The Opioid Epidemic and the Food and Drug Administration: Legal Authorities and Recent Agency Action
Released: 2018-12-27T00:00:00

A ccording to the Centers for Disease Control and Prevention (CDC) , "115 Americans die every day from an opioid overdose," and deaths from prescription opioids have more than quadrupled since 1999. The epidemic's origins are complex, with fingers pointed at pharmaceutical manufacturers and distributors, pharmacies, addicts and dealers, and health care professionals. Like the causes of the opioid epidemic, any solutions to the problem will likely involve many actors, including the federal government. The Food and Drug Administration (FDA)âthe executive branch agency tasked with protecting the public health by ensuring the nation's drug supply is safe and effective âhas a central role in confronting drug abuse, including the opioid epidemic.

Given the severity of the opioid epidemic and its prominence as a matter of national concern, efforts to combat the issue will likely continue to be of significant interest to Congress. This report focuses on FDA as a key player in these efforts. The report provides a brief overview of FDA's role in approving new prescription drugs, including opioids, and also addresses selected examples of the agency's existing legal authorities under the Federal Food, Drug, and Cosmetic Act (FD&C Act or Act) and recent action taken with respect to the opioid crisis. The report concludes with a discussion of selected provisions of the recently enacted Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT Act), which amends the FD&C Act.

FDA Approval of Prescription Drugs and the Challenges of Opioids

In 1938, Congress passed the FD&C Act in an effort to bolster federal protection of public health and safety by creating new requirements designed to keep impure or dangerous products out of interstate commerce. FDA is the primary federal agency responsible for the administration and enforcement of the FD&C Act. With respect to prescription drugs, the FD&C Act establishes a comprehensive federal system of premarket approval for such drugs. The Act generally prohibits introducing or delivering new drugs in interstate commerce unless the drug is approved by FDA. Under current law, in order to market a new brand-name drug, a manufacturer must file a new drug application (NDA) with FDA, which must include, among other things, "full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use." FDA may approve an NDA only if the sponsor of the application (e.g., a drug manufacturer or marketer) demonstrates, among other things, that the drug is safe and effective under the conditions prescribed, recommended, or suggested in the product's labeling. The FD&C Act generally authorizes FDA to refuse to approve an NDA if the agency finds the labeling is false or misleading in any particular way. Additionally, many drugsâincluding a majority of opioid products approved in recent decadesâare reformulations of existing products . Reformulated drugs may also be approved through an NDA under the FD&C Act, and drug sponsors may rely on safety and efficacy data of previously approved products as part of their applications.

In addition to premarket authority, FDA also possesses postmarket authority to monitor drugs that have entered interstate commerce and ensure that the benefits of a drug continue to overbalance the risks. For example, FDA may require postmarket drug labeling changes if the agency becomes aware of certain new information that the Secretary of Health and Human Services (HHS Secretary) believes should be included in the labeling of the drug, as well as postapproval studies, clinical trials, and risk evaluation mitigation strategies (REMS) under certain circumstances. Additionally, the agency may also monitor safety data related to approved drugs through an active postmarket risk assessment system.

In general, FDA has broad authority with respect to the implementation of the FD&C Act. The agency is empowered to promulgate regulations to efficiently enforce the Act's broad mandates and develop guidance documents that set forth the agency's interpretation of the Act or accompanying regulations. The FD&C Act also authorizes FDA to "conduct examinations and investigations" to administer the Act and to disseminate information about regulated products involving "imminent danger to health" or "gross deception to the consumer."

While new opioids are generally subject to the same approval requirements as most other drugs, FDA's task to ensure the safety and efficacy of opioids is particularly difficult. Throughout recorded history , societies have struggled with balancing the medicinal use of opioids in pain management with the concomitant euphoric effects that have induced the substance's abuse. Sixty years ago, the head of surgery at the University of Illinois noted, "we must appreciate that severe constant pain will destroy the morale of the sturdiest individual. . . [b]ut. . . we are often loathe to give liberal amounts of narcotics because the drug addiction itself may become a hideous spectacle." As a result of these difficulties, for nearly a century , opioid pain medications were used in the United States primarily to treat acute and cancer-related pain.

