Experts warn against decoupling safety and effectiveness from FDA approval

Efforts to lower or decouple the standard of safety and effectiveness used by the US Food and Drug Administration (FDA) to approve drugs are “unnecessary and counter to patients’ interests,” experts said in a recent Viewpoint article published in JAMA.

“Rather than empowering patients, such a change would diminish autonomy by robbing patients and clinicians of the evidence needed to make informed treatment decisions, while simultaneously undermining the critical function that FDA approval plays in incentivizing innovation,” Patricia Zettler, of the drug enforcement and policy center in the Moritz College of Law at Ohio State University, and colleagues wrote in their paper.

The authors explained that while all drugs have risks, no risk is acceptable for a drug that is ineffective. “Only with reliable information about both the effectiveness and the risks of a drug can the FDA reasonably judge whether it is ‘safe’ for use in medical care,” they said.

Early signals of clinical safety do not justify broad use of a drug without knowing whether it is effective, the authors said, and “the demonstration of effectiveness for a drug typically requires carefully conducted prospective trials with randomization and takes time.” Drug development is a long process, but the “scientific difficulty of assessing risks and whether drugs work, not the regulatory requirements” is largely responsible for the development time, they said.

Citing the cautionary tale of thalidomide, in which the post-approval discovery that the drug caused birth defects led to a modern approval standard for global regulators, Zettler and colleagues said the US path to bringing a drug to market “exemplifies the inextricable link between drug safety and effectiveness and the shortcomings of a safety-only standard.” Thalidomide was later approved as a treatment for leprosy in the late 1990s and for multiple myeloma in the mid-2000s, the authors said, and these approvals would likely have not occurred in a regulatory environment with safety-only standard, or a reduced standard requiring safety and potential effectiveness.

FDA can grant drugs accelerated approval if their surrogate endpoints are reasonably likely to result in clinical benefit as long as postmarket confirmatory trials are conducted, but there are “substantial obstacles to collecting rigorous information about drugs once they are commercially available,” Zettler and colleagues said.

“If patients can secure access to a desired drug through medical care, they are unlikely to enroll in trials in which they are not guaranteed to receive their desired (promising but unproven) drug. Likewise, companies have little incentive to complete rigorous postmarket studies that may demonstrate a lack of effectiveness, putting profits at risk,” they explained. “These are not theoretical problems—postapproval studies, even when legally required, are often poorly designed, delayed, or not completed.”

Patients already have access to uncertain but promising drugs through the federal Right to Try Act, which has safeguards for patients and does not allow companies to commercialize a treatment. “What is not permitted, and what proposals to lower or eliminate the effectiveness requirement would enable, is for companies to sell their drugs for profit without first demonstrating that they work,” the authors said.

FDA’s current approval standard allows the agency the flexibility to approve drugs on a case-by-case basis. “The adaptability of the approval standard, combined with existing pathways for companies to provide unproven products to patients with unmet treatment needs, suggests that proposals to lower or eliminate preapproval effectiveness requirements are, at best, premised on profound misunderstandings of the role of the FDA, and a failure to recognize the shortcomings of postmarket evidence generation,” Zettler and colleagues said.

Holly Fernandez Lynch, paper co-author, associate professor of medical ethics, and associate professor of law at the University of Pennsylvania, told Focus in an interview “it’s not hard to imagine this getting enough political wind in its sails to succeed” with Republicans in control of Congress and the White House. She noted that lawfully changing the approval standard to a safety-only standard would require an act of Congress.

“Efforts to lower the standards for effectiveness have sometimes garnered bipartisan support in the past, as it can sound appealing on its face to ‘reduce bureaucracy’ and get drugs to sick patients faster,” she explained. “My view is that it’s important for FDA to shore up its effectiveness standard rather than moving in the opposite direction, so that patients and clinicians have the information necessary to guide treatment decisions.”

JAMA Zettler et al.

Experts warn against decoupling safety and effectiveness from FDA approval

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