Cross-posted with permission from Health Affairs Forefront.

[Original Post: Holly Fernandez Lynch, Reshma Ramachandran, Rachel Sachs, Patricia J. Zettler, and Steven Joffe. “Refining FDA’s Plausible Mechanism Framework, Part 1: Understanding The Draft Guidance And Clarifying The Framework’s Scope,” Health Affairs Forefront, June 8, 2026. http://doi.org/10.1377/forefront.20260604.803734, Copyright © 2026 Health Affairs by Project HOPE – The People-to-People Health Foundation, Inc.]

[Original Post: Holly Fernandez Lynch, Reshma Ramachandran, Rachel Sachs, Patricia J. Zettler, and Steven Joffe. “Refining FDA’s Plausible Mechanism Framework, Part 2: Manufacturing Challenges, Product Scope, And Post-Approval Considerations,” Health Affairs Forefront, June 8, 2026. http://doi.org/10.1377/forefront.20260604.485666, Copyright © 2026 Health Affairs by Project HOPE – The People-to-People Health Foundation, Inc.]

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Part 1: Understanding The Draft Guidance And Clarifying The Framework’s Scope

Personalized medicine has advanced to the point that, in some cases, a patient’s unique disease-causing variant can be treated through an individualized genetic intervention. The intervention may be a gene editor, like the one developed by Rebecca Ahrens-Nicklas and Kiran Musunuru in 2025 to treat baby KJ Muldoon’s rare urea cycle disorder, composed of a messenger RNA encoding an editing protein to precisely change the DNA and a customized guide RNA that directs the editing protein to the site of the patient’s specific variant. Another approach, used by Timothy Yu to treat Mila Makovec’s Batten disease in 2018, avoids editing DNA directly, instead relying on antisense oligonucleotides (ASOs) with individualized nucleotide sequences to modify how the gene is read to address the consequences of the patient’s pathogenic variant.

Although gene editors and ASOs can also be used to treat more common genetic disorders, the key feature of individualized interventions is their modularity. The intervention’s “backbone” can remain identical across patients who share the same phenotype, with only the guide RNA, nucleotide sequence, or other individual component altered to address each patient’s n-of-1 or n-of-few variant.

FDA is working to adapt its regulatory approval process to account for these individualized approaches. Traditionally, each variant-specific modification would be deemed a unique product despite substantial overlap between them; each would require its own variant-specific investigational new drug application (IND), all the testing and studies necessary for approval, and its own marketing application. Yet this approach is infeasible for variants affecting just one or a few patients, both economically and in terms of the time necessary to complete comprehensive testing from scratch for each individual.

Previous FDA efforts to address this challenge did not offer a pathway to market approval, instead setting forth criteria for academic investigators to treat one or two patients at a time under FDA’s Expanded Access pathway. Without approval and associated payer reimbursement, however, this approach would not be scalable to bring individualized therapeutics to all patients who could benefit. Instead, academic researchers would be left to scramble for funding to cover selected individuals and commercial developers would lack economic incentive to engage.

Prompted by Baby KJ’s case, FDA leaders published in November 2025 a brief commentary in The New England Journal of Medicine (NEJM) describing a new approval framework for individualized genetic therapies based on a “plausible mechanism” of action. In a previous two-part article in Health Affairs Forefront, we praised the proposal’s potential to address critical problems impeding the development of these therapies for n-of-1 and n-of-few disorders. But we also raised questions about how the approach would work in practice, flagged concerns about scope, and noted troubling transparency and procedural gaps in how the pathway had been announced, ultimately calling for the agency to use its guidance process to allow for public comment and clarification.

Draft guidance has now been published—”Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause”—providing greater insight into FDA’s thinking on how such a framework might be implemented as part of its regulatory approval process. Whether the plausible mechanism framework will suffice to bring individualized genetic therapies to all patients who could benefit remains to be seen. In part one of this article below, we describe the draft guidance and explain the importance of clarifying the framework’s scope, drawing on our recent public comments submitted to FDA. In part two tomorrow, we will conclude analysis of the draft guidance and our list of areas where we suggest improvement, including resolution of difficult manufacturing challenges, clarification of the product that will be granted approval, and attention to post-approval considerations.

