Study finds 20 years of shortcoming in FDA evaluations for new opioid drug approvals

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A new study from Johns Hopkins Bloomberg School of Public Health has found that approvals for prescription opioids by the U.S. Food and Drug Administration have some shortcomings for more than two decades.

The study looked at clinical trial data provided by manufacturers for all new opioid applications approved by the FDA between 1997 and 2018. It found that approvals were based on evaluations in narrowly-defined patient groups and that certain safety-related outcomes have rarely been systematically assessed within those groups.

Researchers found that drug trials never lasted for more than three months for products labeled for chronic pain treatment and often excluded patients who could not tolerate the drugs. Additionally, the trial failed to systematically assess some important and well-known opioid-related adverse events, the study found.

“While the FDA, on the whole, gets much more right than they get wrong in the approval process for prescription opioids, our findings suggest that over time the agency missed important opportunities to strengthen the regulation of opioid products,” says study senior author G. Caleb Alexander, a professor in the Bloomberg School’s Department of Epidemiology.

The study found that 17 of 21 opioids approved for chronic pain based on new clinical trials were set up according to an “enriched enrollment with randomized withdrawal” design – meaning a patient who could not tolerate the drug being tested would be withdrawn from the study before the full treatment and analysis was completed. Researchers found that a median of 37.2 percent of the patient sample was excluded this way.

“This design essentially stacks the deck in favor of finding a medicine safe and effective,” Alexander says, “because it starts by excluding a large group of people for which the drug is not safe or effective.”

The study also found that the opioid trails were relatively short and small-scale, considering the drugs’ potential side effects. In the clinical trials for opioids labeled for chronic pain, a median of the trials consisted of only 299 patients, and none lasted for more than 84 days.

Lastly, the researchers found that when monitoring the trials for safety issues, including the potential for non-medical use and the development of tolerance, the trials relied too much on the patients’ spontaneous reporting.

A third finding was that monitoring of safety issues, including the potential for non-medical use and the development of tolerance, relied too much on patients’ spontaneous reports.

The group recommended that the FDA no longer rely on “enriched enrollment with randomized withdrawal” trials. The FDA should require the trials to be more comprehensive and with a systematic assessment of how well the products are tolerated and what adverse side effects they may produce.

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