FDA leaders propose new ‘plausible mechanism’ pathway for bespoke medicines

Two of the US Food and Drug Administration’s (FDA) top regulators proposed a new approach for approving personalized medicines under a so-called “plausible mechanism” pathway. The pathway would enable the agency to approve individualized gene therapies and other bespoke medicines in cases where randomized trials are not feasible, and the biological cause of the disease is known.

Department of Health and Human Services (HHS) Press Secretary Emily Hilliard told Focus that the FDA plans to issue joint guidance from the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) regarding the plausible mechanism pathway but did not provide a timeline for its release.

In a perspective published in the New England Journal of Medicine on Wednesday, FDA Commissioner Marty Makary and CBER Director Vinay Prasad wrote that, “Bespoke, personalized therapies, which hold tremendous promise, challenge traditional models of drug and biologic development. The [FDA] is committed to providing regulatory guidance and encouragement, outlining a path to market entry for products where a randomized trial is not feasible.”

The agency intends to prioritize this pathway for rare diseases, particularly those that are fatal or can cause severe disabilities in children, Makary and Prasad wrote. They also note that this pathway may be expanded to common diseases, especially in cases where there are no proven alternative treatments or where there is a significant unmet medical need.

The authors presented a recent case study involving a male neonate named Baby KJ, who was born with carbamoyl phosphate synthetase 1 (CPS1) deficiency, which prevents the liver from properly processing protein, to illustrate how the plausible mechanism would work. Without treatment, the natural progression of the CPS1 deficiency and similar urea cycle disorders would lead to progressive neurological damage with frequent bouts of hyperammonemia before the infant grows large enough to undergo a liver transplant.

In that case, FDA processed an investigational new drug (IND) application within one week, allowing Baby KJ's care team to manufacture and administer three consecutive doses of a lipid nanoparticle. This nanoparticle contained guide RNA targeting CPS1 and messenger RNA-encoded adenine base editor (k-abe), designed to address the patient's mutation. Since receiving the treatment, the patient demonstrated an improvement in processing dietary protein and showed overall clinical improvement.

FDA will limit the use of this pathway to diseases where the biological cause is understood, Makary and Prasad stressed. This includes genetic conditions that have a clear link between specific alterations and disease presentation. It will not apply to diseases defined by various clinical findings or numerous “unclear genomewide associations.” This approach aims to prevent the misapplication of the pathway to unrelated conditions that may exhibit similar phenotypes.

Additionally, there should be evidence that the therapy has effectively treated or edited the disease, resulting in improved clinical outcomes. In the case of Baby KJ, sponsors were able to show mouse models which demonstrated successful editing in 42% of liver cells, though the authors noted that a biopsy demonstrating a successful drug effect or gene editing, when clinically appropriate, would be accepted as supportive evidence for the pathway.

The authors stated that once a manufacturer successfully treats several consecutive patients with different customized therapies, FDA is likely to grant marketing authorization for the product. Manufacturers can also use data from these personalized treatments to obtain marketing approval for similar products aimed at other conditions.

Sponsors will have to collect real-world evidence (RWE) to show the treatment’s continued efficacy as part of a postmarketing commitment.

The authors noted that the treatment of individual patients through expanded access has typically been used to allow for the compassionate use of investigational therapies that are already undergoing evaluation in clinical trials. This option is available for patients who have limited or no other treatment options and is used without the expectation that the data collected from these patients will be used for marketing purposes.

The case of Baby KJ “highlights the potential of individualized therapies designed specifically for an individual person’s mutation to generate critical clinical safety and efficacy data and thereby inform development of a product that could be modified to address multiple genetic mutations,” Makary and Prasad wrote.

NEJM

FDA leaders propose new ‘plausible mechanism’ pathway for bespoke medicines

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