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FDA advisors recommended that the agency reconsider its planned postmarketing trial design to evaluate the long-term efficacy and tolerability of opioids in chronic pain patients.

Without holding a vote on Wednesday, the shared concerns about using an enriched enrollment randomized withdrawal (EERW) design as a required phase IV study for certain opioids currently available on the market.

"I don't think this really tells us anything about the most clinically meaningful question for this population, whether opioids are a better treatment than non-opioid analgesics or other approaches to treatment," said committee chair Brian T. Bateman, MD, MSc, of Stanford University School of Medicine in Palo Alto, California. "I think that's really where the agency's attention should be focused."

The 12-month trial, for chronic non-cancer pain patients who had initial tolerability to an extended-release (ER)/long-acting (LA) opioid, would include an open-label portion followed by a tapering period and a placebo period for the control group.

"It's just an awful lot of work for a possibly very predictable answer," said Mary Ellen McCann, MD, MPH, of Harvard Medical School in Boston. "It's called enriched enrollment. I almost think it's enhanced enrollment. It's designed to give a positive result before the study's even begun."

Maura S. McAuliffe, CRNA, PhD, of East Carolina University in Greenville, North Carolina, noted that she's "come away with the impression that, for me, to use an old-fashioned term, it lacks face validity. The outcomes to me are very predictable. If you give somebody ... 42 weeks of opioid therapy at relatively high doses, or potentially up to 240 mg a day, yeah, I think that they will have relief of their pain."

Prior to sharing their overall reservations about the agency's proposal, the committee discussed the practicality of the EERW design, and highlighted several specific concerns, including the shorter tapering schedule and the use of pain scores as a secondary endpoint. Several advisors said a focus on patient functionality would be more clinically meaningful than self-reported pain scores. They also recommended the tapering period be increased to a minimum of 14 days.

"One of the main concerns about this proposed design is a bit of an underestimation of the potential risks that would be there," said Mark C. Bicket, MD, PhD, of the University of Michigan in Ann Arbor. "While the internal validity would be strong, it would have the potential for some difficulty of interpretation, as well as not necessarily providing information that would be as clinically relevant when there is a large opportunity for that, so I would be certainly in favor of thinking about some of these other designs."

The committee also pointed out that it is unlikely that the study design would allow the researchers to maintain a sufficient number of study participants, which could affect the interpretation of outcomes.

While the advisors felt the length of the study (38 to 52 weeks) would be acceptable to evaluate long-term efficacy, they did express concerns about safety and the potential for confounding during such a long trial period. They also said they were doubtful that enough participants would be willing to remain in the placebo arm for the proposed length of the study.

While FDA staff acknowledged several challenges, they also emphasized that the EERW study design would likely be the best available option, considering the difficulties of conducting a placebo-controlled trial for chronic pain over a long time period.

During the public comments portion of the meeting, several stakeholders voiced their disapproval of the EERW design and the failure of the Opioid Postmarketing Requirements Consortium and FDA to successfully study the long-term efficacy and safety of opioids in the 10 years since the original postmarketing requirement was issued in 2013.

"The EERW is not double-blind. It's not even single-blind. Patients who take a drug with a strong psychoactive effect for weeks and months then switch to a placebo are likely to know it," said Andrew Kolodny, MD, co-director of the Opioid Policy Research Collaborative at the Heller School for Social Policy and Management at Brandeis University in Waltham, Massachusetts. "For obvious reasons the results from EERW are not generalizable because only patients who tolerate opioids and find them helpful are randomized."

Caleb Alexander, MD, MS, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, added, "I suppose the question is why more than 20 years into this epidemic, the FDA would risk squandering this valuable moment by examining the persistence of efficacy among a highly select subpopulation, rather than requiring sponsors to demonstrate whether ER/LA opioids work in the first place."

While the FDA typically follows the advice of its advisory committees, it isn't required to do so.

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