FDA proposes new pathway to approve one-patient gene-editing drugs for ultra-rare diseases

On a winter morning in Philadelphia last year, a toddler named KJ lay in an operating room as surgeons infused a gene-editing drug that existed only for him.

Born with a genetic defect that left his liver unable to clear ammonia from his blood, the boy faced a near-certain death without intervention. Doctors at Children’s Hospital of Philadelphia and the University of Pennsylvania rushed to design a bespoke CRISPR-based treatment matched to his exact mutation, moving from concept to first-in-human use in under a year. There was no traditional clinical trial to join; KJ was, effectively, the entire study.

Until now, the federal rules for evaluating that kind of one-patient medicine have been improvised case by case. On Feb. 23, the Food and Drug Administration proposed a new framework that would make such ultra-tailored therapies part of the formal drug-approval system.

A new framework for individualized therapies

In a draft guidance released that day, the agency laid out what it calls the “Plausible Mechanism Framework”—a policy that could allow individualized genome-editing and RNA-based treatments for ultra-rare genetic diseases to win approval based largely on a clear biological rationale, detailed natural history of the disease, and data from very small numbers of patients.

The move is the clearest signal yet that U.S. drug regulators are preparing for a world in which some medicines may be designed for a handful of people, or even for a single child.

The 51-page guidance, issued jointly by the FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research, describes how drugmakers can generate “substantial evidence of effectiveness and evidence of safety” when randomized controlled trials are “not feasible” because too few patients exist.

“For the purposes of this guidance, individualized therapies are considered therapies that target a specific pathophysiologic abnormality serving as the root cause of a disease,” the document states, citing examples such as specific pathogenic genetic variants that cause “severely debilitating or life-threatening” conditions in very small populations.

The guidance does not create a new legal category of “ultra-rare” disease or define it numerically. Instead, officials use the term descriptively, to capture situations where a clinically defined condition and its targetable genetic variant are so uncommon that enrolling enough patients for a conventional trial is unrealistic. In some cases, the total number of eligible patients worldwide may be counted on one hand.

Federal officials pitch faster access

In a news release announcing the policy, HHS Secretary Robert F. Kennedy Jr. linked the initiative to campaign promises from President Donald Trump.

“President Trump promised to accelerate cures for American families—and we are delivering, especially for children with ultra-rare diseases who cannot afford to wait,” Kennedy said. “We are cutting unnecessary red tape, aligning regulation with modern biology, and clearing a path for breakthrough treatments to reach the patients who need them most.”

FDA Commissioner Marty Makary, a surgeon and health policy researcher, framed the move as an attempt to tailor the system to a group of patients long left behind.

“This guidance is a critical step the FDA is taking to tailor our regulatory approach to patients with ultra-rare conditions,” Makary said in the release. “It is our priority to remove barriers and exercise regulatory flexibility to encourage scientific advances and deliver more cures and meaningful treatments for patients suffering from rare diseases.”

What counts as evidence when trials aren’t feasible

Under the new framework, regulators say they anticipate that, for individualized therapies, the standard requirement of “substantial evidence” of effectiveness can generally be met with “a single adequate and well-controlled clinical investigation with confirmatory evidence,” rather than two large pivotal trials.

Confirmatory evidence, in this context, may include laboratory and imaging data showing that the drug hits its intended molecular target, exposure–response relationships on biomarkers, and robust comparisons between treated patients and historical or registry data on how the disease typically progresses without treatment.

Central to the framework are five elements the FDA says sponsors should demonstrate:

• A specific genetic, cellular or molecular abnormality that clearly causes the disease.
• A therapy that directly targets that abnormality or its proximate biological pathway.
• A well-characterized natural history of the untreated disease.
• Confirmation that the target has been successfully “drugged” or edited.
• Evidence of improvement in clinical outcomes, disease course or validated biomarkers that cannot be reasonably explained by chance or typical variability.

Because randomized controlled trials will often be impossible, the agency signals it is prepared to accept externally controlled studies, in which each patient’s post-treatment course is compared to their own pre-treatment baseline and to natural-history data from similar, untreated patients.

In practice, that means a dramatic improvement in a child expected, based on prior data, to decline rapidly might count as persuasive evidence—if other explanations, such as concurrent therapies, can be ruled out.

