Markey and Manchin urge FDA to stop its study of opioids for chronic pain

https://www.statnews.com/2023/09/22/opioids-chronic-pain-study-markey-manchin-fda/

Two Democratic senators are warning the Food and Drug Administration not to proceed with a controversial trial meant to measure opioids’ effectiveness as a chronic pain treatment.

In a letter shared with STAT, Sens. Ed Markey (D-Mass.) and Joe Manchin (D-W.Va.) warned FDA Commissioner Robert Califf against using the method in the agency’s ongoing work to evaluate whether opioids, despite their widespread use, are effective at treating chronic pain. 

The FDA’s plan to use the research method, known as an enriched enrollment randomized withdrawal (EERW) trial, has drawn scrutiny as the agency has attempted to move forward — and as the country continues to reckon with its ongoing drug overdose crisis. 

“The potential harm of EERW studies is avoidable,” the senators wrote in their letter to Califf, which was delivered this week. “Other studies have already evaluated prolonged opioid use without biasing the outcome or exposing patients to risk.”

The senators, however, haven’t proposed an alternative study design, and it remains unclear what future role — if any — they believe prescription opioids should play in pain treatment. And while the FDA has acknowledged there is no ideal option for reevaluating the painkillers’ effectiveness, it says such studies are necessary given the ongoing opioid epidemic and lack of clarity regarding prescription opioids’ safety. 

The letter follows a contentious FDA panel discussion in April, at which the agency’s scientific advisers didn’t pull punches when criticizing the proposed study method. 

One panelist said the trial design “lacks face validity.” Another said it would represent “an awful lot of work for a very predictable answer.” Outside experts piled on during the public comment portion of the hearing, too — largely on the grounds that it will not yield useful data and that it is biased in favor of preserving access to opioids as a chronic pain treatment.

“These arguments suggest a curious and persistent attachment on the part of the FDA to a statistical design that’s completely at odds with the agency’s professed commitment to a fresh new approach,” Caleb Alexander, a professor of epidemiology at Johns Hopkins University, said then.

The study, as proposed, would require trial participants to switch from whichever prescription opioid they’re currently taking to a form of extended-release morphine. A random selection of participants would then be switched to a placebo group and undergo an eight-week taper off of opioids altogether.

Markey, Manchin, and outside experts have contended that as designed, the study would bias the trial in favor of opioids’ efficacy and, by extension, favor drug companies.

Doing so, they argue, would only double down on mistakes the FDA made decades ago when first evaluating the safety and effectiveness of certain prescription opioids, leading to a slew of overprescription and “pill mills” that helped fuel the first phase of the drug crisis. 

“Regrettably, the FDA approved these drugs before it adequately understood their profound impact, helping to facilitate this crisis,” Markey and Manchin wrote in their letter. “This history demands ongoing and careful review of opioid safety.” 

The senators noted that an external review commissioned by the FDA explicitly warned that the agency should “revisit” the use of EERW trials. 

While prescription opioid overprescribing is widely acknowledged to have driven countless addictions and overdoses in the early 2000s, prescription opioids currently account for a much smaller share of drug deaths. Over a quarter-million Americans died of prescription opioid overdoses between 1999 and 2021, according to the Centers for Disease Control and Prevention. 

Still, of the roughly 80,000 opioid overdose deaths reported in 2021, according to the CDC, just 21% were caused by prescription opioids. Synthetic opioids like fentanyl, instead, accounted for a vast majority of opioid deaths. 

While prescription opioid overdoses have held steady in recent years, chronic pain patients and prominent doctors specializing in pain treatment have warned that sharply curtailing prescription access could do more harm than good — potentially some causing stable pain patients to suffer needlessly, and others to switch to far more dangerous opioids, like illegally manufactured pills or fentanyl, once their prescription supply is cut off. 

Nonetheless, Markey and Manchin have held firm in their stance that the FDA should not only avoid using EERW clinical trials in the future, but also reevaluate past opioid approvals that relied on data derived from EERW studies. 

“Based on the risk associated with EERW studies and the availability of other study models, we ask the FDA not to permit the use of EERW to determine the long-term efficacy and tolerability of opioids in chronic pain patients,” the senators wrote. “We also urge you to reject EERW study designs for any future new drug applications for opioids and reconsider past opioid approval decisions using EERW.” 

Filed under: General Problems