The Draft Guidance

The draft guidance describes an approach for developers of therapies individualized to a patient’s unique genetic variant to demonstrate that they have met the conditions for marketing approval, including sufficient evidence of effectiveness and safety and satisfaction of manufacturing standards. While providing substantially more detail than the NEJM article on expectations regarding nonclinical and clinical data, as well as data on chemistry, manufacturing, and controls (CMC), the draft guidance retains the same five elements previously described as defining the plausible mechanism framework:

(1) Presence of a “specific genetic, cellular, or molecular abnormality with a clear connection between specific alteration and disease indication”

(2) A “therapy that targets the underlying or proximate pathogenic biological alterations,” that is, a plausible mechanism of addressing the pathology that is the “root cause” of a disease

(3) A “well-characterized natural history of the disease in an untreated population”

(4) Confirmation that the “target was successfully drugged or edited or both”

(5) Demonstrated “improvement in clinical outcomes or course”

Also like the article, the draft guidance indicates that the framework applies to diseases or conditions “in a small number of patients where a randomized controlled trial typically is not feasible” due to the “specificity of the mechanism of action of the individualized therapy” and “rarity of the treatment-amenable patient population,” such that clinical evidence from only a “limited number of patients will be available.” It does not, however, explicitly limit the framework to n-of-1 or n-of-few disorders.

Clarifying the authority for this approach, the draft guidance indicates that products will be expected to “establish safety and provide substantial evidence of effectiveness” under existing regulatory pathways. Accordingly, the plausible mechanism framework reflects a type of regulatory flexibility to meet current statutory standards for approval, with consideration of “the clinical context for the disease, the level of unmet medical need, and the challenges involved in enrolling participants in a clinical investigation for an individualized therapy.” FDA’s head of the Office of Neuroscience, Teresa Buracchio, recently confirmed that the framework is not intended to offer a lower bar for product approval but instead a distinct way of meeting that bar. Instead of providing a new designation or pathway to which companies can apply, the framework reflects a set of regulatory principles for the review of eligible therapies.

Unsurprisingly, given that exceedingly small patient populations make the framework necessary, the draft guidance indicates that approval will likely be based on a single pivotal trial plus confirmatory evidence. However, FDA indicates that “results should be robust to exclude chance findings that may incorrectly suggest effectiveness.” To meet the statutory requirement for a well-controlled clinical investigation, the draft guidance describes a willingness to accept compelling data that a patient’s disease course with treatment “is inconsistent with the natural history of the disease.”

The draft guidance provides somewhat greater clarity than the NEJM article about what product would obtain FDA approval under the plausible mechanism framework. The article left ambiguity about whether FDA was envisioning a one-gene/one-product approach or perhaps something broader (such as a one-condition/one-product approach), as well as confusion about whether the one product would cover all variants within a particular gene.

In the draft guidance, FDA provides an example of a product that uses multiple different guide RNAs to target different variants in a single gene and notes that these may be included in a single IND—and later, a single biologics license application (BLA)—if the method of correction is the same between the guide RNAs. The draft guidance further clarifies that data could be collected using a defined set of variants to support approval, with a plausible mechanism of action then supporting the addition of other variants “not included in the clinical trial used to support the original approval.” Thus, the approved product seems to be more expansive than a single genetic variant, but it would not necessarily encompass all variants on a single gene at the point of first approval, although those could be added subsequently.

The draft guidance provides substantial detail on nonclinical programs to support individualized therapies, largely focused on supporting safe initiation of the first-in-human study. In line with broader agency priorities, FDA encourages use of New Approach Methodologies (NAMs) rather than animal testing whenever appropriate, although standards for validating and accepting NAMs for regulatory purposes remain unclear. The draft guidance discusses opportunities to leverage data between clinical programs using related individualized gene editors but calls for evaluating editing activity at the target site, off-target editing risk, and dose level for each product variant. For ASOs, the draft guidance emphasizes that they should be from a well-characterized chemical class.

