About a third of the drugs that the Food and Drug Administration deems safe and effective go on to have major safety issues years after their approval, researchers report in JAMA.

The finding lands amid pressure from lawmakers and the Trump administration to hasten the already fast pace of the agency’s drug reviews.

Among 222 novel therapeutics approved by the agency between 2001 and 2010, 71 (or 32 percent) had safety events arise a median of 4.2 years later. Safety events assessed in the study were marked by any of three FDA actions: withdrawing a drug entirely from the market; adding a boxed warning to a drug’s label, which is often added for life-threatening health risks; or issuing a safety communication, which is for serious, but non-life-threatening, health risks.

In all, the agency withdrew three drugs*, added boxed warnings to 61, and issued safety communications for 59.

The authors of the study, led by Joseph Ross, a Yale professor of general medicine and public health policy, hope the analysis helps regulators identify features of drugs that may have hidden health risks at the time of their review. This could allow regulators to beef up reviews, increase post-market monitoring, or boost data sharing for certain drugs.

“The majority of pivotal trials that form the basis for FDA approval enroll fewer than 1,000 patients with follow-up of six months or less, which may make it challenging to identify uncommon or long-term serious safety risks,” Ross and his colleagues note. “The high frequency of post-market safety events highlights the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.”

But the study also may offer a glimpse of what could come from policies designed to quicken the FDA’s already swift reviews.

In his first speech to Congress, President Donald Trump called the FDA’s review process “slow and burdensome.” He vowed to “slash the restraints” at the agency. However, the FDA is moving more quickly than it has in its recent history. Since Congress passed the Prescription Drug User Fee Act in 1992, which allows the FDA to collect review fees from drug makers, the time for reviews has dropped steadily. In 2016, median standard review time fell to around 10 months, down from about 27 months in 1993.

Last month, Ross and colleagues (Nicholas Downing, of Brigham and Women’s Hospital, and Audrey Zhang, of New York University School of Medicine) reported in The New England Journal of Medicine, that the FDA was, on average, two months faster at approving drugs than its European counterpart, the European Medicines Agency.

Unsafe reviews

In their new study, the researchers looked to see how the speed of approval—along with other factors—might affect post-market safety. First, “biologics” (that is, medicines composed of sugars, proteins, living viruses, cells, tissue, or complex combinations of things) were more likely to lead to post-market safety problems than “pharmaceuticals” (medicines made of small molecules). Also, among the different treatment classes, drugs for psychiatric diseases were the most likely to have post-market safety events, as compared with the others, such as those that treat cancers and blood diseases.

When it came to approval time, the results were a bit complicated. The drugs that gained FDA approval right before the deadline for their review were more likely to have post-market safety issues. On the flip-side, drugs with the quickest approvals (under 200 days) were less likely to have safety issues later. The authors interpreted this as suggesting that if drugs have strong pre-market safety data and can sail through their reviews, it may be a good indicator of their overall safety. Whereas, when drugs get hung up in their reviews, possibly because regulators are trying to parse weak or questionable pre-market safety data, it may be a red flag that there are post-market safety problems to come.

Perhaps most useful for future policy discussions, the researchers found that drugs approved through “accelerated” review processes were more likely to have safety issues later. Accelerated reviews can be granted for drugs that address a serious unmet medical need, and they allow the FDA to use “ surrogate endpoints ” for safety and effectiveness. That means instead of testing if a drug achieves a direct endpoint, such as preventing a patient from having a heart attack, drug makers can monitor if it reaches a surrogate endpoint, such as lowering “bad” LDL cholesterol. New policies, included in the 21st Century Cures Act , push for more use of surrogates in drug-approval processes.

The authors noted limitations in their study. For one, they only had safety data until 2015 for drugs approved between 2001 and 2010. Safety events could still pop up later. And the researchers didn’t track other potential safety issues, like label or dosage changes.

Still, the data strongly point to a need for a way to monitor safety once drugs hit the market. Current methods rely on voluntary reporting of safety issues. And, of course, “further research is needed to better understand the dynamics between more rapid and near–regulatory deadline approval and drug safety,” the authors conclude.

*The three withdrawn drugs include valdecoxib, an anti-inflammatory, and tegaserod, a drug used for the treatment of irritable bowel syndrome. Both were withdrawn over concerns of cardiovascular events. The third is efalizumab, a drug used to treat psoriasis, which was withdrawn over the risk of progressive multifocal leukoencephalopathy, a disease that damages the brain.

JAMA, 2017. DOI: 10.1001/jama.2017.5150 (About DOIs).