By: Robert M. Califf, M.D., Commissioner of Food and Drugs
Overdose prevention, reduction in opioid and other substance use disorders (SUD), and effective treatment and support for those with SUD are key priorities for the U.S. Food and Drug Administration and personally for me as Commissioner. In 2016, during my previous tenure as Commissioner, I requested that the National Academies for Sciences, Engineering, and Medicine (NASEM) examine the FDA’s framework for making regulatory decisions regarding opioids. NASEM issued its report, Pain Management and the Opioid Epidemic, in 2017. The report contained seven specific recommendations for the FDA’s consideration, as well as broader recommendations for federal agencies, state and local governments, and health-related organizations.
As we continue to prioritize our substance use and overdose prevention efforts, the NASEM report has been, and will remain, an important source to consider in our decision making. While the FDA has been working diligently to tackle this public health crisis, including taking many actions within our regulatory authority on these recommendations, there is still more work to be done. The ever-changing epidemiology of the crisis demands that we adapt our strategies to meet the evolving underlying causes.
An extensive timeline of our opioid-related activities is available on our website; however, I want to take this opportunity to share an update on our actions aligning with NASEM’s FDA-specific recommendations 6-1 through 6-7: Opioid Approval And Monitoring by the FDA.
Recommendation 6-1. Incorporate public health considerations into opioid-related regulatory decisions.
First and foremost, the FDA makes science-based decisions for all drugs within a benefit-risk framework. As described in a June 2019 statement, our benefit-risk assessment for opioids specifically takes into account how characteristics of a particular new drug product would impact the broader public health. This involves consideration of the risks related to misuse, abuse, opioid use disorder, accidental exposure, and overdose for both patients and others. We ensure drug approval and withdrawal decisions are made within this benefit-risk framework. For example, in June 2017, we requested the removal of the reformulated Opana ER (oxymorphone hydrochloride) from the market due to public health consequences associated with a shift in the route of abuse of the product from nasal to injection. Our request was based on postmarketing data demonstrating that the product’s risks associated with its abuse outweighed its benefit, not only for its intended patient population but also in regard to its potential for misuse and abuse.
In 2019, the FDA also issued draft guidance for industry, Opioid Analgesic Drugs: Considerations for Benefit-Risk Assessment Framework. This guidance summarizes the information that should be included in a new drug application for an opioid analgesic drug to facilitate the agency’s benefit-risk assessment as part of the broader public health effect of opioid analgesic drugs. However, we have learned that even the evolution of our framework is not suited to address all of the risks posed by opioids. The FDA does not have the statutory authority to require that drug developers seeking approval of opioids demonstrate that their products offer material safety advantages (e.g., a reduction in respiratory depression or a reduction in abuse liability) over existing approved opioids; we are exploring the need for potential new authorities to address this.
Recommendation 6-2. Require additional studies and the collection and analysis of data needed for a thorough assessment of broad public health considerations.
The FDA developed a national-level, data-driven system dynamics model of the opioid crisis, with the goal of informing potential regulatory actions to make meaningful gains in addressing the crisis. We recently published two peer-reviewed papers in collaboration with Harvard University and Massachusetts General Hospital: Modeling the evolution of the US opioid crisis for national policy development and Reducing opioid use disorder and overdose deaths in the United States: A dynamic modeling analysis. Continued efforts are underway to further enhance the model, implement a policy analysis tool, and disseminate findings. The agency has also begun to use qualitative systems-based approaches to support internal deliberation on complex opioid-related issues. An important message from these analyses and publications is that there is no “magic bullet” single intervention that will eliminate this ongoing risk, and in fact, even with effective interventions, the number of overdoses and overdose deaths will likely increase for several more years, largely driven by the influx of illicit fentanyl and its analogs.
The solution will require multiple interventions, each with a modest effect, but with the expectation that they will synergistically build off one another to combat this public health crisis. We are actively pursuing multiple strategies identified by the model with a focus on mitigating harms of opioid overdose involving fentanyl use. For example, one of the most impactful interventions identified through our modeling is to increase naloxone distribution to people who use opioids. This March, we collaborated with the Reagan-Udall Foundation to host a public meeting to explore frequently asked questions about access to naloxone. And just last week, we issued an immediately-in-effect guidance that clarifies the applicability of a public health emergency exclusion and exemption from certain requirements under the Drug Supply Chain Security Act, in terms of the distribution of FDA-approved naloxone products to harm reduction programs, and includes a related compliance policy. As stated in the related FDA Voices, we intend to stand by harm reduction programs’ efforts by supporting their ability to acquire FDA-approved naloxone products.
Recommendation 6-3. Ensure that public health considerations are adequately incorporated into clinical development.
The FDA develops guidance documents to represent our current thinking on important topics. These documents are meant to aid in clinical development with a comprehensive, science-based approach. We discussed above the draft guidance Opioid Analgesic Drugs: Considerations for Benefit-Risk Assessment Framework.
The FDA has also published a draft guidance for industry, titled Development of Non-Opioid Analgesics for Acute Pain, to help address challenges to developing non-addictive medical products to manage pain. We recognize the importance of fostering the development of non-addictive alternatives to opioids to manage acute and chronic pain. This is an opportunity to decrease exposure to opioids and associated risks. This guidance provides recommendations about development of non-opioid analgesic products for acute pain, including the application of expedited programs, and labeling claims. We are developing a similar guidance for industry on the development of non-addictive medical products for the management of chronic pain.
