On Monday, the U.S. Food and Drug Administration (FDA) published draft guidance formalizing a “plausible mechanism” approval framework for individualized therapies, particularly genome editing and RNA-based products. Although the guidance does not describe a change to FDA's statutory approval standards, it clarifies areas where the agency may exercise greater regulatory flexibility in its assessments of clinical trial design, while also emphasizing the importance of robust mechanistic evidence, early trial planning, CMC development, and heightened postmarketing safety scrutiny. The “plausible mechanism” pathway was heralded late last year by FDA Commissioner Martin Makary and CBER Director Vinay Prasad in a NEJM article that we analyzed online here. Publication of the guidance follows another NEJM article from the Commissioner and CBER Director announcing the agency will shift to a default drug approval standard of one robust pivotal trial instead of two.
Below we analyze these new policy statements, considering how they could benefit medical product sponsors that have data from a single pivotal trial or that can utilize the plausible mechanism framework, especially for drugs or biologics treating rare diseases. FDA seeks comments on the draft guidance through April 27.
Hogan Lovells' strategic assessment
While some have suggested that a one-trial default could signal lowering of approval standards, it remains to be seen whether, in practice, the new policy will prove to be a lower bar. One possibility is that it ultimately leads to greater focus on the design of the single study, with elements of confirmatory evidence built into the study design or with the expectation, at the outset, that the study will be confirmed by reliance on mechanistic or other confirmatory evidence. This may, in the end, be neither a higher or lower bar but, instead, a more refined approach that better incorporates the totality of the science to reach regulatory and statistical truth. The agency's expectations for the single trial focus on controls, endpoints, effect size, and statistical protocols that will—in one trial, together with confirmatory evidence—satisfy reviewers that the approval standard has been met. Indeed, Makary and Prasad acknowledge that their “proposal for a default of one robust and sound clinical study may even enhance the FDA's standards and reduce the risk of approval of products that may later need to be withdrawn, since greater attention will be placed on the one trial.”
In this respect, the “one-trial default” should be viewed less as a relaxation of evidentiary rigor and more as a consolidation of FDA's expectations into a single, highly scrutinized clinical investigation. Sponsors should assume that weaknesses historically tolerated across two studies—such as modest effect size, endpoint ambiguity, or control-group limitations—may no longer be acceptable when all evidentiary weight rests on one trial. On the other hand, secondary endpoints, anatomical changes, pharmacodynamic response, and biomarker measures may take on added significance in the one study design.
Sponsors should plan FDA communications and development strategy carefully to ensure that data they generate in a single pivotal trial, and the confirmatory evidence they will offer in support, will satisfy FDA's expectations and will not result in a Complete Response Letter.
Plausible Mechanism draft guidance
FDA’s new 20-page draft guidance, “Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause,” describes considerations for generating substantial evidence of effectiveness and evidence of safety for individualized therapies based on the “plausible mechanism” framework.
The guidance specifically discusses genome editing (e.g., CRISPR-Cas, ZFNs, TALENs, base editing, prime editing) and RNA-based therapies (e.g., antisense oligonucleotides (ASOs), small interfering RNAs). Despite this limited focus, FDA advises that the general concepts under the plausible mechanism framework may apply to other types of individualized therapies, which it defines as those that target a “specific pathophysiologic abnormality serving as the root cause of a disease,” such as beta-thalassemia or phenylketonuria.
Application of the plausible mechanism pathway is limited to the same factors that were set forth in the 2025 NEJM article, which we enumerated online here: diseases that have a well characterized, identifiable molecular or cellular abnormality, and the therapeutic product targets the underlying abnormality, its proximal pathogenic pathway, or a well-characterized downstream or compensatory mechanism with a clear mechanistic rationale.
We identified the following notable themes in the guidance:
- Regulatory flexibility. For applications being considered under the plausible mechanism pathway, FDA said it may exercise greater regulatory flexibility regarding trial design, including the study duration, types of studies needed, and model selection. For example, the guidance says an abbreviated nonclinical program can be used to support patient safety.
- Approval standards unchanged. Drugs and biologics approved under the plausible mechanism framework must still meet the statutory requirements for safety and efficacy. For example, the guidance encourages in certain cases: developmental and reproductive toxicology studies, collection of in vitro activity data, use of bioinformatic tools to identify potential off-target gene knockdown effects, and off-target editing activity assessments, among other data submissions. FDA advises that because an adequate and well-controlled clinical investigation in this context will include a small sample size, “investigation results should be robust to exclude chance findings that may incorrectly suggest effectiveness.”
