The head of the Food and Drug Administration (FDA), Dr. Robert Califf, announced on August 30, 2022 that, in addition to an extensive review of opioid regulations, the agency is launching a framework aimed at preventing overdose-related deaths.  Commissioner Califf previously committed to leading a review of opioid regulations during his December 2021 confirmation hearing, in response to repeated questions from Senators regarding FDA’s response to the ongoing opioid epidemic and broader public criticism of the agency’s historical actions in the space.  The commitment to regulatory review also follows criticism FDA has received over the years for approving OxyContin in 1995 and many other addictive opioid drugs since then without requiring more thorough warning labels and other protections that could help combat misuse and over-prescribing.

The FDA framework for overdose prevention (Framework) includes four central components: (1) supporting primary prevention by eliminating unnecessary initial prescription drug exposure and inappropriate prescribing of opioids, (2) encouraging harm reduction through innovation and education, (3) boosting the development of evidence-based treatments for substance-use disorders, and (4) protecting the public from unapproved, diverted, or counterfeit drugs that contain elevated overdose risks.  The agency’s announcement of the Framework follows announcements by the U.S. Department of Health and Human Services of its Overdose Prevention Strategy and by President Biden of the National Drug Control Strategy.

Framework Component One: Supporting Primary Prevention

The first component of the Framework is aimed at eliminating unnecessary initial exposure and inappropriate prescribing of substances with abuse potential.  To that end, FDA is:

• Promoting appropriate prescribing of medications with abuse potential, including opioids, stimulants, and benzodiazepines

• Exploring the need for potential new authorities for opioid approval standards

• Supporting development of alternative, non-addictive therapies and technologies

• Evaluating innovative packaging and disposal solutions of medications with abuse potential

Although training for prescribers exists today in the context of the Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Program, it is not mandatory for health care providers and the agency has been vocal about the fact that such training has not been successful in reducing over-prescribing and opioid overdoses. In addition, with respect to the last action item within Component One of the Framework, FDA requested public input in April 2022 on a proposal to require that mail-back envelopes be included with opioid products dispensed in an outpatient setting. The proposal was accompanied by a public statement from Dr. Califf, who emphasized that the “mail-back envelope requirement under consideration for these unused medications would complement current disposal programs and provide meaningful and attainable steps to improve [opioid] safe use and disposal.”

FDA noted in the recent proposal that the October 2018-enacted Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT Act) amended the agency’s authorizing statute to allow FDA to require, through a REMS, that “a safe disposal packaging or safe disposal system for the purposes of rendering the drug nonretrievable be dispensed to certain patients with opioids or other drugs that pose a serious risk of abuse or overdose if, among other things, FDA determines that such safe disposal packaging or system may mitigate such risks and is sufficiently available.”  The agency also encouraged manufacturers and others to “innovate in this space” and to potentially develop “novel packaging or other safe disposal options that would meet the SUPPORT Act standards.”

In the meantime, however, FDA expressed its view that a requirement for mail-back envelopes as part of the REMS for all dispensed opioid analgesics “could be a significant and readily achievable step toward improving the safe use of opioid analgesics.” Whether and to what extent that April 2022 notice – whose public comment period has ended – leads to changes to the Opioid Analgesic REMS or otherwise results in new rulemaking by FDA in light of the broader goals articulated in the Framework remains to be seen. Comments submitted to the docket suggest, however, that stakeholders had enough safety concerns related to the idea that the agency may potentially need to go back to the drawing board before attempting to implement anything under its new SUPPORT Act authorities.  

Framework Component Two: Encouraging Harm Reduction

The second component of the Framework is designed to reduce morbidity and mortality associated with overdoses.  To achieve this goal, FDA is:

• Expanding availability and access to overdose reversal products, including naloxone, by supporting accelerated review of products and exploring over-the-counter access

• Supporting development of novel overdose reversal products

• Supporting development and authorization of fentanyl test strips to test human specimens at the point of care

Framework Component Three: Advancing Development of Evidence-Based Treatments

The third component of the Framework is aimed at expanding therapy options for Americans struggling with substance use disorders (SUD), as well as the availability of and access to such therapies.  To meet these objectives, FDA is:

• Expanding availability and access to evidence-based treatments for SUD

• Facilitating development of treatments for SUD, with focus on stimulant use disorder

• Facilitating opportunities to incorporate stakeholder engagement into treatment  development

Framework Component Four: Protecting the Public from Unapproved, Diverted, or Counterfeit Drugs Presenting Overdose Risks

The fourth component of the Framework is aimed at enhancing the security of the United States drug supply chain.  To do so, the FDA is taking steps toward:

• Preventing and reducing counterfeit and illegal online sales

• Instituting enhanced targeting and screening methods at International Mail Facilities,  Express Couriers, and Ports of Entry

• Taking compliance and enforcement actions against unapproved, diverted, or counterfeit drug products

As an example of recent actions in this area, Dr. Califf cited the first-ever jointly issued FDA and Drug Enforcement Administration (DEA) warning letters to websites selling illegal Schedule II controlled substances directly to consumers, without receiving and verifying valid prescriptions for such drugs or otherwise complying with DEA requirements for the distribution of controlled substances. This action further highlights that many of the elements of FDA’s new Framework are existing priorities for the agency and its partners, and reiterates for the public how complex the response to the opioid epidemic is and will continue to be. As the Commissioner has said in multiple contexts, there is no “silver bullet” to fix this serious and immensely tragic public health challenge.