With regard to clinical development, the draft guidance anticipates that the first-in-human clinical investigation will also be the primary source of evidence for marketing approval, such that protocols should be adequate and well-controlled, including with prespecified, standardized assessments of efficacy and safety outcomes. Given the importance of data demonstrating a change in disease trajectory compared to that expected based on natural history, the draft guidance encourages sponsors to begin patient observation immediately, even as manufacturing and nonclinical studies are being carried out, to establish baselines. The draft guidance provides substantial additional detail on design, dosing, clinical and biomarker assessments, and safety outcomes. It also expresses an openness to the use of “master protocols (e.g., umbrella or platform trials)”—an approach currently contemplated by Drs. Ahrens-Nicklas and Musunuru for several genes associated with urea cycle disorders—and encourages sponsors to engage FDA early on these matters, without providing further detail.

The draft guidance acknowledges that CMC expectations typically evolve concurrently with clinical development. Indeed, in January 2026, FDA announced a flexible approach to overseeing CMC requirements for cell and gene therapies: These products will not be expected to comply with current Good Manufacturing Practice regulations in Phase 1 trials, among other flexibilities for clinical development, commercial specification, and process validation. However, because the investigational phase for individualized therapies will be substantially shortened with a small number of subjects, starting at the equivalent of Phase 3 clinical trials and skipping Phase 1/2, the draft guidance expects CMC development to occur rapidly. More specifically, it notes that “multiple aspects of the commercial manufacturing process should be considered when developing the manufacturing process to support the initial IND (e.g. scale, validation, commercial feasibility, etc.).”

Issues To Clarify In The Final Guidance

The draft guidance addresses a genuine regulatory challenge facing n-of-1 and n-of-few individualized therapeutics and, in some cases, should enable development of these interventions for marketing approval. However, concerns about the proposed framework remain, some of which will likely continue until it becomes clearer how FDA will use the framework in practice. New concerns have also developed, especially regarding whether the framework will be available in practice to academic developers or only to industry sponsors. Below we discuss one key issue that FDA should address in the finalized guidance, with additional suggestions in tomorrow’s article.

Scope Constraints

We previously raised concern that the plausible mechanism framework might be extended beyond the exceptional circumstances that motivate it—exceedingly small patient populations unable to support traditional clinical evidence development—to allow approvals in more common diseases where traditional studies are both feasible and necessary to ensure clinical benefit. We also worried that the framework might be used to approve products even if they fail to demonstrate clear improvement in clinical outcomes, given pressures often arising in the context of treatments for rare, life-threatening conditions. The draft guidance does not resolve these ambiguities and concerns and should be more explicit.

In addition to its title focused on individualized therapies, the draft includes several statements suggesting the framework indeed will be limited to n-of-1 and n-of-few disorders. For example, it directs sponsors to demonstrate that “the targeted genetic variant(s) are unique to the patient(s), including prevalence estimates in the disease population and projected incidence in new cases based on molecular genetic characteristics.” It describes the guidance as applying “when clinical evidence from a limited number of patients will be available to support the individualized product’s safety or efficacy in the intended patient population.” And it calls on sponsors to justify the clinical study design, “including a discussion of why it is not feasible to conduct a randomized controlled trial.” These are all appropriate limitations.

However, the NEJM article suggested that the plausible mechanism “pathway” would be “also available for common diseases” with unmet need. More recently, during the February 23, 2026, public event in which the draft guidance was announced, then-acting director of FDA’s Center for Drug Evaluation and Research (CDER), Tracy Beth Høeg, stated that “when we were writing the draft guidance, we were very careful to leave it open-ended, to not limit this to ultra-rare diseases.” She added that “this could really apply to any diseases, even common, if they meet the criteria for the plausible mechanism pathway.” Then on April 15, Dr. Buracchio confirmed that although the framework was designed to help advance individualized therapies, its concepts could apply more broadly: “‘Plausible mechanism framework’ and ‘individualized therapies’ are not interchangeable.” Dr. Buracchio went on to explain that although this draft guidance is specific to individualized therapies, “you might be able to use the principles of the plausible mechanism framework to approve other therapies.”