- Early planning. Prior to administration of an individualized therapy, sponsors/investigators should collect potential clinical outcomes and biomarkers in patients eligible for treatment. FDA urges sponsors to initiate an observational protocol as soon as potential study participants are identified while other early product development activities are being conducted (e.g., manufacturing, nonclinical studies), and while natural history data sources are identified and obtained. Natural history data are not treated as merely contextual, but may serve as the external control against which treatment effects are assessed, requiring sponsors to demonstrate that observed improvements are inconsistent with the untreated disease course.
- Postmarketing scrutiny. FDA is signaling a heightened focus on safety data collected in the postmarket setting, and on monitoring adverse event reports. In particular, the guidance emphasizes toxicity profile concerns, noting that additional studies may be warranted if information comes to light that changes the benefit-risk profile.
- Chemistry, Manufacturing, and Controls (CMC). The guidance emphasizes the importance of CGMP compliance for the manufacture of products approved (or submitted for approval) under the plausible mechanism pathway. With CMC development occurring rapidly in this context, there will be a greater focus on utilizing prior development experience and manufacturing knowledge, which can be leveraged to support process validation.
- NAMs, NGS. The guidance continues FDA’s trend toward encouraging use of New Approach Methodologies (NAMs), such as cell-based, organoid, in silico, and in chemico methods—as well as next-generation sequencing (NGS)-based methods—as we previously discussed online here. The draft guidance also encourages use of master protocols (e.g., umbrella or platform trials) for therapies or the same disease that target different genetic changes.
The plausible mechanism pathway continues FDA's trend toward announcing its willingness to use its regulatory flexibility to speed development of drugs and biologics for rare diseases, unmet need, and regenerative medicines, with the release of the draft guidance coinciding with FDA’s “Rare Disease Day 2026,” which we previewed online here. We anticipate an upswing in applications for FDA approval of products aiming to treat rare disease, and with several high-profile FDA decisions are expected in coming months, and we will be closely monitoring how the agency reconciles its commitment to promoting innovation with its decision making.
Two-trial requirement upended
The publication of the plausible mechanism guidance comes five days after publication of an NEJM article in which FDA Commissioner Martin Makary and CBER Director Vinay Prasad outlined a shift from the agency’s traditional approval requirement of two pivotal clinical trials to a default expectation of one pivotal study supported by confirmatory evidence. They write that “as drug discovery becomes increasingly precise and scientific,” an “overreliance on two trials no longer makes sense.” While a single-trial expectation will be familiar to sponsors working in certain therapeutic areas—like oncology and some rare diseases—where FDA has been offering the flexibility to base approval on a single trial, this newly-announced “default” may be a new benefit for sponsors aiming to treat highly-prevalent disease areas where historically two or more pivotal studies were required.
Looking toward novel “powerful alternative ways” to demonstrate safety and efficacy that they say do not require manufacturers to run a second pivotal trial, Makary and Prasad point to the following factors as increasingly important in the agency’s regulatory reviews:
- magnitude of effect,
- use of a contemporary control group, and the nature of that group,
- prespecification of a hypothesis,
- choice of a primary endpoint,
- concordance with biologic correlates (including evidence of alteration of an in vivo target),
- alignment of intermediate endpoints,
- statistical power, blinding, concealment, and independent review,
- whether post-protocol therapy is on par with the U.S. standard of care,
- the use of concomitant therapy, inclusion criteria, exclusion criteria, randomization, run-in periods, how missing data are handled, “and many additional factors.”
Makary and Prasad also suggest examples for which two pivotal trials will remain necessary, including where:
- an intervention has a nebulous, pluripotent, or nonspecific mechanism of action,
- the product affects a labile, short-term, or surrogate outcome, or,
- a trial has some “underlying limitation or deficiency”
Next steps
FDA invites comments on the plausible mechanism draft guidance through April 25, 2026. We note that because agency guidance documents reflect current thinking on a topic, no further rulemaking is required for FDA to apply these principles in the interim. Therefore, both the guidance and NEJM article may represent a near-term advantage for sponsors close to regulatory submission that have data from one trial or that can utilize the plausible mechanism framework. However, taking into account the rapid pace of regulatory change, and the relative ease with which a guidance document can be modified or a new journal article published, sponsors should carefully consider any plans to alter long-term clinical trial practices that have been historically accepted as industry standard.
We recommend that sponsors contemplating a single-trial approval strategy engage FDA early to align on trial design, endpoint selection, and confirmatory evidence expectations, particularly where a single study is intended to carry the full evidentiary burden for approval. We will continue to monitor for formal guidance on how FDA may shift to a “one pivotal trial” default expectation for marketing authorization approval.
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