Why CRISPR and RNA drugs are central

The guidance is explicitly focused on genome-editing products and RNA-based drugs such as antisense oligonucleotides, though regulators note that the conceptual framework could apply more broadly to any therapy that directly addresses a known biological cause. It builds on earlier, narrower policies the agency issued in 2021 on “N-of-1” antisense drugs for individual patients.

One reason gene-editing and RNA medicines are central to the policy is their modular design. The same CRISPR enzyme or delivery vehicle can often be paired with different guide RNAs to target distinct mutations in the same gene. Similarly, antisense platforms can be adapted by changing the nucleotide sequence while keeping the chemical backbone constant.

The FDA guidance envisions that such “product variants” may be developed and evaluated together under a single investigational application or biologics license, with deep data on a core set of variants supporting the addition of new ones with more limited incremental testing.

“The Plausible Mechanism draft guidance creates a novel framework through which cutting-edge treatments tailor-made for patients with ultra-rare diseases can be used as a basis for FDA approval,” Acting CDER Director Tracy Beth Høeg said in the agency statement. “We anticipate our Plausible Mechanism draft guidance will inspire industry to place increased focus on individualized therapies, thereby driving innovation, improving safety, lowering costs and offering more patients with ultra-rare diseases a unique shot at a life-saving treatment.”

Scientists working in gene editing say the policy could reshape their field. Fyodor Urnov, a genome-editing researcher at the University of California, Berkeley, described it as “the best imaginable ‘ready, set, go!’ for the field of personalized gene editing as a therapy” in an interview with NPR, adding that under the new framework, “a disease with 100 causing mutations will no longer require 100 clinical trials.”

Supporters in the rare-disease community, who have long argued that traditional trial paradigms make it impossible to develop drugs for their conditions, welcomed the guidance as a long-awaited signal that regulators are willing to adapt.

Cautions: safety, standards, and access

Legal and policy analysts note that the agency is not creating a new statutory pathway. Instead, it is clarifying how existing authorities under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act can be applied flexibly in extreme small-population settings. Approvals would still proceed through traditional or accelerated approval pathways, depending on whether outcomes or surrogate endpoints are used.

At the same time, ethicists and some health law experts are urging caution. They point out that safety databases for individual or near-individual therapies will necessarily be tiny, especially for first-in-human genome-editing interventions in children. Long-term risks, including off-target effects and late-emerging toxicities, may only become apparent years after a product is used.

Some observers also worry about “regulatory creep”—the possibility that mechanisms designed for situations where randomized trials are impossible could be pushed into areas where such trials remain feasible but costly, effectively lowering evidentiary standards in broader drug markets.

Makary and Vinay Prasad, the FDA’s chief medical and scientific officer and director of CBER, have argued in medical journals that the new approach is grounded in modern mechanistic science and that guardrails will be needed to ensure it remains focused on genuinely infeasible trial settings.

Beyond scientific questions, the framework raises practical issues about cost and access. Many individualized gene therapies are likely to cost at least several hundred thousand dollars per patient, and in some cases more than $1 million, reflecting their complexity and extremely small markets. Insurers and government payers have yet to spell out how they will cover such treatments, especially when long-term benefit is uncertain at the time of approval.

Analysts expect insurers to demand strict prior authorization, outcomes-based payment agreements, and mandatory participation in post-treatment registries as conditions of coverage. Without clear reimbursement paths, some experts say, the therapies that meet the new regulatory criteria may still remain out of reach for most patients.

There are also concerns about equity. Access to individualized therapies often depends on early and comprehensive genetic testing, proximity to specialized academic centers capable of designing and manufacturing bespoke drugs, and the ability of families to navigate complex research and regulatory processes. Advocates worry that, without deliberate policies on outreach and funding, the benefits of the new framework could accrue disproportionately to families with resources and connections.

What happens next

The FDA is accepting public comments on the draft guidance through April 27, under docket number FDA-2026-D-1256. Agency officials say they expect extensive input from drugmakers, clinicians, patient groups, payers and ethicists before issuing a final version.

As children like KJ grow, their progress will provide some of the earliest real-world tests of the FDA’s evolving approach. For families facing a diagnosis that may apply to only one or two people on the planet, the question now is whether the Plausible Mechanism Framework can turn one-off rescues into a consistent—if still extraordinary—pathway, and how far regulators will ultimately allow that pathway to reach.