Applying the framework to the development of individualized therapies for unique, rare genetic variants arising within more common genetic diseases, such as an n-of-few variant associated with phenylketonuria (PKU) or cystic fibrosis, is clearly aligned with the problem the framework is designed to solve. More detail is needed to determine whether the framework could reasonably fit non-individualized genetic interventions for diseases that could not otherwise be feasibly studied. However, applying the framework broadly—to non-individualized therapies for more common diseases that could be feasibly studied through a traditional trial—would be concerning and should be avoided. In these cases, a traditional prospective trial is necessary to address the problem that even plausible mechanisms of action can fail to predict clinical benefit; when available, evidence-based medicine adds critical value to mechanism-based medicine. Thus, FDA should restrict application of the plausible mechanism framework to circumstances when a traditional trial is infeasible, due to individualization of the therapy or otherwise.

It is appropriate to expect sponsors seeking to use the plausible mechanism framework to explain why they are unable to conduct a randomized controlled trial (as the current draft guidance does and which will be obvious for individualized therapies). But RCTs are not the only type of trial that could be superior to the highly limited evidence generation that can be expected under the plausible mechanism approach. When disease presentation is relatively homogeneous, the natural history is clear, and an intervention’s effect size is expected to be substantial, a prospective single-arm study may suffice to demonstrate benefit without randomization. Such trials are already commonly used to support marketing approval in other contexts, such as oncology and rare diseases. Thus, sponsors pursuing the plausible mechanism framework should also be expected to explain why it would be infeasible to conduct any traditional prospective study.

Meanwhile, FDA—through advisory committees, public meetings, workshops, and additional guidance—should further clarify when traditional prospective studies will be considered infeasible in rare disease, as well as acceptable alternatives to randomized controlled designs and when these would apply. Imposing these narrower constraints will help ensure that the plausible mechanism framework is limited to circumstances where products would not otherwise come to market. It should not lower the baseline of evidence expected for products that could otherwise be required to meet current standards. 

Finally, given the limited evidence that will be available for products developed under the plausible mechanism framework, it is critical that FDA maintain a strong standard for demonstrated improvement in clinical outcomes or course, one of the five elements listed as central to the framework. The draft guidance indicates that “investigation results should be robust” but does not further explain what type of outcomes would be insufficient, how the agency would respond to ambiguous or negative outcomes, and what would constitute robustness. We recognize that guidance documents cannot predict every scenario and that some flexibility will be important. However, further discussion of FDA’s thinking on effectiveness would be useful, including examples of what outcomes would or would not be approvable under the framework.

Ultimately, clarifying the framework’s scope will be essential, especially as many of the public comments submitted on the draft guidance called for an expanded scope due to concern about disease urgency and trial difficulty, in contrast to the points expressed above. In part two tomorrow, we will discuss additional areas FDA should consider in its final guidance to promote the utility of the plausible mechanism framework in those cases when it is truly the only pathway to approval.

Part 2: Manufacturing Challenges, Product Scope, And Post-Approval Considerations

The Food and Drug Administration (FDA) is working to adapt its regulatory approval process to account for scientific advances in treating patients with n-of-1 or n-of-few genetic disorders. Recently FDA published draft guidance explaining a new approval framework for individualized genetic therapies based on a “plausible mechanism” of action. This followed a commentary penned by FDA leaders in The New England Journal of Medicine (NEJM) that first proposed the plausible mechanism concept. In an earlier two-part article in Health Affairs Forefront, we praised the proposal’s potential to address critical problems impeding the development of these therapies. But we also raised questions about how the approach would work in practice, flagged concerns about scope, and noted troubling transparency and procedural gaps in how the pathway had been announced, ultimately calling for the agency to use its guidance process to allow for public comment and clarification.

In this new two-part article, we analyze the draft guidance and propose ways it could be improved when finalized, drawing on our public comments to FDA. In part one yesterday, we provided background on the development of individualized genetic therapies, described key elements of the draft guidance and examined the appropriate scope of a plausible mechanism approach. In part two below, we set forth further proposals for improving and clarifying FDA’s plausible mechanism framework. A summary table of recommended revisions for the final guidance is provided in exhibit 1 at the end of this post.

