FDA Introduces New Approval Pathway for Individualized Rare Disease Therapies

The FDA has introduced a new approval process for targeted individualized therapies, including genome editing and RNA-based therapies, intended to treat rare and ultra rare diseases in which randomized controlled trials are not feasible. The HHS Secretary and FDA Commissioner announced the new process, called the "plausible mechanism pathway" during a press conference on Monday.

According to the draft guidance, issued by the Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research, the FDA may approve or authorize certain bespoke, personalized treatments by "generating substantial evidence of effectiveness and safety." Under the framework, one well-controlled clinical investigation, supported by confirmatory evidence, can support approval.

The press conference centered on the case of an infant in the Philadelphia area born with a rare disease called carbamoyl-phosphate synthase 1 deficiency (CPS1), which is caused by a deficiency in the CPS1 gene. The director of the Children's Hospital of Philadelphia Gene Therapy for Inherited Metabolic Disorders Program and a cardiologist, geneticist and gene editor at the University of Pennsylvania had conducted research into the use of gene editing to create personalized interventions for patients with heart disease. They had the idea to apply the treatment to the infant with CPS1.

The treatment was successful for the infant at CHOP. The therapy has a small component that acts like a GPS, and by switching the address in that GPS, the therapy will go to another gene and make a desired change. This approach can be individualized to many patients with liver-centered diseases by just changing the GPS again and again, to correct each patient's genetic misspelling.

With this case in mind, the FDA created a phased operational model for patients with rare diseases to be treated with such individualized, experimental therapies. The plausible mechanism framework aims to bridge the gap between promising science and regulatory approval, which is what allows treatments to become commercially available, reimbursed and scaled, so all patients who need them can access them.

According to an HHS press release, the proposed pathway will include five key elements — identifying molecular or cellular abnormalities, targeting the underlying alteration, use of natural history data, evidence of successful application of the technology, and demonstration of clinical benefit. Stipulations for FDA approval and post-marketing analyses are also part of the protocol.

Approximately 30 million Americans have rare diseases. The types of individualized, genetic therapies being developed simply do not fit in the traditional model of drug development, particularly for rare and ultra-rare diseases.