The US Food and Drug Administration (FDA) plays an important role in addressing the ongoing challenge of opioid abuse.1 The agency is strongly committed to taking forceful action to address this public health crisis2—as reflected by FDA’s recent move to request that an oxymorphone formulation (Opana ER, Endo Pharmaceuticals) be taken off the market.3 Opioids present unique challenges: they have significant benefits when used as prescribed, yet cause enormous harm when misused and abused. Recognizing these challenges, FDA has been taking specific steps to ensure that decisions are science-based and made within a benefit-risk framework that evaluates not only the outcomes of prescription opioids when used as prescribed, but also the public health effects of inappropriate use. By ensuring that FDA’s decision-making tools are properly matched to the reality of how opioids are used—and misused or abused—the agency can do more to confront the crisis.
Whenever FDA assesses the benefits and risks of a product, it must make certain that its decision making is based on all of the available information. Whether the question is initial marketing of a novel drug, or about a drug that has been on the market for years, and whether the drugs are approved for treating minor skin irritations or debilitating pain, the labeling and approved indications for those drugs must reflect the best judgement of FDA scientists based on all available evidence. To ensure that the full range of evidence is properly considered, FDA’s regulatory decisions are made by a team of experts that includes health care professionals (eg, physicians, pharmacists) as well as the needed scientific experts in epidemiology, communications, and manufacturing (among many others). For opioid drugs, reviewing all the available information requires extensive additional review—in both preapproval and postapproval settings—to assess the risk for misuse and abuse. In addition, to make certain that FDA is incorporating all relevant viewpoints and expertise into its decision making, the agency has expanded its use of advisory committees. FDA uses this input not only to make decisions regarding approval and the continuation of marketing, but also to put in place measures to prevent unsafe use of opioids, such as labeling for opioids that calls for rapid secure disposal as soon as the drugs are no longer needed, as a way to prevent misuse and abuse.4
Coordinating this complex assessment is challenging, but FDA has implemented a structured approach that allows the agency to conduct benefit-risk assessments effectively for prescription drugs that present complicated benefit-risk trade-offs.5 During the review process, FDA staff members use a structured benefit-risk assessment framework that includes an analysis of the nature and severity of the condition the drug is intended to treat or prevent, the available treatment options, and remaining uncertainties. This is in addition to specific appraisals of benefits, harms, and risk management, as well as specialized analyses relevant to safety, efficacy, and quality.6 Applying this framework to reviews helps structure multidisciplinary approaches, enhances review consistency, and improves communications within the team as well to the public and patients about the findings.
For many kinds of prescription drugs, FDA’s framework focuses largely on the benefits and risks of drugs when they are used by patients as prescribed. But for other types of drugs, such as antibiotics and opioids, more information is needed. For these products, FDA also assesses the benefits and risks from a larger public health framework and includes these considerations qualitatively in its decision making. For example, antibiotics used appropriately can have important and life-saving benefits for individuals. However, inappropriate use of antibiotics, whether for human or veterinary use, can contribute to the development of drug resistance. FDA should—and does—consider these competing benefits and risks in the course of its approval and labeling decisions for antibacterial drugs, so that physicians can properly take these considerations into account in their prescribing decisions.
When it comes to regulating opioids, FDA assesses diverse risks and benefits to ensure that it is considering the full public health implications of any decisions. For example, FDA’s decision to seek the market withdrawal of Opana ER reflects the agency’s concerns about the effects of the illicit use of this product in a population that is abusing it. As a result of FDA’s review of postmarketing data and discussions at a recent advisory committee meeting, the agency concluded that reformulated Opana ER was associated with a dangerous shift in the route of abuse from nasal snorting to injection. This was linked to a serious outbreak of HIV and hepatitis C infections in Indiana and multiple cases of thrombotic microangiopathy. The agency incorporated the data about these trends into its overall assessment of the benefits and risks of the product, resulting in a decision to call for withdrawal of the drug from the market. (FDA does not have mandatory recall authority for drug products but in urgent situations may request that a company remove a product from the market. If the company does not comply, the agency has the authority to initiate formal withdrawal proceedings.)
FDA’s emphasis on assessing the full public health effects of opioids also is reflected in the agency’s ongoing work to support the development of forms of prescription opioids that deter abuse2 and efforts to improve the safe prescribing of opioids through prescriber education.6 In specific cases, FDA has placed substantial restrictions on opioid use when they are needed to prevent abuse. For example, the agency has placed specific restrictions on the use of certain prescription fentanyl formulations that include restrictions on prescribers, pharmacies, and patients to address concerns about fentanyl abuse. These formulations of fentanyl, collectively termed transmucosal immediate-release fentanyl (TIRF), deliver a potent opioid analgesic rapidly across the oral mucosa and have the potential to cause life-threatening respiratory depression at any dose—a significant risk that justified the restrictions FDA enacted.
This approach to evaluating the full range of the public health implications related to opioids is very much in keeping with FDA’s approach to assessing other drugs with complicated benefit-risk profiles. For instance, to address antimicrobial resistance, FDA has included language in the labels of antibiotics to encourage their appropriate use and limited their use to treating infections that are proven or strongly suspected to be caused by bacteria. Another example involves sodium oxybate, a drug that has important therapeutic uses for narcolepsy. Sodium oxybate is the sodium salt of γ-hydroxybutrate, which has not been approved for any medical use and has the potential for abuse, such as in cases of sexual assault. Because of the risks of this drug, including central nervous system and respiratory depression, FDA limits prescribing of sodium oxybate to certified prescribers. In addition, the drug may be dispensed only to an enrolled patient by a certified pharmacy, and only by a certified pharmacy that ships drugs directly to patients. Sodium oxybate is not available in retail pharmacies.
Going forward, FDA is working to incorporate the effects of decisions on public health into its benefit-risk framework in a more quantitative manner that will supplement and enhance the strong qualitative work that the agency already performs. In so doing, FDA hopes to draw on the extensive work that has been done on tools in other settings.7 FDA is working to identify which tools are best suited for application to prescription opioid assessment, to ensure that the agency appropriately acknowledges and includes the public health effects of opioids into its regulatory decision-making framework. To assist in these efforts, FDA has commissioned a study from the National Academies of Sciences, Engineering, and Medicine (NASEM). NASEM has been asked to identify additional actions FDA should consider to address the opioid crisis with a particular focus on approaches the agency can take to improve its benefit-risk framework for opioids to support a more formal assessment of the public health risks and benefits.
Addressing the opioid crisis is a national priority, and the role prescription opioids have in that crisis is a critical focus for FDA. As the agency takes further regulatory steps, it must consider both the significant benefits of opioids for patients with severe and chronic pain, as well as the multiple adverse effects involving patients and public health. FDA is committed to taking decisive actions, grounded in the available science, following analysis conducted by FDA experts using the appropriate decision-making tools and templates and informed by FDA public advisory committees.
Corresponding Author: Janet Woodcock, MD, US Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993 (firstname.lastname@example.org).
Published Online: July 6, 2017. doi:10.1001/jama.2017.9205
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Gottlieb S, Woodcock J. Marshaling FDA Benefit-Risk Expertise to Address the Current Opioid Abuse Epidemic. JAMA. Published online July 06, 2017. doi:10.1001/jama.2017.9205