Additional Issues to Clarify In The Final Guidance

Manufacturing Challenges

Baby KJ’s case, involving development of a personalized gene editor at an academic medical center, spurred the plausible mechanism framework. One goal is for the framework to render development of individualized therapies viable for industry sponsors. But academic researchers and patient communities also hope it will allow academic sponsors to secure approval for n-of-1 or n-of-few genetic interventions on their own, given the unlikelihood of finding a commercial sponsor for all conditions. However, considering the draft guidance’s stated expectations regarding manufacturing standards, Rebecca Ahrens-Nicklas and Kiran Musunuru have expressed that, in practice, the plausible mechanism framework may exclude academic developers and be available only to well-established gene editing companies.

This is a difficult problem. For example, Musunuru acknowledged that the manufacturing standards applicable to Baby KJ’s treatment, which was provided via FDA’s Expanded Access pathway, would not satisfy the draft guidance’s expectations. He went on to ask, “If an academic group can show in a Phase 1 context that individualized therapies are safe, and, importantly, *effective*—would you really want to argue to patients and families that they can’t have access to the therapies just because they aren’t manufactured to super-stringent standards?”

FDA’s manufacturing standards are intended to ensure that products can be manufactured safely and consistently, including to protect study participants and to ensure safety, quality, and effectiveness for patients after approval. As noted in part one, FDA has taken recent steps to increase flexibility in manufacturing requirements applicable to cell and gene therapies to lower their intensity in early-stage development, while increasing intensity as the product continues through the phases of testing leading to approval. That staged approach cannot work, however, when the first-in-human study is also the pivotal study supporting approval, as envisioned under the plausible mechanism framework for individualized therapies.

The problem is not necessarily that academic developers will never be able to meet the Chemistry, Manufacturing, and Controls (CMC) standards applicable to approved products. Instead, it is that in many cases they will not be able to initiate the research needed to get to approval under the plausible mechanism framework if they must meet commercialization-level standards from the start of the research or very soon thereafter. The cost of doing so will typically be too high without an industry partner, which may not be available.

Grant or other funding, such as public-private partnerships, to support academic developers of n-of-1 or n-of-few therapies where industry engagement is not otherwise forthcoming might help in some cases and should be encouraged. But it is unlikely to be available or sufficient for all cases. Among other reasons, the costs of achieving full CMC may substantially exceed typical grant levels, grant timelines will impede timely research initiation delaying start dates beyond the point of scientific readiness, and grants likely will not be forthcoming for all disease areas that could benefit from individualized therapies. Current shifts in the federal funding landscape have made grants even more difficult to secure.

It is not clear how best to address this challenge, considering the importance of both access to effective therapies and confidence in their quality—as well as the need to avoid establishing a precedent of lowering CMC expectations that could extend beyond the plausible mechanism framework and to commercial sponsors. Yet the framework’s impact will be limited if its demands exceed the capacity of academic researchers developing n-of-1 or n-of-few interventions. FDA should recognize the potential harms of relegating academic developers exclusively to the unreimbursable use of the Expanded Access pathway or perpetual Investigational New Drug-status for individualized therapies, which will not be practicable, sustainable, or promote the ultimate goal of access for patients.

To address this dilemma, academic centers will likely need to work toward improved manufacturing capacity while FDA considers whether appropriate and limited manufacturing flexibilities for academic developers might exist. To better understand these challenges and possible solutions, stakeholders and officials should consider public engagement, including an advisory committee or other public meeting.

Finally, since the draft guidance contemplates allowing data to be leveraged across development programs, including for CMC purposes, it will be important to find ways to encourage or require sponsors using the framework to share data, manufacturing processes, validated assays, and the like once CMC standards have been met for a product or platform. Although CMC challenges will remain for the first individualized product developed for a given disease, these collaborative steps may minimize the need for continued CMC flexibilities as the field develops.

