The Food and Drug Administration has been lax in how it's approved prescription opioid treatments dating back to the late 1990s, according to a new study out Monday. The study found that the FDA has routinely approved new opioid drugs or new formulations of existing drugs on the basis of limited evidence from clinical trials and often with little information on their potential safety risks-a concern, given the role that prescription opioids are thought to have played in the drug overdose crisis.
The study, published in the Annals of Internal Medicine, looked at 48 new drug applications (NDAs) for opioid products meant to treat pain that were successfully submitted to the FDA between 1997 and 2018. NDAs are the formal paperwork that pharmaceutical companies have to file for an experimental product to receive FDA approval, and they usually include data from clinical trials that involve human volunteers. During that time, all but one of these NDAs were for existing opioids, with the company either asking for approval of a new method for taking it, a new approved dosage, or for a new approved combination of existing drugs.
"We examined one important facet of opioid regulation-how high a bar the FDA has set for new products reaching the market," lead author Caleb Alexander, an epidemiologist, doctor and drug safety researcher at Johns Hopkins University, said in an email.
The vast majority of the NDAs, 39 in total, concerned a product intended to treat chronic pain. But only 21 of these NDAs for chronic pain provided data from Phase III clinical trials, the stage of clinical research considered the gold standard for evidence of a drug's effectiveness or safety. And even these trials were relatively small and brief, with the median study size being around 300 participants, who were followed for a median length of 84 days (a similar size and trial length was seen in the NDAs for opioid treatments for acute pain).
Moreover, these trials were often designed to exclude patients who weren't expected to respond well to the drug or who were at higher risk of bad side effects, which is a common practice in the industry and is known as an enriched enrollment randomized withdrawal (EERW) trial. Basically, volunteers who don't respond well to a drug in early trials are left out of the next phase of the research, which is randomized and placebo-controlled. While advocates have claimed that EERW trials allow doctors to better study drugs that only work for a minority of patients-opioids being a well-known example-critics have argued that these trials can be manipulated by drug companies to make a drug seem more effective or safer than it would be in a real-world setting.
Another common problem, Alexander said, is that drug companies often didn't collect or present data to the FDA on how often their drugs were being diverted or used for nonmedical reasons.
The FDA does allow companies to submit for approval new products that are based on existing drugs with less evidence than what's needed for a wholly new drug. But the shortcuts taken in the trial data from these NDAs make it harder for doctors to know how truly safe or effective these drugs will be for any one patient, Alexander said. And that's especially worrying for opioid drugs intended to be taken by chronic pain patients for months or years at a time.
Last year, an estimated 71,000 Americans died from a drug overdose, most often involving an opioid. Prescription opioids are no longer the leading cause of opioid overdose deaths, with more potent synthetic opioids such as fentanyl having emerged since. The vast majority of people who use opioids for pain relief do not develop opioid use disorder, but many people who develop opioid use disorder often report first using prescription opioids. The first wave of the opioid crisis during the 1990s and 2000s was fueled by the glut of prescription opioids that became easily available on the market around then-a trend that the FDA played a part in causing and has not done enough to stop.
In particular, the FDA has been criticized for approving the opioid Oxycontin in 1996, based on evidence of its lower addiction risk that was later found to be misleading. And critics continue to allege that the agency is bending over backward to approve new opioid products, without much clear evidence that these products are fulfilling an unmet need.
Alexander's study isn't meant to quantify the impact that the FDA's handling of new opioid approvals during the past 20 years has had on the overdose crisis. But he notes that "both clinicians and patients rely on the FDA to ensure that medicines are safe and effective when they are approved, and the FDA missed important opportunities to increase the evidence base underlying these products." Though his study does point to some encouraging trends, with more recent approvals based on larger sample sizes, there are other signs that the FDA is still falling flat. The use of data from EEWR trials has actually gone up in recent years in submitted NDAs, for instance.
Going forward, Alexander said, the FDA can improve opioid regulation by requiring manufacturers to produce more, and more relevant, information about the systematic safety and efficacy of opioids, as well as developing better guidelines for these companies to follow.
"The FDA should also relabel chronic opioids so that the labelling for these important products better reflects the conditions under which they have been studied for regulatory approval," he added.
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