New FDA Protocol For Ultrarare Disease Therapies

Ultrarare diseases have always received short shrift from the American medical community because there is little money to be made from drugs and treatments. These diseases each affect small numbers of individuals, reducing the profitability of pharmaceuticals and other therapies.  The Orphan Drug Act (ODA) of 1983 encouraged the development of drugs for these rare diseases, but there is more to be done for the afflicted.  The FDA just issued a draft guidance for individualized therapies targeted at orphan diseases:

https://www.hhs.gov/press-room/fda-launches-framework-accelerating-development-individualized-therapies-ultra-rare-diseases.html

https://www.federalregister.gov/public-inspection/2026-03713/guidance-considerations-for-the-use-of-the-plausible-mechanism-framework-to-develop-individualized

FDA Launches Framework for Accelerating Development of Individualized Therapies for Ultra-Rare Diseases

By HHS Press Office - February 23, 2026

WASHINGTON — FEBRUARY 23, 2026 — The U.S. Food and Drug Administration (FDA) today issued draft guidance for sponsors seeking full approval for targeted individualized therapies by generating substantial evidence of effectiveness and safety when randomized controlled trials are not feasible due to small patient populations.

The draft guidance, issued by the Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research, specifically discusses genome editing and RNA-based therapies such as antisense oligonucleotides but leaves open the potential that this framework may apply to additional tailored therapeutics provided they directly address the underlying specific cause of the disease.

“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,” said Health and Human Services Secretary Robert F. Kennedy, Jr. “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.”

“This guidance is a critical step the FDA is taking to tailor our regulatory approach to patients with ultra-rare conditions,” said FDA Commissioner Marty Makary, M.D., M.P.H. “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.”

The draft guidance focuses on therapies that target a specific genetic, cellular or molecular abnormality and are designed to correct or modify the underlying cause of disease. Key criteria include:

• Identifying the disease-causing abnormality.
• Demonstrating the therapy targets the root cause or proximate biological pathway.
• Relying on well-characterized natural history data in untreated patients.
• Confirming successful target drugging or editing.
• For traditional approval, therapies should demonstrate improvement in clinical outcomes, disease course, or biomarkers if they are established to predict clinical benefit.

“Designing treatments unique to individual patients has always been the promised goal of personalized medicine,” said Center for Biologics Evaluation and Research Director Vinay Prasad, MD, MPH. “After 25 years the FDA has, for the first time, outlined a framework to facilitate these approvals. The Plausible Mechanism framework is a revolutionary advance in regulatory science.”

“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,” said Center for Drug Evaluation and Research Acting Director Tracy Beth Høeg, MD, PhD. “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.

”Because genome editing technologies are designed to be highly specific to unique DNA sequences, a product targeting different mutations in a single gene could be included in a single product application and potentially evaluated through the use of master protocols that evaluate these product variations in a single trial. A highly supported “plausible” mechanism of action may then be used to support the addition of other such genome editing product variants, intended to treat patients with mutations that were not included in the clinical trial used to support the original approval.

The FDA recognizes that an adequate and well-controlled clinical investigation in this context will include a small sample size, therefore, investigation results should be sufficiently robust to exclude chance findings. When determining effectiveness, the FDA considers the specific disease, the strength of the evidence and the challenges of conducting clinical investigations for individualized therapies.

The draft guidance, Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause, is available for public comment. Comments must be submitted within 60 days of publication in the Federal Register at Regulations.gov.

The FDA is committed to advancing safe and effective therapies for rare diseases and ensuring no family is overlooked because their condition is uncommon.