FDA announces “plausible mechanism” approval pathway for certain personalized therapies, with few details

Drawing parallels to the case of “Baby K.J.” – a newborn with a genetic disorder whose care team developed a custom DNA base-editing therapy authorized by FDA within one week under a single-patient expanded access IND – Dr. Makary and Dr. Prasad describe in the NEJM a new FDA “plausible mechanism” approval pathway that will permit drugs and biologics to obtain marketing authorization in cases where all of the following factors are present:

1. The medical product aims to treat diseases for which the biologic cause is known (e.g., genetic conditions with a clear connection between specific alteration and disease presentation), “rather than diseases defined by a constellation of clinical findings or dozens of unclear genomewide associations.”
2. The product targets the underlying or proximate biological alterations.
3. There is a well-characterized natural history of the disease in the untreated patient population.
4. There is confirmation that the target was successfully drugged or edited (or both), in at least one patient.
5. There is evidence of “improvement in clinical outcomes or course.” In assessing this factor, Makary and Prasad specify that:

• In conditions with progressive deterioration, consistent improvements will be viewed favorably by FDA.
• In conditions with episodic waxing and waning, FDA will look for prolonged periods of disease remission.
• Taking into account previous clinical course, FDA will view patients as their own control – in some cases.
• Clinical data must be strong enough to exclude regression to the mean.

Approval process under the pathway

As described in the NEJM article the plausible mechanism pathway has particular application for bespoke cell and gene therapies. After a manufacturer has demonstrated success with several consecutive patients with different bespoke therapies, FDA will move toward granting marketing authorization. Manufacturers will then be able to leverage “platform data” from such personalized products to gain marketing approval for similar products in additional conditions – utilizing either accelerated or traditional approval pathways.

In the postmarket setting, the sponsor will be required to collect real-world evidence (RWE) “to confirm continued preservation of efficacy and to show that there were no off-target edits” based on agreed-upon metrics, and “to study the effect of early treatment on childhood growth and developmental milestones and to detect unexpected safety signals,” the JAMA article states. FDA may utilize a platform “master file” system to manage data collection and regulatory review for these therapies.

Notably, this new pathway appears different than other expedited programs (such as breakthrough therapy designation), in that the plausible mechanism framework would not include a formal designation process, instead operating under the stages described above.

Drs. Makary and Prasad write that the plausible mechanism pathway will “prioritize rare diseases, particularly those that are fatal or associated with severe disability in childhood,” but “will be also available for common diseases, particularly diseases for which there are no proven alternative treatments or in which there is considerable unmet need after use of available therapy.” They further remark that although the pathway is focused on biologics – and gene and cellular therapies in particular – they “see no reason that such principles will not also extend to other drugs over time.”

Next steps

The NEJM article does not include details regarding process for the nascent plausible mechanism pathway, and so we anticipate FDA guidance will follow.

We see the plausible mechanism pathway as an extension of FDA's trend toward announcing its willingness to use its regulatory flexibility and recognizing the challenges in the development of drugs and biologics for rare diseases, unmet need, and regenerative medicines in particular. For example, this approval pathway announcement comes after FDA in September announced a new process called “Rare Disease Evidence Principles” (RDEP), under which eligible drugs and biologics for ultra-rare diseases caused by known genetic defects will receive assurance of FDA consideration of additional supportive data that may be used to meet regulatory approval standards, as we described at the time online here. FDA also recently published draft guidance documents, “Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations” and “Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products” that seem to dovetail with some of the principles described in the NEJM article.

We will continue to monitor FDA’s evolving regulatory paradigms, including how they are applied in practice, and keep you apprised of any changes.

Authored by Lynn Mehler, Komal Nigam, and Jason Conaty.