Researchers at the Yale School of Medicine found that almost a third of drugs approved by the U.S. Food and Drug Administration (FDA) between 2001 and 2010 ended up with warnings about unexpected side effects or complications years later.
The study, published in the Journal of the American Medical Association May 9, took a look at what issues arose after the 222 prescription drugs were approved by the agency.
Of the 222 drugs, 71 were flagged for safety issues. Sixty-one received the agency’s strongest warning that it carries a significant risk, 59 were issued safety communications for less serious problems, and three were completely removed from the market for safety reasons.
The anti-inflammatory drug Bextra and irritable bowel syndrome medication Zelnorm were withdrawn over cardiovascular risk. Psoriasis drug Raptiva was withdrawn over an increased risk of a rare but fatal infection that causes damage to the brain.
Physicians and researchers in the field praised the study as bringing to light the need for postmarket surveillance and getting a conversation started around making drugs safer for the public.
“All too often, patients and clinicians mistakenly view FDA approval as [an] indication that a product is fully safe and effective,” Dr. Caleb Alexander, co-director of the Johns Hopkins Center for Drug Safety and Effectiveness, said about the study to Kaiser Health News. “Nothing could be further from the truth. We learn tremendous amounts about a product only once it’s on the market and only after use among a broad population.”
Even though many of the issues that arose after FDA approval were not serious enough to warrant a significant number of recalls, drug safety expert Thomas Moore told the Los Angeles Times that the findings of the study raise questions about the approval process of drugs.
New Drugs Subject to Quicker Approval and Inadequate Tests
News of the study come in light of remarks earlier this year from President Donald Trump criticizing the “slow and burdensome” process of approving drugs in the United States. He told a joint session of Congress that the current FDA process “keeps too many advances … from reaching those in need.”
“We seem to have decided as a society that we want drugs reviewed faster,” Joseph Ross, lead author of the study, said to The Washington Post. He added that the focus on speed makes it even more important “that we have a strong system in place to continually evaluate drugs and to communicate new safety concerns quickly and effectively.”
Ross, associate professor of medicine and public health at Yale, and other researchers also recently compared review times for new drugs approved by the FDA against review times for new drugs approved by the European Medicines Agency (EMA). The report found that the FDA approved drugs faster than its European counterpart.
“While the administration pushes for less regulation and faster approvals, those decisions have consequences,” Ross told NPR.
The latest study found that the FDA’s accelerated approval process had some of the highest rates of safety issues that arose after approval. According to Kaiser Health News, those drugs usually depend on measured outcomes other than survival to determine a drug’s effectiveness. Those are called surrogate endpoints and are currently becoming a bigger topic.
“This [finding on surrogate endpoints] has the greatest relationship to policy today,” Ross said. “In the 21st Century Cures Act, there’s a push to have the FDA move to further support the use of surrogate markers … [but] they’re more likely to have concerns in the post-market setting.”
President Barack Obama signed the 21st Century Cures Act into law in December after it passed Congress with bipartisan support. The act may allow the FDA to use evidence beyond survival rates, such as the size of a tumor, to approve a drug. Some, like Dr. Vinay Prasad of Oregon Health and Science University, say that the new process could make things worse.
“I’m actually sympathetic to the idea that there are ways in which the FDA can be more streamlined and do a quicker job,” Prasad, who was not involved with the study, said. “The one place you don’t want to cut a corner is safety and efficacy prior to coming to market.”
Mixed Reactions and Silver Linings of the Findings
While many were surprised at how high the numbers were, others were also relieved that they weren’t higher.
“That’s the million-dollar question: What’s the right amount? What’s the appropriate level of safety concerns to have identified only once the product is out of the gate?” Alexander said.
He also added that the issues range in severity and that it would be beneficial to dig deeper to see if the FDA could have spotted issues sooner or missed any.
Dr. Eric Topol, founder and director of the Scripps Translational Science Institute in La Jolla, also said the study was unsurprising but still found it troubling. He told The San Diego Union-Tribune that clinical trials are partly to blame for the problems because they are subject to cherry-picking to produce the best results.
“Usually those clinical trials are relatively small, and they are not representative of the real world of patients, with multiple medical conditions and variable age, and all other things that you don’t capture in a clinical trial,” Topol said. “Clinical trials have inclusion and exclusion criteria — it’s a contrived setting. And then, when the drug is put out in the real world, with mass quantities of exposure, all of a sudden you find things that you never saw before.”
FDA Reviewing the Findings of the Study
Ross praised the FDA for doing postmarket analysis to find issues and the agency said that it regularly monitors drugs after they have been approved. In a statement, a spokeswoman for the FDA said that it is reviewing the findings of the study.
“In general, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health,” FDA spokeswoman Angela Hoague told Kaiser Health News.