The FDA’s latest proposed trial design for evaluating the effectiveness of opioids as chronic pain treatments has been met with backlash from pain management and anesthesiology experts who contend the protocol is flawed on multiple fronts.

The design, an enriched enrollment randomized withdrawal (EERW) study, assigns participants to extended-release morphine for a period of time in an open-label, prerandomization stage. Patients who see positive effects and tolerate the side effects are then selected, at random, to either continue treatment or switch to placebo and taper off.

The trial design looks to answer whether opioids remain effective as analgesics over longer time periods and have additional risks associated with long-term use, another important question in the ongoing and controversial debate around opioid use and prescribing.

But some experts on the Anesthetic and Analgesic Drug Products Advisory Committee, which met to discuss this latest plan on Wednesday, believe there are a number of issues with the agency’s proposal. Public speakers, too, expressed concerns, mainly about the trial design’s potential biases toward patients placed in the treatment arm.

Maura McAuliffe, professor emeritus at East Carolina University’s College of Nursing, for instance, says the agency’s proposed trial places “very, very significant” burden on participants, risks unblinding patients in the placebo arm during tapering, will have limited generalizability in its findings to other types of pain patients, and has risks of bias.

Maryam Jowza, associate professor of anesthesiology and pain management at the University of North Carolina-Chapel Hill, echoed McAuliffe’s sentiments, expressing concern about unblinding as well as the randomized withdrawal element of the trial and the fact that it screens out patients who don’t find the treatment effective.

“I think something that we underplay is that with long-term opioid use, there’s changes that take place in the nervous system that are not readily reversible,” she said. “What we’re assuming is that once the medication is tapered or withdrawn, that those changes no longer are present, and clinically, I don’t find that this is the case. When we talk about randomized withdrawal, and we’re taking a look at that to study efficacy, I’m not sure if that’s the best way to do it for an opioid study.”

The way the FDA intends to use the results of the proposed trial to inform indication language is another critical question that needs to be answered, Jay Horrow, clinical professor of anesthesiology and critical care medicine at the University of Pennsylvania’s Perelman School of Medicine, added.

If the findings will be used to support an indication along the lines of “effective for chronic pain,” the EERW approach will be a severe limitation, said Horrow, who also is a researcher with Bristol Myers Squibb. But if the data will be used to support such language as “effective to treat chronic pain in those who respond to initial treatment,” it is a well-suited trial type, he said.

Timothy Ness, professor emeritus at the University of Alabama at Birmingham’s Department of Anesthesiology and Perioperative Medicine, expressed similar views. The trial would only potentially answer whether there is a subset of patients that might benefit from long-term opioid therapy, he said, not broader questions on long-term opioid use.

The FDA itself has acknowledged the significant challenges inherent in designing opioid efficacy trials due to their intended target populations and the pharmacology of the drugs themselves.

Watch the full advisory committee meeting here: https://bit.ly/41hAl9v.