Drugmakers Wrestle With FDA Oversight of Rare Disease Treatments

Drug companies that specialize in care for rare diseases are growing frustrated with the FDA, despite agency leadership’s proclaimed agenda to accelerate approvals and heighten flexibility for promising new treatments.

“They’ve said everything that literally has us stand up and shout that they are going to work with us, yet in their actions, they haven’t really followed through on what they are saying publicly,” said Linda Marban, chief executive officer of Capricor Therapeutics Inc. The biotech company received a letter from the FDA in July that rejected its duchenne muscular dystrophy cell therapy in its current form.

The Food and Drug Administration under President Donald Trump touted plans to speed up drug approvals and introduce more opportunities for treatments targeting rare diseases, with the latest plan shared on Sept. 3 seeking to provide greater predictability in drug reviews.

Yet the FDA in the last few months issued at least seven complete response letters to rare disease drug and gene therapy makers. The letters don’t outright reject a drug application, but rather determine that the agency can’t approve a product in its current form.

Drugmakers now find themselves grappling with the FDA’s communications—navigating decision letters that ask for more clinical data, while also feeling optimistic about the agency’s vision to be more flexible with rare treatments. How the FDA moves forward in this space matters as rare disease drugmakers, which are often small biotech companies, are seeking approval for challenging patient populations that face few treatment options.

“It’s the switching of the gears,” Marban said in an interview. “That really drives a lot of confusion in the space and has really negative impacts on companies.”

The FDA made a controversial move this year that requested and then lifted the suspension of Sarepta Therapeutics Inc.‘s distribution of its duchenne muscular dystrophy drug, Elevidys, over safety issues. That decision sparked backlash from patient advocates and was followed by more whiplash with the resignation and then return of the FDA’s gene therapy chief, Vinay Prasad.

The latest letter was issued Monday to Saol Therapeutics. The company said it remains committed to identifying a path forward with the agency, but “traditional clinical trials often take many years.”

Complete response letters were also sent this year to rare disease drugmakers including PTC Therapeutics Inc., Rocket Pharmaceuticals Inc., Ultragenyx Pharmaceutical Inc., and Replimune Group Inc. The letters range from asking the company to provide additional data to show the drug’s effectiveness or provide more information on manufacturing operations.

The FDA in May issued a letter to Stealth BioTherapeutics Inc. for its Barth syndrome drug, but recently accepted the company’s resubmitted application and is expected to have a planned decision date of Sept. 26.

Mixed Communication

Through public statements, the FDA has shared support for rare disease drug development.

One of FDA Commissioner Marty Makary’s first proposals when he joined the agency was to roll out a new rare disease approval pathway that would allow authorization without data from a randomized controlled clinical trial. Prasad said last week the agency plans to unveil that framework soon.

The FDA also held a roundtable in June on cell and gene therapies, where US Health Secretary Robert F. Kennedy Jr. backed the agency and said his office will “sweep away the barriers” and figure out ways to accelerate approvals.

But some drugmakers are finding that the FDA’s recent skepticism in complete response letters doesn’t line up with the administration’s vision for flexibility.

For Capricor, the letter was unexpected because the company had not been told there were any problems in its application, Marban said.

The issues highlighted in Replimune’s letter “were not raised by the agency during the mid- and late-cycle reviews,” according to a company statement.

“We remain steadfastly committed to patient access while we work with the FDA to secure regulatory approval,” Replimune said in a statement that shared it will meet with the FDA to discuss the letter. However, without accelerated approval based on the current application, the drug’s program to treat advanced melanoma will not be viable, the company said.

Despite industry concerns over the agency’s decisions, a recent FDA approval issued another signal of how it could rare disease therapy development.

The agency in August approved Precigen Inc.’s Papzimeos, a first-of-its-kind immunotherapy to treat adult patients with recurrent respiratory papillomatosis.

The approval, touted by Prasad, was significant because it was authorized without a post-market confirmatory trial, signaling the agency’s regulatory flexibility with rare diseases.

“This is a great example of you don’t need a randomized study to know this works,” Prasad said last week at a workshop on rare disease clinical trials. “This is a great example of tremendous regulatory flexibility for rare conditions.”

Helen Sabzevari, CEO of Precigen, said in an interview that the company had a “close interaction” with the FDA, where the agency understood that the “right design was done for the right indication.”

“This is a great example of patients serving as their own controls,” Prasad said.

Future Decisions

The rare disease drug industry is now eyeing how the agency will react to upcoming decision dates for applications.

Scholar Rock is expecting a decision by Sept. 22 for its spinal muscular atrophy drug, GSK Plc should have a decision by Oct. 23 for its multiple myeloma drug, and Amgen Inc. is expecting a decision by Dec. 14 for its treatment targeting myasthenia gravis.

“Rare disease drug development is already one of the riskiest and most resource intensive areas of biomedical research,” said Stacey Frisk, executive director of the Rare Disease Company Coalition, a group representing rare disease drugmakers.

“FDA’s clarity in their decision making is really important for companies who are developing treatments for small, challenging patient populations,” Frisk said in an interview. “Now is the time to really reinforce the FDA mission driven approach to rare disease drug development.”