However, studies from the 1970s revealing inadequate management of chronic pain, followed by influential articles published in the 1980s reporting a low incidence of addictive behavior in small groups of cancer and noncancer patients, led to a trend toward more liberal prescribing of opioids within the medical community. The shifting views on the safety and efficacy of opioids culminated in FDA's 1995 approval of Purdue Pharma's controlled-release opioid pain medication, OxyContin, the product some point to as the catalyst for the current opioid epidemic. Between 2000 and 2009 , the medical community established new standards for pain management, which included pain as a new vital sign , and prescriptions for opioids increased. By 2016, an estimated 11.5 million Americans were abusing prescription painkillers.

FDA's legal authorities and recent actions taken in response to the opioid epidemic may be considered against the backdrop of challenging legal and policy questions about the role FDA can or should play with respect to regulation of products that have public health consequences. As part of these questions, FDA officials have discussed the importance of striking the right balance between taking aggressive action to fight opioid misuse and addiction, while simultaneously protecting patients who experience severe pain. Additionally, given that the agency's approach to evaluating and approving drugs is based on "the conditions prescribed, recommended, or suggested" in FDA-approved labeling, questions may arise about the extent to which the agency has legal authority to consider drug misuse in carrying out its regulatory actions. Under a number of FD&C Act provisions, FDA has considerable discretion in determining the information that is relevant to its regulatory decisions. The following sections of this report illustrate how FDA has exercised its discretion, particularly in its response to prescription opioid abuse and addiction.

FDA Authority and Recent Agency Action Related to the Opioid Epidemic

FDA is taking a multifaceted approach in its response to the opioid epidemic. FDA officials have indicated that the agency focuses its efforts in four areas:

1. decreasing exposure and preventing new addiction; 2. supporting the treatment of those with opioid use disorder; 3. fostering the development of novel pain treatment therapies; and 4. improving enforcement and assessing benefit risk.

Using these four categories as a framework, the following sections highlight some of FDA's recent strategies for addressing the opioid epidemic and the agency's existing authority to pursue such strategies.

Decreasing Exposure and Preventing New Addiction

FDA Commissioner Scott Gottlieb has stated that the agency is concentrating on ways to lower overall exposure to opioid drugs and, consequently, reduce the number of new cases of addiction. The Commissioner has also averred that one contributing factor to the opioid epidemic is inappropriate prescribing practices, in which clinicians write unnecessary prescriptions for opioid products or prescribe a dose that is beyond the patient's needs. FDA has recently explored various measures to influence health care provider behavior, particularly through its Risk Evaluation and Mitigation Strategy (REMS) authorities.

FDA may only approve drugs for marketing if there is sufficient evidence to demonstrate that the medication is safe and effective for its intended use. As FDA has stated, the agency's approval of a drug does not indicate an absence of risk, but rather that the drug has an "appropriate benefit-risk balance." For most drugs, such a balance is achieved through proper labeling and other postmarket surveillance measures. However, in order to mitigate potentially serious risks for certain drugs, FDA has authority to require certain additional safety controls. Such controls may be implemented through a risk evaluation mitigation strategy, or REMS.

The FD&C Act generally allows FDA to require submission of, and compliance with, a proposed REMS if the agency determines that this strategy is necessary to ensure that the benefits of a drug outweigh its risks. A REMS is essentially a mandatory risk management plan for "responsible persons" (commonly drug manufacturers) that is subject to FDA approval. For example, as part of a REMS, drug manufacturers may be required to provide certain information to patients and/or health care providers (such as a medication guide or patient package insert) or impose limitations on a product's distribution. In general, FDA may require a REMS as a condition of a product's approval, or the agency may impose a REMS on a product it has already approved when new information arises. FDA officials, various industry stakeholders, and others have recently discussed REMS requirements in the context of opioid prescriber education, including the possibility of requiring some form of mandatory health care provider training on proper opioid prescribing and other issues related to opioid use.

