Diana Zuckerman, National Center for Health Research, January 14, 2020
I am Dr. Diana Zuckerman, president of the National Center for Health Research. We conduct research and scrutinize the research conducted by others, to determine whether treatments have benefits that outweigh the risks. I previously was a researcher and faculty member at Vassar, Yale, and Harvard. I’m trained in epidemiology and public health and have spoken at dozens of FDA Advisory Committee meetings over the last 30 years.
I reviewed the same materials that you have reviewed for this meeting. As you know, FDA requested two adequate and well-controlled clinical trials in order to show evidence of efficacy for oxycodegol. One of these two trials failed to demonstrate efficacy. The second study showed serious problems with the drug. Moreover, when the FDA requested other types of additional data, the sponsor often did not provide it.
Forthcoming research conducted by Dr Caleb Alexander and his colleagues at Johns Hopkins indicate that for the last 20 years, the FDA typically approved opioids based on Phase III trials of short duration, often in narrowly defined pain populations. Important safety outcomes, such as opioid intolerance, aberrant use, diversion or overdose, have rarely been studied.
Your recommendations this week can help the FDA reverse that track record, which has resulted in tragedy for families across the country.
Approving this opioid as safe and effective for the management of chronic low back pain would directly contradict opioid prescribing guidance from federal agencies and professional societies. State and federal agencies and public health groups are actively discouraging the use of long-term opioids for chronic pain, including low back pain. This isn’t new –in 2016, the CDC stated that “The science of opioids for chronic pain is clear: for the vast majority of patients, the known, serious, and too-often-fatal risks far outweigh the unproven and transient benefits.” In 2017, the Department of Veterans Affairs and the Department of Defense issued “strong” recommendations “against initiation of long-term opioid therapy for chronic pain.” The American College of Physicians and the American Academy of Neurology have also cautioned clinicians to avoid using opioids for low back pain. There is a growing body of evidence that using opioids for chronic pain (other than cancer pain) is dangerous and not as effective as other options.
I urge you to urge the FDA to reject approval of this opioid for chronic pain, given these strong recommendations against ANY opioids for chronic pain.
One of the two efficacy trials failed to show benefit. The one “successful” trial was not that successful. Patients reported less pain during the pretrial period when they knew they were getting the drug, but the benefits for both the drug group and placebo group dropped precipitously after randomization and stayed at that lower benefit throughout the trial. This clearly suggests a major placebo effect. Even though the drug appeared to be slightly more effective than the placebo, the difference was only HALF a point on a 10-point pain scale – not enough to justify the risks.
I wish we could be confident that FDA’s Opioid Risk Evaluation and Mitigation Strategy (REMS) would reduce the risks of inappropriate use, but the training that FDA has required for physicians has unfortunately had little impact of inappropriate prescribing or use. In fact, neither the FDA nor opioid manufacturers have been able to demonstrate effectiveness of the REMS program.
In these enrichment studies, prior to randomization, all patients are made physiologically dependent on opioids in an open-label phase. Those randomized to placebo will experience withdrawal symptoms, including hypersensitivity to pain. Comparing patients who remain on an opioid to patients undergoing opioid withdrawal results in bias in favor of the opioid.
In conclusion, I respectfully request that you tell the FDA that if we have learned anything from the opioid epidemic, it is that FDA needs higher standards of evidence before approving any new opioids, and under no circumstances should a withdrawal study design be used in a study of chronic pain. And no opioid should be approved for chronic pain unless there is very solid evidence that the benefits outweigh the risks compared to other treatment options.
The Advisory Committee members agreed with our concerns and voted 27 to 0 against approval of the drug.