The FDA has outlined a new review process for drugs and biologics designed to treat ultrarare genetic diseases that would allow a single-arm trial, plus other supportive data, to serve as pivotal evidence.
The proposed process comes from the agency’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) and builds off the work of ex-CBER leader Peter Marks, M.D., Ph.D., and 2023 draft guidelines.
The program is called the Rare Disease Evidence Principles (RDEP), which historically has been known as a framework of principles guided by the specific challenges tied to rare disease research.
For certain rare diseases, “substantial evidence of effectiveness may generally be established based on one adequate and well-controlled study that may be a single arm trial,” the FDA wrote Sept. 3.
Studies should be supported by data coming from other sources, such as evidence of treatment effect on direct pathophysiology of a disease, relevant clinical pharmacodynamic data, relevant nonclinical model data, and case reports and expanded access data.
The CDER and the CBER will also consider confirmatory evidence provided through appropriate external controls or natural history studies.
To be eligible for the RDEP process, the investigational medicine must take aim at correcting or replacing the specific genetic defect underlying the disease.
The drug must be for an ultrarare condition, or one impacting fewer than 1,000 Americans. The disease should be marked by a progressive deterioration in function before rapid and significant disability or death, according to the FDA.
Eligibility for the program also means that there aren't any available alternative therapies that sufficiently alter the course of the disease.
“Drug developers—and the patients they hope to treat—deserve clear, consistent information from the FDA,” FDA Commissioner Marty Makary, M.D., said in a Sept. 3 release. “These principles ensure that FDA and sponsors are aligned on a flexible, common-sense approach within our existing authorities, and that we incorporate confirmatory evidence to give sponsors a clear, rigorous path to bring safe and effective treatments to those who need them most.”
Makary announced plans for a new rare disease pathway in an April episode of "The Megyn Kelly Show." The proposal follows former CBER Director Marks’ efforts to adjust regulatory pathways for investigational rare disease treatments.
"While we are encouraged that the FDA is continuing to exhibit flexibility in evaluating gene therapies for rare diseases, it remains unclear what tangible impact the framework will have on the development process and approval timeline, given several gene therapies in development are already utilizing single-arm trials for registration," William Blair analyst Sami Corwin, Ph.D., wrote in a Sept. 3 note.
The analyst cited Neurogene, Rocket, Lexeo, Ultragenyx and uniQure as companies with development programs already using single-arm trials for registration.
"In addition, given the restrictions on patient size for the program, most therapies in development won't be eligible to apply," Corwin wrote. However, the analyst did note that the process could benefit platform companies addressing rare diseases caused by a mutation in one of several genes if a different treatment is needed for each genotype.