Questions may be raised about the scope of FDA's authority under the FD&C Act to compel physicians and other drug prescribers, through a REMS, to obtain certain training or education in order to prescribe opioid drug products. Such questions may arise in light of the fact that the regulation of health care providers and their prescribing practices has traditionally been a state function. As part of a REMS, FDA may require that it contain additional, potentially more restrictive safety precautions, referred to as "elements to assure safe use" (ETASU), because of a drug's "inherent toxicity or potential harmfulness." In order to require ETASU, FDA must determine that the drug has been shown to be effective, but is associated with a "serious adverse drug experience" and can be only marketed if (1) such elements are required as part of the REMS, and (2) other components of the REMS are not sufficient to mitigate the risk. The ETASUs must include one or more goals to mitigate a risk listed on the drug's label, and may require, among other things, that

health care providers who prescribe the drug have particular training or experience, or are specially certified (the opportunity to obtain such training or certification with respect to the drug shall be available to any willing provider from a frontier area in a widely available training or certification method (including an on-line course or via mail) as approved by the [HHS] Secretary at reasonable cost to the provider)...

Accordingly, assuming FDA has made the requisite determinations concerning the need for a REMS and the need for it to contain elements to assure safe use, then it appears that the agency may potentially compel a drug manufacturer and other responsible persons, through a REMS, to require that a health care provider obtain certain training in order to prescribe a particular drug. While the FD&C Act does not expressly provide details on how a prescriber training requirement must be implemented, the responsible person is generally obligated to carry out the requirements of the REMS and must provide assessments as to whether each element of the approved REMS is meeting the goals of the strategy.

In 2012, FDA approved a REMS for extended-release and long-acting (ER/LA) opioid analgesics. As part of this REMS, drug manufacturers had to make voluntary training available at low or no cost to health care providers who prescribe these drugs, but the REMS contained no requirement that prescribers receive this training as a precondition to dispensing applicable drugs to patients. In September 2018, FDA approved an expanded version of the opioid analgesic REMS. This newly modified REMS covers not only ER/LA opioid analgesics, but also more commonly prescribed immediate-release opioids used in the outpatient setting. Pursuant to the recently amended REMS, opioid analgesics manufacturers must provide educational programs for opioid prescribers, as well as nurses, pharmacists, and other health care providers who treat and monitor patients with pain. Training provided through the modified REMS must be based on an FDA-developed blueprint, which outlines core components of the educational programs. While the modified Opioid Analgesic REMS does not compel health care providers to take this training in order to prescribe opioids, FDA officials continue to examine whether the REMS should include some type of mandatory educational training, and, if so, under what circumstances.

Supporting the Treatment of Those with Opioid Use Disorder

In responding to the opioid epidemic, FDA is also focusing on measures that would better assist individuals struggling with opioid addiction. These efforts include promoting broader access to opioid antagonists that can stop or reverse an overdose, including the drug naloxone. Naloxone is a medication that generally treats an overdose by quickly blocking the effects that opioids have on the brain, and it is commonly viewed as an effective and frequently life-saving intervention.

One perceived legal barrier to more widespread naloxone access is its current classification as a prescription drug. Under the FD&C Act, certain drugsâbecause of their toxicity, potential for harm, method or measures necessary for use, or a requirement of a drug's NDAâcan only be dispensed upon a prescription of a licensed practitioner. Similar to prescription drugs, the FD&C Act governs, among other things, the safety and efficacy of over-the-counter (OTC) medications, including the approval, manufacture, and distribution of such drugs. In general, OTC drugs, unlike prescription drugs, are those that can be adequately labeled so that they do not pose a risk of misuse or abuse and can be safely and effectively used without the supervision of a health care provider. Thus, OTC drugs are publicly available for consumers to purchase for treatment of a variety of conditions. Currently, there are more than 300,000 marketed OTC drug products that fall into over 80 therapeutic categories (such as analgesics or antacids).

