backThe Food and Drug Administration (FDA) has issued a statement, published electronically in the New England Journal of Medicine (NEJM) on November 12, 2025, proposing a new process for obtaining marketing authorization for drugs and biological products where a randomized trial is not feasible and the focus is on treatment of single patients or very small patient populations. The article, which was authored by Vinay Prasad (Director of FDA’s Center for Biologics Evaluation and Research) and Martin A. Makary (Commissioner of FDA), coins this new program the “Plausible Mechanism Pathway.”1See Prasad V, Makary MA. FDA's New Plausible Mechanism Pathway. N Engl J Med. 2025 Nov 12. DOI: 10.1056/NEJMsb2512695. Access to details of the proposal requires purchase from the New England Journal of Medicine and is not yet freely accessible to all stakeholders. The announcement follows FDA’s earlier publication of “Rare Disease Evidence Principles,” which outlined a potential framework to approve products for rare diseases caused by a specific genetic defect, for which no adequate alternative therapies exist. 2See CDER/CBER Rare Disease Evidence Principles (RDEP), https://www.fda.gov/industry/fda-rare-disease-innovation-hub/cdercber-rare-disease-evidence-principles-rdep.
The Plausible Mechanism Pathway contemplates FDA approval of “bespoke” novel drug treatments, in which the approval would be based on biologic plausibility of the treatment and evidence of clinical improvement in a small number of patients who received a variation of the proposed product (not necessarily the identical product or for the same disease). The proposal raises many issues, including the legal authority under which FDA would implement the proposal, potential benefits and deficiencies of this pathway in comparison with Expanded Access3See 21 C.F.R. Part 312, Subpart I–Expanded Access to Investigational Drugs for Treatment Use. or discretionary allowance of treatment use under investigational new drug applications (INDs), and implementation challenges for drug manufacturers, medical centers, and prescribing physicians.
Here we highlight certain major issues and considerations regarding the Plausible Mechanism Pathway described in the NEJM.
- Potential Need for an Adapted Legal Framework It may be possible to implement the Plausible Mechanism Pathway without amendment of the Federal Food, Drug, and Cosmetic Act or Public Health Service Act. However, the article does not address whether formal rulemaking is planned for implementation. The proposed pathway may implicate and require revision of multiple FDA regulations including the provisions for INDs (21 C.F.R. Part 312), Protection of Human Subjects (21 C.F.R. Part 50), Financial Disclosure by Clinical Investigators (21 C.F.R. Part 54), and Institutional Review Boards (IRBs) (21 C.F.R. Part 56), suggesting that formal notice-and-comment rulemaking may be required. In addition, it is possible that FDA, IRBs, and/or the public will expect routine use of independent Data Monitoring Committees (DMCs) to evaluate post-approval data and emergent safety issues in a timely and expedient manner. In guidance, FDA has emphasized the importance of using DMCs in clinical investigations in which subjects are at risk of serious morbidity or mortality.4See Guidance for Clinical Trial Sponsors. Establishment and Operation of Clinical Trial Data Monitoring Committees https://www.fda.gov/media/75398/download.
- Case Study of “Baby K.J.” Prasad and Makary highlight the example of “Baby K.J.,” who was a neonate with deficiency of the essential enzyme CPS1 and who rapidly developed high serum levels of ammonia. Under a single-patient Expanded Access protocol approved by FDA, Baby K.J. was infused with an urgently manufactured novel RNA-based therapy encased in a lipid nanoparticle that targeted the aberrant RNA mutation for repair. This reportedly has enabled the baby to process more dietary protein and reduced the need for medicine to lower serum levels of nitrogen. This case study illustrates key components of how Prasad and Makary envision the Plausible Mechanism Pathway will operate.
- Key Components of the Proposed Approval Pathway.
- Identification of a specific molecular or cellular abnormality. The proposed Plausible Mechanism approval pathway is intended to be used only for conditions in which a specific identified genetic or molecular abnormality (i.e., a downstream protein encoded by the gene) has a “clear connection” to the specific clinical presentation of the disease. The pathway is not intended for use in diseases with multiple different clinical findings or conditions with unclear associations with a gene or multiple genes. Although this appears to be a clear distinction, it will rely on data that can confirm a strict, direct match of a genetic or molecular abnormality with a disease.
- Development of a “bespoke” medical treatment that is targeted to the specific biologic abnormality. Prasad and Makary contrast the use of a personalized “bespoke” treatment with, for example, the use of corticosteroids that are used to treat a variety of medical conditions but are not designed as a treatment for a specific biologic abnormality directly linked to a specific medical condition.