Approval Reach

Beyond manufacturing concerns, there are questions about the scope of the product that will be approved under the plausible mechanism framework. Neither the NEJM article nor the draft guidance explicitly defines the precise parameters of the product that will be granted approval for individualized use across patients with related conditions. Through examples in the draft guidance, it appears that FDA envisions that the approved product eventually could include all pathogenic variants of a particular gene, so long as the method of correction is the same across variants. Critically, however, it does not appear that FDA plans to issue such expansive approval from the start. Instead, the draft guidance mentions adding variants that were “not included in the clinical trial used to support the original approval,” suggesting that these would be subsequent additions.

This interpretation is further supported by the fact that the draft guidance indicates sponsors will need to return to FDA after approval for each patient with a new variant:

“To add a product variant that targets a mutation that has not been evaluated in the clinical trial to the BLA, in vitro activity data should be provided for the specific product variant to support editing activity at the target site, and an off-target editing activity assessment should be performed to support safety” (emphasis added).

As stated, the draft guidance requests only in vitro data to support these additions, a relatively light standard compared to the comprehensive package needed to support initial approval. Nonetheless, this is a more substantial requirement than another conceivable alternative in which FDA might grant approval up front to include all related, future modifications for pathogenic variants of the same gene. Indeed, by requiring submission of new data for each new patient, the draft guidance takes the plausible mechanism framework further from the sort of “process approval” currently under consideration in the United Kingdom and that may be important to scaling the approach to more patients.

Given that the product “backbone” can remain the same across individual patient variants, FDA should consider applying flexibility regarding the timing of data submission on new variants, the type of submission, and the type of review conducted by FDA—all while recognizing the importance of developers pre-testing relevant changes to the approved product to make sure it will retain safety and effectiveness for new patients.

At present, it is not clear how the draft guidance contemplates the requested in vitro data being provided to support each new variant after approval. Will sponsors be expected to submit supplemental applications to FDA for pre-approval or will a less formal clearance or notification approach suffice?

Notice to FDA, alongside data submission, could perhaps be treated as a condition of enforcement discretion in these cases. However, if pre-approval is required, it is essential to clarify how rapidly FDA will be able to review and greenlight (or hold) the anticipated modification. Will agency reviewers be able to respond quickly enough to meet patient treatment needs, especially given agency staffing shortages and anticipated growth in these submissions, or will they become a problematic bottleneck? An alternative possibility might be for FDA to prespecify in vitro assays that must be performed before intervention on a patient presenting with a new variant, without requiring pre-submission or pre-approval by FDA, perhaps with annual or more frequent public reporting requirements of these changes.

Relatedly, it might be feasible to credential treatment sites to follow a prespecified process for adding patients with new variants or to follow a process analogous to predetermined change control plans for medical devices in which such plans are part of the product’s marketing authorization. Both options would likely require statutory authority from Congress, beyond FDA’s authority to pursue in guidance, but should be considered.

It is essential for developers to test the changes made to individualize an approved therapy. The question is only how to avoid approaches to overseeing that testing that will unduly inhibit patient access to products approved under the plausible mechanism framework. Overall, we agree with former FDA commissioner Scott Gottlieb and his coauthor, former director of CDER’s Office of New Drug Policy Maarika Kimbrell, that FDA should “define all the regulatory boundaries for grouping multiple genetic variants under a single approval” and help “show scientists where adaptation is permitted and where it begins to alter the identity of the product.”

We note that it is also important to clarify the scope of approval to clarify associated exclusivities for individualized therapies approved under the plausible mechanism framework, with potentially substantial implications for patients with different variants to access care across centers.

Post-Approval Considerations

The amount of evidence available to support product approval under the plausible mechanism framework will inevitably be far slimmer than that available for traditional approvals. This makes post-market evidence generation even more important. Yet the draft guidance simply states that “FDA will likely require a PMR [postmarketing requirement] or issue a PMC [postmarketing commitment] to provide additional safety information” (emphasis added) and notes that efficacy PMRs will be issued for products granted accelerated approval, as is typical.

FDA should impose substantial and consistent requirements for postmarketing safety and effectiveness assessments for all products approved under the plausible mechanism framework. It should also clarify how existing guidance regarding long-term follow-up after administration of human gene therapy products will apply. PMRs—not only PMCs, which lack the same enforcement authority—should be expected for safety and effectiveness, regardless of whether the product is granted regular or accelerated approval under the framework. Ideally, PMRs would include patient registries with minimum, standardized datasets for collection, although this would necessitate collaboration and funding that may be beyond FDA’s reach.

