves unresolved. Some of the key questions and potential developments that industry will be tracking closely include:
- How widely will the PM Framework be used in practice? Although FDA has indicated that the PM Framework could theoretically be applied to non-rare diseases if the relevant criteria are met, it is not clear what common diseases might meet that bar (e.g., where randomized clinical trials would not be feasible). FDA appears to be anticipating high demand, with CDER Acting Director Høeg asserting that the agency “is likely going to be overwhelmed with applications” and will need to “be creative in the way that we meet this new demand.” However, it is not clear whether the PM Framework will spur development of novel products or whether sponsors will simply seek to use the framework as an alternative and less burdensome method for obtaining marketing authorization for products already in development. Similarly, it remains to be seen whether FDA will reallocate review resources to accommodate this anticipated volume, assuming it materializes, and what impact that may have on review timelines of products pursuing more conventional development programs.
- How exactly will manufacturing-related flexibilities be applied for products under the PM Framework? In a January 2026 announcement, FDA touted all the regulatory flexibilities it has applied to CMC requirements for CGTs in order to expedite product development. FDA championed these flexibilities largely because many CGTs “target serious or life-threatening conditions with an unmet medical need,” are “small-batch products,” are “often individualized for patients, and may need sophisticated manufacturing under particular time constraints.” Despite many of these considerations logically also applying to products that would be developed under the PM Framework, the Draft Guidance curiously does not reference FDA’s January 2026 announcement, nor does the CMC section of the Draft Guidance discuss any particular CMC flexibilities that might be specifically applied to products under the PM Framework. Certain statements in the Draft Guidance create ambiguity or potentially suggest heightened manufacturing-related expectations from FDA. For example, FDA asserts that the exemption for Phase 1 trials from cGMP regulations in Part 211 generally applies to studies “designed to establish basic safety” but does not explicitly address whether first-in-human studies used as the primary source of evidence for FDA approval under the PM Framework (and thus intended to establish safety and efficacy) are able to take advantage of the exemption.
- Will FDA apply the flexibilities described in the Draft Guidance in practice? The Draft Guidance explains that sponsors may demonstrate substantial evidence of effectiveness under the PM Framework through a single adequate and well-controlled clinical investigation with confirmatory evidence, and that this standard can, in certain instances, be satisfied by externally controlled clinical investigations: “In patients for whom the natural history of the disease in the untreated state can be reasonably characterized, it may be possible for an externally controlled clinical investigation that assesses a patient’s change following treatment compared to baseline to serve as the adequate and well-controlled clinical investigation necessary to support approval/licensure.” FDA also recently issued a guidance document regarding innovative trial designs for CGTs explaining how natural history studies might be used in clinical development programs (discussed in a previous Ropes & Gray Alert). This stated policy position, however, appears to be in tension with several notable and highly publicized FDA review decisions within the past year where FDA declined to approve certain novel CGTs and other rare disease therapies based upon these kinds of and instead has requested more traditional randomized, controlled trials. This apparent contradiction raises the question as to whether FDA will, in practice, apply the flexibilities described in its recent guidance documents when reviewing specific applications for individualized therapies.
Next Steps
While the Draft Guidance reflects yet another expression of FDA’s focus on accelerating rare disease drug development, the numerous important—yet unresolved—questions make it difficult to predict how plausible the new framework will prove to be in practice. The Draft Guidance’s frequent citations to existing guidances on key issues compounds this uncertainty and raises the question of how much of the Draft Guidance’s content reflects genuine new flexibility versus a consolidation of prior agency positions. Moreover, recent high-profile rejections of rare-disease-related product applications have intensified industry skepticism about whether FDA will actually exercise the regulatory flexibilities the Draft Guidance promotes.
In the near term, sponsors interested in taking advantage of the flexibilities outlined in the Draft Guidance should confirm their eligibility for the PM Framework and plan to meet with FDA early in the development process to ensure alignment on, among other things, the non-clinical data necessary to initiate clinical trials, clinical development plans, sources of confirmatory evidence, CMC development, and post-marketing obligations.
FDA is accepting comments on the Draft Guidance until April 27, 2026. Ropes & Gray will continue to monitor developments related to the PM Framework.