- Reliance on well-understood natural history of the disease in the absence of treatment. By way of example, Prasad and Makary highlight how, in the case of Baby K.J., the team relied on the natural history of deficiency of the CPS1 enzyme, which showed a linkage to elevated ammonia. The pathway, however, does not appear to encompass the clinical circumstance where a very rare disease may have been publicly disclosed as a single case report, but the natural history is not well-understood.
- Demonstration that biologic target was successfully “drugged” or edited. Prasad and Makary state that that the proof of gene delivery or modification (editing) may be met by clinical biopsy of the target organ, if clinically appropriate, or by demonstration in an animal model. However, they acknowledge that animal models may be misleading, and for some organ sites in humans (such as the retina) biopsy may not be feasible. Further, they suggest that demonstration of target editing in select cases may be limited to the first patient dosed. This requirement is likely to be a source of negotiation between manufacturers and FDA. Requirements for invasive and high-risk biopsy in vulnerable patients, such as infants, may be challenged by IRBs.
- Demonstration of improvement in clinical outcome. The article clarifies that, in conditions with progressive deterioration, demonstration of “consistent improvements” is expected. For conditions with “episodic waxing and waning” of the condition, FDA expects demonstration of prolonged periods of remission. Any criteria for clinical improvement are clearly disease-specific and cannot be generalized. This requirement does not address common nuances in drug treatment outcomes—for example, patients treated with the identical investigational drug regimen may have different efficacy and/or safety responses associated with sex, age, and other variables such as the presence of other medical disorders.
- Market Authorization. Prasad and Makary envision that FDA will grant marketing authorization for the product after demonstration of “success with several consecutive patients with different bespoke therapies.” Implicit in the Plausible Mechanism Pathway is the concept that a manufacturer will develop a “platform” of data from investigational use of a product that is modified to address multiple genetic conditions. When the manufacturer has demonstrated “success” with treatment of several consecutive patients, FDA will consider granting marketing approval to support marketing for similar products in additional clinical conditions using either the regular or accelerated approval pathway. The pathway also would involve a postmarketing commitment to acquire additional data. Manufacturers contemplating use of this pathway are likely to need much more explicit information from FDA specific to the novel gene or molecular therapy regarding prospective study design to develop an adequate data platform.
- Unanswered Issues. The Prasad and Makary article fails to address the benefits and limitations of the proposed pathway in comparison with the well-established, IND-based, regulatory pathway for Expanded Access (21 C.F.R. Part 312, Subpart I). The article simply asserts, at a high level of generality, that “current regulations are onerous and unnecessarily demanding, provide unclear patient protection, and stifle innovation.” It is notable that the Baby K.J. patient case study successfully relied on access to the novel, bespoke investigational product via Expanded Access. The Expanded Access regulations provide clear protections and requirements for all parties involved, including FDA, the physician as Investigator, the IRB, and the patient, including disclosures of known and unknown risks in the Informed Consent process. Expanded Access is readily accessible, and in our experience emergency access to an investigational drug can be obtained immediately from FDA via telephone authorization under 21 C.F.R. § 312.310(d). FDA data for the past five years demonstrate that it is extremely rare for FDA to refuse to authorize Expanded Access for drugs and biological products. 5See Expanded Access (Compassionate Use) Submission Data. https://www.fda.gov/news-events/expanded-access/expanded-access-compassionate-use-submission-data#CBERCDER.
Concerning Expanded Access for an individual patient, FDA regulations (specifically 21 C.F.R. § 312(c) and (d)) explicitly limit the manufacturer to charging only for the direct costs of making the investigational drug available in addition to other controls. The Plausible Mechanism Pathway, at least as currently articulated, does not address these protections and requirements. Presumably manufacturers could charge for products approved under the Plausible Mechanism Pathway using broader commercial considerations.
Finally, the article does not address how drug sponsors will go about requesting marketing approval through the Plausible Mechanism Pathway. Both standard and accelerated approval authorities are noted. We anticipate that additional detail will be forthcoming about how sponsors should contact FDA to participate in the program and what types of information FDA will expect to be provided.
Conclusion
In the proposal for a new Plausible Mechanism Pathway, Prasad and Makary envision a novel regulatory pathway to enable approval of “bespoke” genetic and drug therapies to address rare diseases. While the pathway holds promise, the latest description of this program is high-level and does not address key questions regarding implementation. We encourage drug manufacturers to closely track further developments regarding this proposal and to be aware that new public disclosures may be issued in “pay to read” medical journals rather than announcements on the FDA website or in the Federal Register.
If you have questions regarding the Plausible Mechanism Pathway or would like assistance in preparing comments to FDA or “letters to the editor” of the New England Journal of Medicine, we are glad to help. Please contact Beverly Lorell, Chris Markus, Lauren Roth, or Kyle Sampson for more information.