N-of-1 Trials: FDA Plots Path to Regulation

Regulatory NewsRegulatory News | 10 October 2019 |  By 

The US Food and Drug Administration (FDA) is taking notice of a unique and recent phenomenon where physicians and specialists can create a tailored treatment to help or even cure an individual patient with a rare genetic mutation that could prove fatal.

In an editorial published Tuesday in the New England Journal of Medicine, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, and Peter Marks, director of the agency’s Center for Biologics Evaluation and Research, explain how these new technologies can “permit the delineation of pathways for truly individualized drug development," but currently this type of "drug discovery and development is most advanced for ASOs [antisense oligonucleotides], other types of treatments, including individualized cell and gene therapies, are following closely behind.”

An FDA spokesperson told Focus the agency expects to publish a draft guidance on individualized therapies regulation soon.

But Woodcock and Marks pose a series of questions that show how difficult such a guidance will be to create, including, “what type of evidence is needed before exposing a human to a new drug? Even in rapidly progressing, fatal illnesses, precipitating severe complications or death is not acceptable, so what is the minimum assurance of safety that is needed? How persuasive should the mechanistic or functional data be? How should the dose and regimen be selected? How much characterization of the product should be undertaken? How should the urgency of the patient’s situation or the number of people who could ultimately be treated affect the decision-making process?”

Questions on efficacy were also raised, especially as caregivers or patients might believe there has been disease improvement or stabilization when that may not be the case.

“At the very least, during the time needed to discover and develop an intervention, quantifiable, objective measures of the patient’s disease status should be identified and tracked, since, in an N-of-one experiment, evaluation of disease trends before and after treatment will usually be the primary method of assessing effectiveness,” Woodcock and Marks explained.

In addition, specific criteria should be discussed, they said, ideally with the assistance of an ethicist, before administration of the treatment and to provide a common understanding of how effectiveness will be gauged.

The agency also needs to address potential n-of-1 failures, and what happens when a success occurs for one patient but others with the same condition or disease are identified.

“On a larger scale, we need to consider how such truncated programs fit into the spectrum of drug development in general: what are the differences between treating one, ten, or thousands of patients? Although the FDA and other regulators typically allow streamlined preclinical data generation for rare, serious diseases, programs for a single patient are likely to set the floor for the minimum preclinical evaluation. How should this be escalated for slightly more prevalent diseases of equal seriousness?” they wrote.

NEJM Editorial


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