New Research Framework Proposed for Developing and Testing Opioids

Applied Clinical Trials

With the rise in deaths, injuries, and treatment costs related to the abuse and misuse of opioid painkillers, the biomedical research community is seeking more effective and informative methods for testing and evaluating new pain medicines. Jill Wechsler reports.

With the rise in deaths, injuries, and treatment costs related to the abuse and misuse of opioid painkillers, the biomedical research community is seeking more effective and informative methods for testing and evaluating new pain medicines. A new report from the National Academies of Sciences, Engineering and Medicine (NASEM), which FDA requested as part of its February 2016 opioid action plan, outlines a “public health” framework for FDA review of new pain treatments.

Considering broader risks

The expert panel emphasizes the need for significant change in prescribing practices for opioids and greater public awareness of methods for preventing overdose deaths and other harms. A  main proposal is for FDA to shift from a product-specific approach for developing opioids and other pain medications to strategies that more explicitly incorporate public health considerations into opioid-related research and development decisions. This involves developing  a comprehensive, systems approach that fully considers a drug’s impact on families and communities and on the potential for abuse and addiction and diversion to illicit markets. Research plans and protocols for investigational products should weigh the benefits of providing pain relief and functional improvement to individual patients with the likelihood of harm and abuse, off-label or illicit use, and serious adverse events and death.

Also important are risks to specific subpopulations such as pregnant women and individuals with mental health conditions. A more comprehensive approach to conducting clinical trials for pain medicines is to include at-risk subpopulations in studies, to measure outcomes reported by household members or other third parties to overcome underreporting of misuse, and to examine potential interactions with other drugs commonly used with opioids. New abuse-deterrent formulas (ADFs) should be tested to better understand the mechanisms of manipulation that might be used to defeat deterrent features. While well-designed clinical trials should remain the main source of safety and efficacy evidence, public health related information may come from less traditional data sources able to provide real-world evidence.

The panel further advises FDA to create an internal system to scrutinize all investigational new drug (IND) applications for opioids on whether public health considerations are adequately incorporated into clinical development. New guidance, moreover, should address how sponsors may identify specific public health data most relevant to different types of opioids and to encourage firms to meet with agency staff during development to address these issues. Additional advisories may outline opioid-specific clinical development considerations, including how studies of these products differ from existing analgesics. The panel emphasizes that expedited development or accelerated review pathways should rarely be used for opioids.

In evaluating a new pain therapy for approval, FDA should weigh the product’s ability to provide relief from serious pain, with how vulnerable it is to diversion and to causing overdoses and other diseases such as AIDS and hepatitis. The panel proposes that the agency release summary versions of complete response letters to ensure transparency in decision-making, while also calling for stronger FDA post-approval oversight, with periodic evaluations of marketed products to ensure continued safe and appropriate use. Following a full “re-review” of all marketed opioids, FDA should consider withdrawing from the market those medicines found to raise high risks.

FDA initiatives

Many of the NASEM recommendations resemble initiatives announced by FDA commissioner Scott Gottlieb to update FDA’s response to the opioid crisis. Gottlieb and Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), outlined a quantitative framework for assessing opioid product risks, similar to the NASEM report recommendation, in an article posted by the Journal of the American Medical Association (JAMA) July 6, 2017.

Gottlieb opened a July workshop on evaluating ADFs by urging a “fresh look” at how FDA balances patient access to appropriate painkillers with efforts to ensure public safety. He announced an update to the opioid Risk Evaluation and Mitigation Strategy (REMS) for extended-release opioids to also cover immediate-release products and expanded provider training under the REMS to a broader range of health professionals, raising the possibility of making such provider education mandatory. A new FDA Opioid Policy Steering Committee headed by deputy commissioner Rachel Sherman will examine that issue, as well as the impact of limits or caps on pills and prescriptions and FDA’s consideration of risk of abuse in evaluating new drug applications.

The ultimate solution to opioid misuse is to replace these dangerous products with more effective, non-addictive pain medicines. Experts question whether newer extended-release opioids are really beneficial or if they actually worsen pain. The National Institutes of Health has formed a public-private partnership to speed development of new pain therapies and addiction treatments, including opioids with less euphoric effect and fewer side effects for chronic pain patients. There’s growing excitement over experimental drugs and gene therapies that block nerve pathways of pain and hope that precision medicine may lead to tailored pain treatments for individuals.