To evaluate the long-term efficacy and tolerability of a representative extended-release (ER)/long-acting (LA) opioid in a 12-month placebo-controlled trial, FDA staff are considering an enriched enrollment randomized withdrawal (EERW) study design, they noted in a briefing document ahead of an advisory committee meeting.
On Wednesday, the Anesthetic and Analgesic Drug Products Advisory Committee will consider the advantages and limitations of using an EERW design to evaluate morphine sulfate ER in a phase IV trial -- part of a postmarketing requirement -- among patients with chronic non-cancer pain who had initial tolerability to the ER opioid.
The committee will also discuss looking at the incidence of opioid-induced hyperalgesia (OIH), a condition in which a patient's increase in pain can be attributed to the treatment with an opioid, among other objectives, such as changes in physical function and in levels of anxiety and depression.
FDA staff said the EERW study protocol might be the best available design amid the many challenges of conducting placebo-controlled clinical trials for chronic pain over an extended time period.
"Due to the unique clinical considerations regarding patients with chronic pain appropriate for long-term opioid therapy, the design of the clinical trials intended to evaluate the treatment effect of analgesics in this patient population poses certain challenges," they wrote. "There are different options with respect to clinical trial designs, each with their own advantages and disadvantages."
"There are also challenges in selecting appropriate patients, controls, and endpoints, as well as to retain enough patients to generate interpretable data," they added.
To address these concerns, FDA staff wrote that the EERW design "varies from the conventional clinical trial design in the timing of randomization and dichotomization to two treatment groups, opioid or placebo," noting that this design uses "a long prerandomization period and a relatively short period where patients will be on double-blind drug."
"The EERW design, while not ideal, appears to offer the best compromise to answer this public health question," they wrote.
In addition, the EERW study design "may inform the incidence of OIH provided that the protocol includes appropriate OIH surveillance and a prospective definition of OIH," they added.
The advisory committee will also be asked to discuss the likelihood of maintaining a sufficient number of study participants using the study design, specifically considering the acceptable degree of dropout related to its effects on the interpretation of outcomes.
FDA staff noted that dropout during a 12-month trial could be the most challenging aspect of evaluating the long-term efficacy of opioids. "Our prior experience suggests a substantial dropout rate even over the 12 weeks of prior randomized trials (in the 40-50% range), and therefore raises the real concern that a dropout rate in a 52-week duration trial would be higher, undermining the robustness of the between-group comparison at the trial primary timepoint," they wrote.
Other factors, such as the adequacy of the length of the study (38 to 52 weeks) and secondary endpoints, including time-to-treatment failure, pain scores, and a proposed tapering scheme to mitigate concerns over unblinding the participants, will also be discussed.
Finally, the advisory committee will be asked to consider other potential study designs that could be used in the assessment of long-term use of opioids.
"With respect to the parallel-group, placebo-controlled randomized controlled study, this approach poses the challenges of recruiting patients into a long duration placebo-controlled study -- in patients who have severe pain intensity having failed other treatments," FDA staff wrote. "The prior study included a long-term placebo-controlled period and failed due to recruitment issues."
After the original postmarketing requirement was issued in 2013, the Opioid Postmarketing Requirements Consortium (OPC) started a 26-week study in patients with high opioid requirements in 2016, but decided to end the study in 2018 due to several factors, including challenges with patients and changes to opioid prescribing requirements. The OPC submitted an updated protocol for a 52-week trial in January 2020. With guidance from FDA staff, the EERW protocol was refined and submitted for consideration.
Last week, the FDA issued several updates to the prescribing information and labeling for immediate-release (IR) and ER/LA opioids that will make the increased risk of overdose with increased doses more clear. The changes will also highlight the risk of OIH.
While the FDA typically follows the advice of its advisory committees, isn't required to do so.