FDA introduces new pathway for personalised medicines

The US Food and Drug Administration (FDA) has laid out the process and requirements of its novel plausible mechanism pathway for personalised medicine in a New England Journal of Medicine (NEJM) editorial by Commissioner Martin Makary and Deputy Vinay Prasad. The editorial acknowledges that personalised therapies “challenge traditional models of drug and biologic development”, that the current system “stifles innovation”, and the need for a “path to market entry for products where a randomised trial is not feasible”. It draws on the recent case of ‘Baby KJ’, where DNA base editing was used to treat a child with carbamoyl-phosphate synthetase 1 (CPS1) deficiency, to illustrate the tenets of the new pathway. The editorial lists five aspects of the case that define the plausible mechanism pathway: The identification of a specific molecular or cellular abnormality, rather than a broad set of consensus diagnostic criteria. The development of a medical product that targets the underlying or proximate biological alterations. A well-characterised natural history of the disease in the untreated population. Confirmation that the target was successfully drugged, edited, or both. This was done using mouse models though the authors say the FDA will embrace nonanimal models where possible. An improvement in clinical outcomes or course. Evolution of regulatory strategies They state that the case highlights “the potential of individualised 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”. Therefore, manufacturers will be able to use individual successful cases to secure marketing approval for a product and then leverage platform data to gain approval for similar products in additionalconditions. The editorial states that the company will be required to acquire real-world evidence to confirm continued efficacy, adding “tolerance of risk is contingent on the risk–benefit balance”. Although the FDA will prioritise rare diseases, the authors say that a plausible mechanism pathway will be also available for common diseases, particularly diseases for which there are no proven alternative treatments. They also emphasise that these principles could extend beyond cell and gene therapies to include small molecules and antibodies too. The editorial concludes: “Nearly 30 years after the sequencing of the human genome, bespoke therapies are close to reality. The FDA will work as a partner and guide in ushering these therapies to market, and our regulatory strategies will evolve to match the pace of scientific advances.” Diana Turner, Deputy Editor, DDW