There are two main regulatory mechanisms through which a drug like naloxone may be switched from prescription to OTC status. First, FDA is authorized to implement a switch through rulemaking. The FD&C Act specifies that FDA may remove drugs from the prescription requirements by regulation when such requirements "are not necessary for the protection of the public health." Under current regulations, a proposal to exempt a drug from the prescription requirements may be initiated by the FDA Commissioner or any interested person. The second mechanism is through the drug sponsor's submission of an NDA or a supplemental NDA, under which the sponsor, typically the manufacturer, requests that FDA approve the switch. The latter approach is the more common pathway for drugs to switch to OTC status, and FDA officials have stated that it is, among other things, a much more expeditious process (as compared to FDA's notice-and-comment rulemaking). With respect to both approaches, FDA takes a "fresh look" at all the safety and efficacy data used in the prescription drug's NDA. Additionally, a central element necessary for FDA's determination that a product is safe for OTC use is the establishment of a label that conveys key messages about the product to a lay consumer, as well as adequate testing to ensure that consumers comprehend the label and can use the product correctly and safely in an OTC setting.

FDA officials have frequently expressed support for giving naloxone OTC status. The agency has also noted ways in which it is taking steps to assist naloxone manufacturers in submitting an application and pursuing approval of an OTC product. For example, in 2016, FDA officials announced that the agency had developed a consumer-friendly model Drug Facts Label (DFL), a required label for OTC products, which is intended to convey the information a consumer would need to administer naloxone in the event of an emergency overdose. FDA also arranged for scientific testing of this model labeling.

Despite the fact that FDA has not approved naloxone for OTC use, states have taken action to make naloxone more accessible. Although FDA has exclusive authority to approve prescription drugs, states maintain authority with respect to who may prescribe these medications and the required format for valid prescriptions. Many states, for example, permit third-party prescriptionsâissued to a friend, family member, or other third party who is not at risk of overdoseâfor use on someone else. These laws provide an exception to the typical state law requirement that prescriptions be written only for the person who will actually take the medication. Additionally, some states permit medical practitioners to prescribe naloxone through standing orders, through which the drug may be dispensed by a pharmacy or other entity based on certain criteria, without the prescriber's examination of a particular patient. Notwithstanding these state laws, some entities still argue a need for FDA to give naloxone OTC status.

Fostering the Development of Novel Pain Treatment Therapies

FDA has stated that it is working with industry and other government entities to spur the development and marketing of new pain treatments that have less potential for abuse, including generic abuse-deterrent formulations (ADFs) of opioid products. ADF technologies are those intended to make abusing a drug more difficult or less rewarding, and the benefits of these technologies have been the subject of debate. To date, FDA has approved 10 opioid analgesics with these characteristics. However, currently, opioids with ADFs are only available as brand-name products, and there are no generic opioids with FDA-approved abuse-deterrent labeling on the market. FDA Commissioner Scott Gottlieb has noted that because opioids with ADFs are only available as brand-name products, they are fundamentally more expensive than available generic versions of non-ADF opioids.

In order to provide a quicker route for the approval of generic drugs, Congress passed the Drug Price Competition and Patent Term Restoration Act of 1984, commonly known as the Hatch-Waxman Act, which created the abbreviated new drug application (ANDA) process. Under this act, a generic drug may be approved for marketing without the same clinical studies and safety and effectiveness evidence required for brand-name drug approval if the generic drug mimics the approved brand-name drug in certain key ways. For example, an ANDA generally must contain information demonstrating that the route of administration, the dosage form, and the strength of the new generic are the same as those of its brand-name analog. In addition, ANDA applications must contain "information to show that the labeling proposed for the new drug is the same as the labeling approved for the [brand-name] drug," subject to certain specified exceptions.

