Was FDA Lax in Approving Opioids Too Easily?

For at least two decades, the U.S. Food and Drug Administration has been approving new formulations of prescription opioids without requiring drug manufacturers to gather important information on safety and effectiveness, a new study claims.

The FDA approved dozens of these highly addictive medications for treatment of chronic pain between 1997 and 2018 based on clinical trials that:

Lasted no longer than 12 weeks,
Failed to systematically gather data on adverse events or safety concerns,
Actually weeded out of the final results from people who didn’t initially respond well to the drug.

“No trial was longer than 84 days, whereas people take these medicines for years and they’re labeled for chronic use,” said senior researcher Dr. G. Caleb Alexander, co-director of the Center for Drug Safety and Effectiveness at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

The FDA continued to approve opioid drugs based on limited and flawed information even as the opioid epidemic swept across the United States, Alexander and his colleagues argue.

“The primary harms that have driven the opioid epidemic have been because of the oversupply of opioids, especially for chronic use,” Alexander said. “The FDA has missed important opportunities to require manufacturers to produce more meaningful and clinically useful information about the safety and effectiveness of these products.”

PhRMA, the leading trade group for pharmaceutical manufacturers, responded to the new study with a statement from Public Affairs Director Jasmine Gossett.

“The biopharmaceutical industry is committed to ensuring the safety and efficacy of prescription medicines,” Gossett said. “Industry aims to bring innovative medicines to the patients that need them, while also remaining focused on the U.S. Food and Drug Administration’s regulatory requirements regarding science-based safety and efficacy throughout the process.”

More than 46,000 people in the United States died of opioid overdoses in 2018, including nearly 15,000 who died from using prescription opioids, the researchers said in background notes. The number of drug overdose deaths in 2018 was four times higher than in 1999, according to the U.S. Centers for Disease Control and Prevention.

FDA kept approving new formulations of opioids as epidemic raged

In the study, Alexander’s team reviewed all 48 new drug applications for opioid medicines approved by the FDA between 1997 and 2018, the years during which the opioid epidemic overwhelmed the United States.

Of the 48 applications, only one was for an entirely new opioid — tapentadol, marketed by Janssen Pharmaceuticals under the brand name Nucynta. The rest were new dosages, new formulations or new combinations of existing opioids such as oxycodone, fentanyl, morphine, hydrocodone, oxymorphone and tramadol.

The clinical trials that gathered data for these applications never lasted longer than three months, even though the opioids were intended for long-term use, Alexander noted.

Even as late as 2012 to 2018 — when the impact of the opioid epidemic had been widely documented across the country — the FDA still approved 16 new prescription opioids based on such short-term clinical trials, the researchers found.

These applications also failed to systematically assess well-known safety problems related to opioid use:

Only 38% tracked whether people developed a tolerance to the opioid, which would require greater doses to achieve the same pain relief.
Just 1 in 5 considered whether patients handed their prescription opioids off to other family members or sold them to acquaintances.
Only about 18% tracked misuse of the drug by the patients.
Only 13% reported opioid overdose symptoms.

“It’s one thing if a trial that was designed in 1998 excluded these outcomes, but it’s much harder to understand how a trial designed 10 years later could have excluded these outcomes,” Alexander said.

Alexander said part of the problem stems from the FDA’s acceptance of a clinical trial design called “enriched enrollment randomized withdrawal,” or EERW.

Participants in an EERW clinical trial are started on the study drug, but only patients who respond to the drug and tolerate its side effects are included in the study. Those patients who initially respond to the drug are then randomized to receive either it or a placebo.

Common trial design excluded those who didn’t respond to opioids

Defenders argue that EERW trials are necessary because most pain relievers only work in 30% to 50% of patients. Since the drugs are only effective in a minority of patients, they say, it’s better to remove in advance those who only would receive a placebo effect during the trial and instead focus on people who might really use it.

But Alexander argues that this trial design is flawed because it fails to consider the full range of potential bad reactions and lack of effectiveness that should be captured in a clinical trial.

Due to the EERW design, as many as 40% of potential participants were tossed out of these clinical trials because they didn’t initially respond to the drug, the researchers noted.

“This trial design [EERW] is controversial and fundamentally flawed, because it stacks the deck in favor of finding a product safe and effective when it very well may not be,” Alexander explained.

The FDA did not respond to HealthDay’s request for comment.

The new findings were published in the Sept. 29 issue of the Annals of Internal Medicine.

Dr. Michael Sinha, a visiting scholar at the Center for Health Policy and Law at Northeastern University School of Law in Boston, said the results align with an earlier study of his that found most new pain medications tend to be reformulations of already approved prescription opioids.

“Though two pivotal trials is the gold standard for FDA approval, the agency is increasingly willing to accept a single pivotal study as evidence of approval,” Sinha explained. “Reformulated pain medications, by definition, are not new molecular entities, so the companies can rely in part on data submitted for earlier approvals.”

Alexander said the FDA should abandon the EERW trial design, require manufacturers to conduct longer trials that gather more information regarding adverse effects, and re-label prescription opioids to reflect what has been learned about the pitfalls of chronic use.

“This isn’t a guessing game,” Alexander said. “The potential risks of these products have been exhaustively demonstrated.”

More information

The U.S. Centers for Disease Control and Prevention has more about the opioid epidemic.