FDA-Approved Drugs Have Few Postmarket Efficacy Studies

Diana Swift

May 10, 2017

Very few postapproval studies using clinical endpoints are performed for novel drugs approved by the US Food and Drug Administration (FDA) on limited evidence for faster entry into the marketplace. The FDA approves many new agents on the basis of a single pivotal trial or pivotal trials that use surrogate markers, in contrast to actual clinical outcomes such as death, hospitalization, and patient functional status, or even clinical indices of disease activity such as the visual analog scale or the Crohn's disease activity index.

"These drugs are widely used after approval, even if subsequent clinical studies are not conducted to confirm the expected benefits," Alison M. Pease, a medical student at State University of New York Downstate College of Medicine in Brooklyn, and colleagues write.

"These findings have important implications for clinical care," the authors write. "Both doctors and patients have high expectations for the safety and efficacy of a drug approved by the FDA. They anticipate these results will help guide clinical decisions and regulatory policy before and after the approval of novel drugs.

Published online May 3 in the BMJ, the study found this: at a median of 5.5 years postapproval, fewer than 10% of approved indications had been examined in at least one published randomized controlled, double-blind study that showed superior clinical efficacy for the indication that led to FDA approval. Less than one third of indications approved on the basis of a single pivotal trial had at least one postapproval trial showing superior efficacy, and even fewer used clinical outcomes.

With the bipartisan passage of the 21st Century Cures Act in December 2016, Congress instructed the FDA to allow the use of surrogate-marker trials to speed up drug approvals. "But what we're seeing is that very rarely, either by manufacturers, by government funding, or by independent investigators, are we getting postmarket trials that confirm the benefits of drugs with more rigorous study," senior author Joseph Ross, MD, an associate professor of medicine at Yale University in New Haven, Connecticut, told Medscape Medical News.

"If we're going to have an accelerated system like that, and we want drugs quickly, we need the FDA to have very stern postmarket requirements that ensure that the benefits of the drugs are determined within the first 3 years after approval so we can reassure our patients that the potential risks are outweighed by the benefits of the medications."

Dr Ross added that physicians are generally unaware of this deficit. "There's an assumption that once a drug is approved, it's based on very rigorous evidence."

What struck him most about the study findings was the overwhelming adherence to nonclinical measures of efficacy. "I thought it was interesting that when a drug was approved on the basis of surrogate markers, there were lots of studies done [during] the postmarket period, but almost all were more studies using surrogate markers of disease," he explained. But if a drug is approved on limited evidence, the trade-off should be that more time-consuming clinical studies with more robust data must be performed later, he added.

"These findings have important implications for clinical care," the authors write. "Both doctors and patients have high expectations for the safety and efficacy of a drug approved by the FDA." They anticipate these results will help guide clinical decisions and regulatory policy before and after the approval of novel drugs.

Focusing on the period 2005 to 2012, the researchers conducted an exhaustive literature search and identified 188 novel drugs for 206 indications approved by the FDA. They specifically targeted prospective controlled postapproval studies for drugs approved on the basis of a single pivotal trial, pivotal trials using surrogate disease markers as primary endpoints, or both. The researchers identified 117 new drugs approved for 123 indications on those evidence bases.

At a median of 5.5 years postapproval, the median total number of postapproval clinical studies of the first approved indication was one (interquartile range [IQR], zero to two) for drugs based on a single pivotal trial, three (IQR, one to eight) for drugs approved on surrogate markers, and one (IQR, zero to two) for approvals based on both.

Only 18.2% (six of 33), 2.0% (one of 49), and 4.9% (two of 41) of indications approved by the FDA on the basis of a single pivotal trial, surrogate markers, or both, respectively, had at least one published postapproval, randomized controlled, double-blind study that used a clinical outcome as the primary endpoint and showed superior efficacy. The researchers found no postapproval studies for 43 (35.0%) of the 123 approved indications.

The current study parallels previous research, and in particular a 2016 study showing that oncology drugs approved on the basis of surrogate markers are rarely reassessed in subsequent clinical studies demonstrating improved overall survival.

"We did a study just of cancer drugs approved for market on surrogate markers, and we found that 5 years later, only about 10% showed improved survival. But the vast majority were still on the market, although they only improved surrogate endpoints," Vinay K. Prasad, MD, an oncologist at Oregon Health & Science University in Portland and a coauthor of the 2016 study, told Medscape Medical News.

Dr Prasad said the current findings confirm his group's observations more broadly. Calling them "very sobering," he added, "It is pointless to prove what has already been proven when what really matters is whether people live longer and live better."

In Dr Prasad's view, the current situation is "a classic case of how you cannot have your cake and eat it, too. You cannot allow drugs to be approved based on less and less evidence and not validate them after the fact," he said.

Right now, the system wants both: "We have a low bar for approval with no real follow-up at the back end, and that is extremely concerning," he said. "We may be willing to take a chance on some drugs, but we need to show within 5 or 10 years that they actually make people live better."

He said the FDA, which already has the authority to enforce their postmarketing commitments, should consider asking Congress for additional funding, if necessary, to fulfill these. "Submission fees for drug companies could be increased to support this important activity," he said.

Congress, which writes the regulations for the FDA, should instruct it to require rigorous postmarket studies, Dr Ross told Medscape Medical News.

According to Dr Prasad, the current situation leaves enormous uncertainty for physicians and patients who lack information when choosing to use drugs. It also favors "right to try" patients who want more drug options sooner. "But there are other patients who are starved for information that they desperately need but is not generated at time of approval or a long time afterward."

Looking ahead, the researchers urge caution around recent proposals for FDA reform that include increasing reliance on surrogate markers, smaller and shorter trials, evidence from registries and observational studies, and a move to a "consumer reports approach" for grading drug efficacy, safety, and degree of evidence. "[H]igh quality postapproval evidence does not necessarily accumulate and may require additional regulatory requirements," they write. "To strengthen lifecycle evaluation of recently approved drugs, requirements for postapproval studies should be heightened and may need to specify study design characteristics or trial endpoints in detail to ensure that these studies provide high quality evidence to further inform clinical practice."

Last year, a report by the General Accountability Office found shortcomings in the FDA's postmarket surveillance of the safety of drugs given expedited approval.

This project was supported in part by the Robert E. Leet and Clara Guthrie Patterson Trust Awards Program in Clinical Research, Bank of America, NA, Trustee. The study authors and Dr Prasad have disclosed no relevant financial relationships.

BMJ. Published online May 3, 2017. Full text

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