Experts: FDA has legal authority to require greater postmarket safeguards

In the US Food and Drug Administration (FDA) Accelerated Approval program, the tradeoff for early approval of medicines is that confirmatory evidence is required in the postmarket setting. In a special communication in JAMA Health Forum, health policy experts argue that FDA should put in place similar postmarket safeguards for any drug approval that has some uncertainty about clinical benefit.

In recent years, FDA officials have exercised greater flexibility in the evidence required for a full drug approval, such as approving drugs based on a single pivotal trial. For example, from 1995-1997, 81% of novel therapeutic approvals were supported by at least two pivotal trials. By 2015-2017, the proportion had dropped to 53%, according to an analysis from a different group of researchers published in 2020 (RELATED: Study tracks sharp drop in FDA approvals based on 2 pivotal trials, Regulatory Focus 24 April 2020).

In the special communication, Holly Fernandez Lynch, JD, assistant professor of medical ethics and law at the University of Pennsylvania, and colleagues asserted that FDA has the legal authority to require postmarket efficacy studies and expedited withdrawal procedures for drugs that gain full approval but still have some uncertainty about clinical benefit.

“FDA is willing to exercise regulatory flexibility in approvals,” Lynch told Regulatory Focus. “The more flexible you are at the point of approval, the more stringent you should be about postmarket authorities and requirements.”

FDA would not need congressional action to put such safeguards in place, Lynch said. The agency could rely on legal authority from three parts of the federal Food, Drug, and Cosmetic Act (FDCA): one that authorizes withdrawal if new information shows an approved drug is not safe or effective; another that authorizes FDA to produce regulations requiring sponsors make records and reports of data to help the FDA determine if withdrawal is necessary; and a third that authorizes the agency to impose regulatory requirements for efficient enforcement of the FDCA. Those are the same three elements of the FDCA that the agency used as the basis of the Accelerated Approval program when it was first created through regulation in 1992, Lynch said.

In applying broader postmarket authority, the FDA should be clear about what conditions would trigger the need for additional studies, Lynch and colleagues wrote. For instance, it could include cases in which approvals are based on efficacy data from a single study; there are inconsistent findings across multiple pivotal studies; there is a reliance on surrogate endpoints outside of accelerated approval; or cases where a drug fails to meet primary endpoints in a pivotal study but achieves them in a subgroup.

“A general rule might be that the FDA should impose efficacy [postmarket requirements] whenever it exerts flexibility regarding the substantial evidence standard, in acknowledgment of the reduced quantity or quality of evidence supporting the decision to allow certain drugs on the market,” the authors wrote.

FDA also should consider requiring that postmarket efficacy requirements are designed to answer questions about benefit using clinical endpoints, not surrogate endpoints. Additionally, tighter competition timelines should be strictly enforced, potentially through automatic expiration dates, the authors wrote.
But Lynch and colleagues are not advocating for a lower standard of evidence for drug approvals. Instead, she said they are urging the FDA to pair its flexibility on the approval side with more robust postmarket requirements.

“It’s reasonable to be flexible in approvals so long as FDA is also able to enforce these postmarket study requirements,” Lynch said in an interview. “In some cases, that’s going to be harder than others because one really important challenge in the postmarket space is can you continue to collect rigorous data that you need to confirm whether these drugs are safe and effective.”

Lynch reported receiving grants from Arnold Ventures during the conduct of the study.

JAMA Health Forum

Experts: FDA has legal authority to require greater postmarket safeguards

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