Inspired by the Baby KJ case, the agency proposes a flexible framework allowing personalized treatments for individual patients to contribute to shared, platform-based approvals.

The announcement appeared on November 12 in the New England Journal of Medicine under a seemingly cautious title: “The FDA’s New Plausible Pathway.” Yet the article, written by two senior figures at the Food and Drug Administration, reveals vision and leadership. For once, it is worth starting from the end, which reads like a strong statement of intent: “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.”

The case of Baby KJ, treated with a base-editing therapy designed specifically for him, has become more than just an example of (rapid) research and (ultrafast) manufacturing of therapeutic options to correct the unique mutations of individual rare patients. It has also become a model for redefining future regulatory platforms for the testing and eventual commercial approval of advanced treatments that do not fit the traditional pathway. In the six months since that breakthrough, the FDA has worked closely with the group that strove to save Baby KJ, as well as with other researchers aiming to ensure that the experience does not remain an exception but evolves into a repeatable process.

To achieve this, the “plausible pathway” needed to navigate between Scylla and Charybdis: on one side, the impossibility of replicating for every single patient the extremely costly, collective effort from scratch; on the other, the impracticality of classical clinical trials, which by definition are unsuitable for rare patients carrying often-unique mutations and facing extremely narrow windows for intervention. The FDA says it is ready to travel this narrow and intrinsically flexible route, combining data from similar protocols, cutting redundant procedures, reducing animal testing, and using the patient’s own medical history as a control, provided certain conditions are met. These include a precise understanding of disease biology and natural evolution, a clearly defined molecular target, measurable therapeutic intervention, and observable clinical benefit.

Traditionally, treating individual patients under compassionate use does not allow the collected data to be used for commercial authorization. However, if the only variable that changes from one patient to another is a module of the technological platform (for example, when the nanoparticles and editor remain the same and only the short guide RNA sequence changes), the first case can provide useful information for evaluating subsequent ones. And here comes the biggest novelty: “Once a manufacturer has demonstrated success with several consecutive patients with different bespoke therapies, the FDA will move toward
granting marketing authorization for the product. Manufacturers will then be able to leverage platform data from such personalized products to gain marketing approval for similar products in additional conditions.” This mechanism is conceived for rare diseases and advanced therapies, but the agency does not rule out its future extension to common diseases lacking treatment options and to other drug classes.

The two authors of the NEJM article are ready to address predictable objections. “Critics may contend that there is no need for an alternative pathway and that existing FDA operations are able to address bespoke, transformative therapies. Unfortunately, the FDA has heard from patients, parents, researchers, clinicians, and developers that current regulations are onerous and unnecessarily demanding, provide unclear patient protection, and stifle innovation. We share this view. […] The FDA is always open to additional
feedback and suggestions. Meanwhile, for patients and families, there is no time to wait,” write Vinay Prasad and Martin A. Makary.

Among the first to applaud was David Liu, the base-editing pioneer and Breakthrough Prize winner, who wrote on his social media channels: “That FDA is recognizing here the urgent need for regulatory strategies to evolve to match the pace of scientific advances in ways that streamline bringing the science safely to patients is incredibly important. I hope these new policies provide a foundation that will eventually allow certain kinds of genetic surgeries to become as routine as life-saving conventional surgeries, in which the process is robust and standardized enough to be rapidly adapted to each patient, without the need for a separate multi-year regulatory process for each surgery.” A similar parallel had been drawn by KJ’s pediatrician, Rebecca Ahrens-Nicklas, during a video interview with Endpoints: “I think ultimately moving towards a genetic surgery model might allow us to scale more quickly and have access for a wider number of patients. And if you think about this sort of analogous to like an interventional cardiologist or an interventional radiologist, they are adapting what they’re doing for the patient in front of them using tools. In this case, our tools are gene editing tools that are being developed by our manufacturing partners. And so I think, I hope that someday we do get to a point where we essentially have personalized genome editing centers that can be credentialed and monitored and make sure that this is done in an appropriate and safe way, but would allow for the degree of flexibility that’s needed to essentially meet the need of any patient.”

The regulatory shift had been foreshadowed on October 31, when the American Journal of Human Genetics published an article signed by the two physicians who developed and delivered Baby KJ’s treatment at the Children’s Hospital of Philadelphia. Metabolic disease specialist Rebecca Ahrens-Nicklas and geneticist Kiran Musunuru described consultations with the FDA aimed at simplifying the rules, with a goal of moving from bespoke treatments for a single patient (“N of one”) to customized solutions applicable to multiple individuals (“N of many”). The discussions were constructive, to the point that the Philadelphia group expects to launch in 2026 an “umbrella” trial for phenylketonuria—a disease caused by various mutations in the same gene (PAH)—as well as a trial for early-onset urea cycle disorders, linked to variants across seven different genes (in KJ’s case, the CPS1 gene was involved).

Normally, the negotiations between scientists developing innovative therapies and regulatory authorities remain confidential. In this case, however, anyone can access the correspondence that unfolded over months in search of a balance between participant protection and the need not to hinder the pursuit of a cure. Open access to these documents will help other groups seeking to initiate similar clinical trials, starting with the new Pediatric Center for CRISPR Therapies. Its director, Fyodor Urnov, indeed told Nature that he is ready to ride the wave created by the clinician–researchers in Philadelphia.

(translated from the article written by Anna Meldolesi for Osservatorio Terapie Avanzate)