Even if post-approval data collection is not carried out under PMRs, FDA should “establish criteria for standardized, long-term follow-up registries across related therapies,” as Gottlieb and Kimbrell suggest. Such a registry might be modeled on the Stem Cell Therapeutic Outcomes Database, managed by the Center for International Blood and Marrow Transplant Research, which collects, analyzes, and reports data on all allogeneic hematopoietic stem cell transplants performed in the US. Notably, FDA often imposes PMRs and PMCs to study approved products in extended populations beyond those included in pivotal trials; in addition to PMRs focused on the already-approved product, then, this could be another approach to gathering data on product modifications to address new patient variants without requiring pre-approval, as discussed above.

An additional post-approval consideration is how FDA will manage accelerated approvals of individualized therapies under the plausible mechanism framework. Following the current recommendation for FDA-approved drugs and biologics, the draft guidance states that confirmatory studies generally should be underway before accelerated approval. However, it does not explain what a confirmatory study will look like in n-of-1 or n-of-few circumstances, nor how it could be initiated before approval.

Finally, the draft guidance fails to address a critical challenge: If a patient receiving an individualized therapy approved under the plausible mechanism framework experiences a serious adverse event, how will that influence subsequent treatment of patients with the same or similar product? The draft guidance states that FDA will “closely monitor reports of adverse events from the trial and any signals of unexpected or delayed adverse events in the post-market setting” and investigate safety signals “to determine if any action is warranted.” Of course, it is impossible to predict the appropriate response in advance outside the specific context of any given safety concern. However, it would be helpful to understand FDA’s thinking on what types of adverse events could lead to safety actions across products customized to specific variants on a given gene or across related genes affecting the same phenotype. FDA should also make safety investigations publicly available and clarify how it resolves safety signals.

Further Considerations

FDA’s view seems to be that creating the plausible mechanism framework does not require statutory amendment, given the draft guidance’s position that approved products will need to satisfy existing requirements for safety and effectiveness through adequate and well-controlled clinical investigations. Nonetheless, statutory amendment could support the framework. For example, statutory reforms could provide explicit authority for FDA to require post-approval registries or data sharing across development programs. Moreover, although guidance is preferable to regulating via journal article, notice-and-comment rulemaking for a program this substantial would be better. Regulations can impose legally binding requirements that guidance generally cannot and offer more certainty for developers about the permanence of this framework. Accordingly, while the final guidance, when issued, will reflect an important step, both regulatory and statutory change should also be considered.

As described in part one of this review, we recommend that the final guidance clearly limit the plausible mechanism framework to products that could not otherwise be developed for marketing approval. We also recommend, as set forth above, that it:

• recognize and, if possible, address manufacturing challenges facing academic developers of individualized therapies;
• clarify the scope of the product granted approval and how changes can be made for future variants; and
• strengthen postmarketing requirements.

In addition, FDA should promote transparency in how it implements the framework, for example, committing to public reporting regarding products approved under this approach, for which disorders, and why they were unable to be studied using traditional clinical investigations. Given various statements about how the framework will apply beyond individualized therapies, FDA should commit to offering further guidance on the framework as soon as possible, expressly limiting its application to treatments that could not otherwise be developed.

Finally, we encourage FDA to ensure that it has sufficient staff capacity to support the framework, especially given the extent to which the draft guidance encourages sponsors to engage FDA in the design and progress of their development programs and calls for substantial continuing FDA oversight of individualized product variants. Patients and developers alike should recognize that the promise of this framework depends on recovery from the recent decimation of FDA’s workforce.

Overall, we hope that FDA’s flexible approach to supporting the development of individualized therapeutics, with the refinements described in these two articles, will spur treatments that can reach many more patients like Baby KJ and Mila Makovec.

