Last month, the FDA withdrew its approval of multiple myeloma drug Pepaxto, three years after the medication was okayed under the agency’s accelerated approval program.
Although the move didn’t get much notice, it marked the FDA’s first use of its new authority to stamp out instances in which drugs can maintain their marketing authorization despite little evidence that they help patients.
That nagging problem of ineffective and potentially harmful drugs lingering on the market factored into the intense backlash against the FDA’s greenlighting in 2021 of Aduhelm, a pricy Alzheimer’s drug with worrisome side effects and very weak evidence of clinical benefit.
Reform legislation passed in late 2022 addressed flaws in the accelerated approval pathway, which has been in use since 1992 and accounted for 16% of new drug approvals in 2023. Still, some experts say the new law doesn’t do enough to protect patients.
The upshot is that journalists still need to be diligent about covering the limited evidence on which accelerated approvals are often based.
What the new law does
In exchange for earlier market access for products for serious conditions that address an unmet need, drugmakers promise to conduct post-approval confirmatory studies, with the aim of ultimately converting to traditional approval.
But too often manufacturers fail in their obligation to promptly complete confirmatory studies or get a negative result, resulting in what’s been termed a “dangling” approval.
Until now, it has been difficult for the FDA to rescind an approval, although some drugs are voluntarily withdrawn from the market by their manufacturers.
The new law established clear procedures for the FDA to withdraw accelerated approvals and empowered the agency to require that a confirmatory trial be underway before accelerated approval is granted.
The law also added transparency. If the FDA does not require a post-approval study, it must publish its rationale. Sponsors must submit progress reports on confirmatory research, which the FDA must post online.
Advocates for greater rigor in drug approvals say those are positive steps.
“Now we see increased predictability” on the timely withdrawal of drugs that don’t show a benefit, Reshma Ramachandran, M.D., M.P.P., M.P.H., a family physician and health services researcher at the Yale School of Medicine, said in an interview.
Ramachandran, who chairs a task force on FDA policy for the advocacy group Doctors for America, said she’s also encouraged by reports that the FDA has required some drugmakers to enroll patients in confirmatory trials prior to granting accelerated approval.
How Congress fell short
The law didn’t take steps to strengthen the evidence base that is required for accelerated approvals, which many advocates would like to see. Opponents of such measures contend that looser standards amount to a trade-off that benefits patients with severe or life-threatening diseases.
Ramachandran called the law “a mixed bag,” adding that it may shorten the time that patients and clinicians must grapple with uncertainty about a drug’s effects but won’t reduce that uncertainty in the first place.
Congress sidestepped proposals to strengthen evidentiary standards such as requiring the FDA to demand that confirmatory trials assess meaningful clinical outcomes, confirm the validity of surrogate endpoints, and use randomized controlled trials as a default.
Nor did lawmakers act on other patient protections endorsed by physicians, medical ethicists and public policy experts, including:
- Banning accelerated approval of drugs with negative trial results on clinical outcomes. Accelerated approval has been used as a back door to put ineffective drugs on the market.
- Establishing mechanisms for payers such as Medicare and Medicaid to avoid paying high list prices for drugs without evidence of a clinical benefit.
- Requiring prominent alerts, similar to boxed warnings, on labels of drugs with accelerated approval.
Although the FDA can do some of these things on its own, codifying them in law would protect against legal challenges that are likely if the Supreme Court decides to limit the regulatory powers of federal agencies.
What journalists can do
It’s up to journalists to inform the public about the quality of evidence on which a drug is approved.
For example, accelerated approvals are typically based on improvement of a biomarker or other surrogate endpoint, but that surrogate may not have been proven to reliably predict a clinical benefit. Such was the case with Aduhelm, which was approved based on its ability to reduce beta-amyloid plaque in the brain, which is not associated with improved cognitive function.
Other problems to highlight in your reporting:
- The FDA may allow a sponsor to use a surrogate market as its primary endpoint in a confirmatory trial, which means that patients and physicians may never know whether a drug really helps patients live better or longer.
- The FDA in recent years has largely abandoned the gold standard of two large randomized controlled trials, and may allow trials with no control arm or a small number of patients.
Big-picture issues to follow
The FDA continues to face industry pressure to expand accelerated approvals into areas such as neurological disease and gene therapy.
Journalists can push for transparency in FDA policy-making, Ramachandran noted. The new law required the agency to create an internal coordinating council to ensure consistent use of accelerated approval, but the agency didn’t disclose many details in its 2023 report on council activities.
News coverage can also focus on how forcefully the FDA wields its new power to jumpstart confirmatory research and rescind approvals.
The recent withdrawal of Pepaxto was a relatively easy call, said Diana Zuckerman, Ph.D., of the National Center for Health Research, a not-for-profit think tank that focuses on patient safety. By the time the FDA acted, the manufacturer had already pulled Pepaxto off the U.S. market. The reason: confirmatory research showed that rather than helping patients, it shortened their lives.
Zuckerman said it’s worrisome that Pepaxto was okayed for patients, only to prove dangerous a few months later. With accelerated approval, she said, “There are too many loopholes that have harmed patients.”
Resources
- FDA Accelerated Approval Program.
- “Modernizing accelerated approval,” Section 3210 of the Food and Drug Omnibus Reform Act of 2022.
- FDA’S Accelerated Approval Pathway: A rare disease perspective, published by the National Organization for Rare Disorders.
- AHCJ web post on evaluating concerns about accelerated FDA drug approvals.
- White paper on reforming accelerated approval by the Institute for Clinical & Economic Review.
