FDA creates new approval pathway for gene therapies tailored to individual rare disease patients

Overview

For decades, the Food and Drug Administration (FDA) required the same basic proof for every drug: show it works in a controlled trial with enough patients to be statistically meaningful. That standard made sense for common diseases but created an impossible barrier for conditions affecting a handful of people worldwide. On February 23, 2026, the FDA issued draft guidance creating a fundamentally different standard—called the "plausible mechanism" framework—that would let developers of individualized gene-editing and ribonucleic acid (RNA) therapies win full approval by demonstrating their treatment targets the root genetic cause, successfully edits or engages the target, and improves outcomes compared to the disease's documented natural course.

In This Story

3 Videos

4 People

3 Orgs

Framework finalized, first wave of individualized therapies approved within two years

3 Context

Orphan Drug Act (1983)

Key Indicators

7,000+

Known rare diseases

Roughly 7,000 rare diseases have been identified, approximately 80% of which are genetic in origin

300M

People affected globally

An estimated 300 million people worldwide live with a rare disease

~5%

Diseases with approved treatments

Fewer than 5% of known rare diseases have an FDA-approved therapy

60 days

Public comment period

The draft guidance is open for public comment before potential finalization

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Debate Arena

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People Involved

Marty Makary

FDA Commissioner (In office; co-architect of the plausible mechanism pathway)

Vinay Prasad

Director, Center for Biologics Evaluation and Research (CBER) (Returned to CBER director role after brief departure in mid-2025)

Tracy Beth Høeg

Acting Director, Center for Drug Evaluation and Research (CDER) (Leading CDER's role in the new framework)

Timothy Yu

Neurologist, Boston Children's Hospital (Pioneer of individualized antisense oligonucleotide therapies)

Organizations Involved

U.S. Food and Drug Administration

Federal Regulatory Agency

Status: Issued draft guidance creating the plausible mechanism framework

The United States agency responsible for approving drugs, biologics, and medical devices for public use.

N=1 Collaborative

Nonprofit Research Organization

Status: Coordinating platform for individualized therapy development

An international network of researchers, clinicians, and patient advocates working to build scalable pathways for individualized genetic medicines.

Children's Hospital of Philadelphia

Academic Medical Center

Status: Site of the first personalized CRISPR therapy for Baby KJ

The pediatric hospital where researchers designed and delivered the first individualized CRISPR base-editing therapy, treating Baby KJ for a fatal urea cycle disorder in early 2025.

Timeline

FDA issues draft guidance for individualized therapy framework
Regulatory

The FDA released the formal draft guidance creating the plausible mechanism pathway, allowing developers of individualized gene-editing and RNA therapies for ultra-rare diseases to seek full approval using mechanistic rationale and natural history comparisons rather than traditional clinical trials.
5 days ago
Makary and Prasad publish plausible mechanism concept in NEJM
Publication

FDA Commissioner Makary and CBER Director Prasad outlined the plausible mechanism pathway in the New England Journal of Medicine, citing Baby KJ as the model for the kind of individualized therapies the framework would enable.
November 12th, 2025
FDA introduces Rare Disease Evidence Principles
Regulatory

The FDA established new evidence standards for ultra-rare diseases affecting fewer than 1,000 Americans, allowing approval based on a single pivotal trial combined with mechanistic or biomarker evidence.
September 3rd, 2025
Baby KJ receives first personalized CRISPR therapy
Medical Milestone

An infant with CPS1 deficiency—a fatal urea cycle disorder—received a custom CRISPR base-editing therapy at Children's Hospital of Philadelphia, becoming the first patient treated with a bespoke gene-editing drug.
February 25th, 2025
FDA announces Rare Disease Innovation Hub
Regulatory

The FDA created a cross-agency hub to coordinate expertise between its drug and biologics centers, with particular focus on treatments for small patient populations where natural history data is limited.
July 1st, 2024
Milasen results published in the New England Journal of Medicine
Publication

Yu's team published the first peer-reviewed account of a patient-customized antisense therapy, establishing a precedent that would inform future n-of-1 treatment protocols.
October 9th, 2019
Milasen: first individualized antisense drug administered
Medical Milestone

Timothy Yu's team at Boston Children's Hospital began treating Mila Makovec, a six-year-old with fatal Batten disease, with a custom antisense oligonucleotide designed in under a year. The case proved individualized genetic therapy was feasible.
January 1st, 2018
Orphan Drug Act becomes law
Legislation

President Reagan signed the Orphan Drug Act, offering tax credits, market exclusivity, and grants to incentivize development of drugs for diseases affecting fewer than 200,000 Americans. Before the law, only 38 drugs existed for rare diseases.
January 4th, 1983

Scenarios

Framework finalized, first wave of individualized therapies approved within two years

Discussed by: STAT News, BioSpace, and biotech investors including Menlo Ventures (which invested in Aurora Therapeutics, a company founded by CRISPR co-inventor Jennifer Doudna to scale Baby KJ-style treatments)

After the 60-day comment period, the FDA finalizes the guidance with minor revisions and begins accepting applications under the plausible mechanism pathway. Several academic medical centers and biotechs that have been developing individualized antisense oligonucleotides and base-editing therapies submit applications for conditions where the scientific groundwork is already established. The first approvals under the new framework arrive by late 2027 or early 2028, establishing precedent and attracting further investment. This scenario depends on industry readiness and the FDA processing applications efficiently despite limited staffing for individualized review.