Exhibit 1. Recommended Revisions For The Final Guidance

Domain	Revision
Scope constraints	Clarify that the plausible mechanism framework is not available to products intended to treat common diseases/conditions that reasonably could be subjected to traditional prospective investigation. Add an expectation for sponsors to describe why it is infeasible to conduct any appropriate traditional prospective investigation (not only a randomized controlled trial), such that the plausible mechanism framework offers the exclusive pathway to approval. These explanations should be shared publicly as part of FDA’s commitment to transparency. With the input of advisory committees, clarify when traditional prospective investigations will be considered infeasible in rare disease. Provide further discussion of what FDA means by “robust” results under the plausible mechanism framework and how FDA will respond to results that fall short of that threshold.
Manufacturing challenges	Consider whether appropriate adjustments both exist and can be made to allow academic developers of individualized therapies to feasibly meet manufacturing standards during research studies needed to secure approval under the plausible mechanism framework. To inform the agency’s consideration, FDA should solicit public input, through an advisory committee or other public meeting, on the CMC challenges facing academic developers of individualized therapies and possible solutions that could be applied under the plausible mechanism framework. Work with HHS and other partners to consider how resources could be provided to support academic developers in meeting CMC standards under the plausible mechanism framework. Evaluate approaches to encourage or require sponsors using the plausible mechanism framework to share data, processes, validated assays, and the like to minimize future challenges meeting manufacturing standards.
Approval reach	Explicitly define the product and state the scope of approval granted under the plausible mechanism framework when applied to individualized therapies, as well as how exclusivities will apply to the product and its associated variants. Clarify appropriate tests that should be conducted prior to using the approved individualized therapy to treat a patient with a new genetic variant. Consider whether alternatives to pre-submission and/or pre-approval could be appropriate for oversight of further individualization of products approved under the plausible mechanism framework, such as clearance, notification, reporting, and prespecified tests or processes included in the marketing authorization. If information must be provided to FDA before adding a new product variant after approval under the plausible mechanism framework, clarify how that information will be handled (e.g., preapproval, notification, etc.) and on what anticipated turn-around time from FDA. Require public transparency when new variants are added to approved individualized therapies under the plausible mechanism framework.
Post-approval considerations	State an expectation that all products approved under the plausible mechanism framework, whether through regular or accelerated approval, will have postmarketing requirements (PMRs) for both safety and effectiveness. Clarify what type of long-term follow-up will be expected for gene therapies approved under the plausible mechanism framework. Describe expectations for patient registries, including as PMRs, for products approved under the plausible mechanism framework. In addition to PMRs for the initially approved product, explain whether and how PMRs may be used to extend products approved under the plausible mechanism framework to new patient variants. Clarify the expectations for confirmatory studies when an individualized therapy receives accelerated approval under the plausible mechanism framework. Describe in more detail how safety concerns presenting for products approved under the plausible mechanism framework may affect other related products and commit to sharing safety investigations publicly.

Source: Authors’ analysis

Authors’ Note

Fernandez Lynch, Ramachandran, Sachs, and Zettler report funding from Arnold Ventures outside the present work. Fernandez Lynch and Ramachandran report research funding from the Greenwall Foundation, and Fernandez Lynch, Ramachandran, Joffe, and Zettler report research funding from NIH, also all outside the present work. Ramachandran receives personal fees from The Roosevelt Institute and Debevoise & Plimpton, LLP, outside the present work, and serves on the Board of Directors for Doctors for America as an unpaid volunteer. Zettler reports serving as Deputy General Counsel to the U.S. Department of Health & Human Services (HHS) from November 2023 to January 2025, and conducting an external review of opioid analgesics regulation from September 2022 to January 2023 for FDA. Sachs reports serving as a Senior Advisor to the U.S. Department of Health & Human Services Office of the General Counsel, Centers for Medicare & Medicaid Services Division, from April 2023 to April 2024. Fernandez Lynch and Joffe have collaborated with Rebecca Ahrens-Nicklas and Kiran Musunuru on grant proposals relevant to ethical and regulatory considerations arising in their work on individualized therapeutics. We thank Drs. Ahrens-Nicklas and Musunuru for providing background relevant to several points raised in this article. The conclusions and recommendations we offer are ours alone and should not be attributed to others.

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