Recommendation 6-4. Increase the transparency of regulatory decisions for opioids in light of the committee’s proposed systems approach.
The FDA is committed to being transparent about regulatory decisions to the extent possible for all topics, and opioids are no exception. In addition to the extensive history of our opioid-related actions publicly available on the FDA website, the agency regularly seeks public feedback from patients, health care providers, professional organizations, and other experts through public hearings, meetings, and workshops, as well as other forms of stakeholder engagement. The FDA also publishes materials online describing our current thinking and explaining our regulatory decisions, such as guidance documents and scientific reviews. We also make our advisory committee meetings and materials available and open to the public.
Recommendation 6-5. Strengthen the post-approval oversight of opioids.
One of the ways the FDA has worked to strengthen our post-approval oversight of opioids is through our Risk Evaluation and Mitigation Strategies (REMS). REMS are drug safety programs that the FDA can require for certain medications, such as opioids, that have serious safety concerns to help ensure the benefits of the medication outweigh its risks.
In response to findings suggesting that changes were needed to improve patient safety and feedback from advisory committee meetings, the FDA modified two opioid REMS programs. First, the FDA approved a modification to the Transmucosal Immediate-Release Fentanyl (TIRF) REMS, in part to ensure that only patients who were opioid tolerant are prescribed and dispensed TIRF medicines. Second, the FDA approved the Opioid Analgesic REMS, which expanded the requirements under the Extended-Release and Long-Acting Opioid Analgesic REMS to include all opioid analgesics intended for outpatient use.
Furthermore, as I mentioned in a recent posting, currently we are re-examining the role of opioid analgesic prescriber education (including the need for a mandatory unified curriculum) to adequately inform opioid analgesic prescribers on managing pain. To support our considerations, we partnered with Duke-Margolis on two public workshops in the past year: Reconsidering Mandatory Opioid Prescriber Education and Identifying Key Competencies for Opioid Prescriber Education. You can find many interesting ideas and perspectives on this complex problem in the proceedings of these two meetings. We will need to reach agreement with relevant federal partners, professional groups, and other stakeholders, but the ample evidence that prescribing is improving but far from ideal, coupled with the increasing overdose death rate, compels us to seek more effective educational programs.
Recommendation 6-6. Conduct a full review of currently marketed/approved opioids.
The FDA cannot ignore that the science and context in which previous regulatory decisions were made has changed, and we must be flexible to evolve with the data. To help inform our future approach, I have initiated a review with the intended goal of understanding what revisions are needed to better support appropriate use of opioid analgesics. The review will be conducted by external experts associated with Ohio State University, who are familiar with the FDA, the 2017 NASEM recommendations, and opioid prescribing issues.
We have asked the reviewers to provide actionable recommendations for the FDA both within existing authorities and where additional authorities are needed. This is a multistep process, but we are working expeditiously. I look forward to sharing the findings of this review as soon as it is available. An area of particular importance is the long-term use of opioids. The pending Centers for Disease Control and Prevention guidelines on prescribing will contain the latest evidence overview about what is known as we reassess decisions in light of current evidence and prescribing.
Recommendation 6-7. Apply public health considerations to opioid scheduling decisions.
Drug scheduling is a multi-step process that involves several federal agencies, and it is spelled out under the Controlled Substances Act (CSA) (see 21 U.S.C. 811(b)). As part of this process, the FDA, at the behest of the U.S. Department of Health and Human Services (HHS), conducts a medical and scientific analysis looking at eight factors and then makes a recommendation on scheduling to the U.S. Drug Enforcement Administration (DEA). One of the eight factors that the FDA must consider in its assessment is what, if any, risk there is to public health. Thus, the FDA has applied and will continue to apply public health considerations to its assessments and scheduling recommendations regarding opioids. The final responsibility of designating drugs into schedules lies with the DEA, but we recognize the important role that the FDA has in informing this decision.
While the NASEM recommendations have been an important source of information for our extensive actions, there is still a lot of work ahead of us and the crisis has evolved in new directions. The opioid crisis has evolved beyond prescription opioids into a broader drug overdose crisis, largely driven by illicit fentanyl and its analogs. Other controlled substances, including benzodiazepines and stimulants (particularly methamphetamine), also are being used in combination with opioids. This crisis is killing more Americans than ever, and while overdose deaths are accelerating for all demographics, they are disproportionately affecting certain populations, such as non-Hispanic Black and non-Hispanic American Indian or Alaska Native populations. For these reasons, I recently introduced the FDA Overdose Prevention Framework to share our vision to undertake impactful, creative actions to prevent drug overdoses and reduce deaths. Addressing the overdose crisis is a top priority for me personally and the FDA. We remain committed to taking new steps to confront this crisis, including preserving appropriate access to controlled substances for patients who need them and expanding access to substance use disorder treatments.
We also acknowledge that the FDA acting alone is not enough. We are working to implement the HHS Overdose Prevention Strategy with our HHS partners and to stop the influx of illicit fentanyl and its analogs with the DEA and Customs and Border Protection. We recognize the critical importance of working with patient groups, affected families, and the clinical community to define appropriate use of controlled substances, and then to diligently pursue implementation strategies that optimize benefit and minimize risks at the individual and population levels.