Comment period reveals safety concerns, guidance significantly revised or delayed

Discussed by: Ropes & Gray LLP legal analysis, bioethicists, and some rare disease advocacy groups with safety-focused mandates

Public comments raise substantive concerns about long-term safety monitoring, informed consent for n-of-1 treatments, and the adequacy of natural history data as a comparator. Critics argue the framework could lower the evidence bar below what is needed to ensure treatments do not cause harm, particularly for pediatric patients. The FDA substantially revises the guidance, adding more stringent post-approval monitoring requirements and narrowing eligibility criteria. Final guidance is delayed into 2027, slowing the pathway's impact but potentially strengthening its durability.

Framework sparks global regulatory convergence on individualized therapies

Discussed by: UK Medicines and Healthcare products Regulatory Agency (MHRA), Ropes & Gray comparative analysis of US/UK/EU approaches, and the N=1 Collaborative

The FDA guidance accelerates parallel efforts already underway at the UK's MHRA, which has been developing its own framework for individualized therapies, and prompts the European Medicines Agency to formalize a similar pathway. International coordination reduces redundant regulatory requirements, making it feasible for developers to treat patients across borders with a single regulatory submission. Mutual recognition of safety data and shared post-market surveillance lower costs and speed access for patients outside the United States.

Cost and manufacturing barriers prevent broad patient access despite regulatory pathway

Discussed by: Health economists, the Commonwealth Fund, and rare disease patient advocates at the National Organization for Rare Disorders (NORD)

The regulatory framework works as designed, but the economics of individualized therapy remain prohibitive. Each bespoke treatment requires custom design, manufacturing, and quality testing for a single patient, with costs potentially reaching hundreds of thousands to millions of dollars per treatment. Without a reimbursement model that accounts for these costs, insurers and health systems resist coverage. The pathway exists on paper but benefits primarily patients at well-resourced academic centers, creating an access gap between those who can navigate the system and those who cannot.

Historical Context

Orphan Drug Act (1983)

January 1983

What Happened

Before 1983, pharmaceutical companies had little financial incentive to develop drugs for diseases affecting small populations—only 38 such drugs existed in the United States. Congressman Henry Waxman shepherded the Orphan Drug Act through Congress, and President Reagan signed it on January 4, 1983, creating tax credits, seven-year market exclusivity, and development grants for drugs targeting diseases affecting fewer than 200,000 Americans.

Outcome

Short Term

Drug development for rare diseases began immediately. Within a decade, the FDA had granted hundreds of orphan drug designations.

Long Term

Over four decades, the FDA granted more than 6,300 orphan drug designations and approved treatments covering nearly 400 rare diseases. Japan and the European Union adopted similar laws in 1993 and 2000.

Why It's Relevant Today

The Orphan Drug Act proved that regulatory incentives could redirect pharmaceutical investment toward neglected diseases. The plausible mechanism framework tackles the next barrier the 1983 law could not solve: what happens when the patient population is too small for even a modified clinical trial.

Milasen and the birth of n-of-1 genetic therapy (2018)

January 2017 – October 2019

What Happened

Neurologist Timothy Yu at Boston Children's Hospital saw a Facebook post about Mila Makovec, a six-year-old girl in Colorado dying of Batten disease caused by a unique genetic mutation. In ten months, his team identified the mutation, designed a custom antisense oligonucleotide to bypass it, manufactured the drug, obtained FDA authorization, and began treatment—all for a single patient. The drug, named milasen, reduced Mila's seizures.

Outcome

Short Term

Mila's seizures decreased. The case, published in the New England Journal of Medicine in October 2019, demonstrated that individualized genetic therapy could move from diagnosis to treatment in under a year.

Long Term

Mila died in February 2021 at age ten, but her case opened the door for more than 85 additional patients to receive individualized antisense therapies and led to creation of the N=1 Collaborative, a network coordinating the field.

Why It's Relevant Today

Milasen proved the scientific concept but exposed the regulatory gap: each individualized treatment required ad hoc FDA authorization because no formal approval pathway existed. The plausible mechanism framework directly addresses this gap.

Accelerated approval pathway established (1992)

1992

What Happened

Amid the AIDS crisis, the FDA created the accelerated approval pathway allowing drugs to reach market based on surrogate endpoints—laboratory markers reasonably likely to predict clinical benefit—rather than waiting for definitive outcome data. The pathway was formalized under regulations that required post-approval confirmatory trials.

Outcome

Short Term

Multiple HIV/AIDS drugs reached patients years earlier than traditional approval would have allowed, materially changing survival rates.

Long Term

Accelerated approval became a standard tool for cancer drugs, rare diseases, and other conditions with unmet need. The pathway has been used for more than 300 approvals, though it also generated debate about confirmatory trial requirements.

Why It's Relevant Today

Accelerated approval showed the FDA could maintain safety standards while accepting different forms of evidence when patient need demanded it. The plausible mechanism pathway extends this logic further, accepting mechanistic rationale as primary evidence when even surrogate-endpoint trials are impossible due to tiny patient populations.