In November 2017, as directed by Congress as part of the Comprehensive Addiction and Recovery Act of 2016, FDA issued a nonbinding guidance document for industry, which contains recommendations about what studies a potential ANDA applicant should conduct and submit to FDA to demonstrate that the generic drug's abuse deterrent properties are on par with its prescription counterpart. Additionally, in July 2018, FDA issued additional draft guidance documents that are intended to assist drug developers in bringing generic ADF opioid products to market.

Improving Enforcement and Assessing Benefit Risk

As part of its response to the opioid epidemic, FDA officials have expressed a desire to better leverage the agency's enforcement capabilities. The FD&C Act contains a number of enforcement mechanisms, both civil and criminal in nature, which may apply to the marketing of diverted opioids, as well as drugs not approved by FDA. Persons who violate the requirements of the Act may be subject to a variety of sanctions, including civil monetary penalties, injunctions, seizures, fines, and imprisonment, depending on the particular misconduct at issue. Commonly, FDA may issue a warning letter to encourage voluntary compliance with the FD&C Act before initiating further enforcement action. Under one example of recent opioid-related enforcement, in May 2018, FDA issued a number of warning letters to marketers and distributors of kratom products. According to FDA, these products were sold with unproven claims that the products could treat opioid addiction and withdrawal. In the warning letters, the agency states, among other things, that the products are not generally recognized as safe and effective for the referenced uses and are therefore considered unapproved new drugs sold in violation of the FD&C Act. The letters request the parties take immediate corrective action, and include notice of FDA's intention to take further enforcement actions if the recipients fail to comply.

Additionally, with respect to the assessment of the benefits and risks of a particular drug, one question that may be raised is whether FDA can withdraw approval for certain opioid medications when it is determined that the benefits of treating pain are outweighed by the potential for abuse. The FD&C Act authorizes FDA to withdraw approval of an approved NDA when, among other things, there is new clinical evidence showing that the product is unsafe for its approved use. FDA must first provide the manufacturer with notice that the agency is proposing to withdraw approval and an opportunity for a hearing on the merits. However, the agency may suspend new drug approval immediately if it is determined that the product poses an immediate hazard to the public health. Although it is not a common occurrence, it has been estimated that FDA has withdrawn approval of approximately 600 new drug and abbreviated new drug applications.

FDA has signaled its willingness to withdraw approval of products with serious potential for abuse. In June 2017, FDA requested that Endo Pharmaceuticals recall from market Opana ERâa potent painkiller reformulated to make it difficult to crush and snort. Although the product was intended to curb opioid abuse, it reportedly led to the largest HIV outbreak in Indiana history when addicts resorted to liquidizing and injecting the drug with shared needles. Ultimately, the company announced in July 2017 that it would comply with FDA's request.

SUPPORT for Patients and Communities Act and FDA

In October 2018, Congress passed the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT Act), P.L. 115-271 , comprehensive legislation primarily aimed at opioid misuse and abuse. Title III, subtitle A of the SUPPORT Act contains provisions that amend the FD&C Act in various ways to address the opioid epidemic, including the following:

FDA's REMS Authority and Drug Packaging/Disposal Features

To promote appropriate prescribing practices and decrease exposure to opioids, the SUPPORT Act bolsters FDA's REMS authority, expressly permitting the agency to compel a REMS if there is a serious risk of overdose or drug abuse. Further, under specified circumstances, FDA may compel manufacturers through this REMS to make drugs available with certain packaging systems (such as packaging that provides a set treatment duration) or safe disposal features to render the drugs irretrievable for illicit uses.

FDA Postmarket Authorities and Drug Effectiveness

FDA has authority to monitor drugs that are on the market. For instance, FDA may require postmarket labeling changes if the agency becomes aware of certain information about a drug, and postapproval studies or clinical trials under certain circumstances. According to the FDA Commissioner, despite widespread use of opioid analgesics to treat chronic pain, limited data exists on the long-term efficacy and impacts of these products, and further research is warranted. However, prior to enactment of the SUPPORT Act, FDA Commissioner Scott Gottlieb and some Members of Congress indicated that while FDA had authority to request postmarket studies based on drug safety concerns, the agency lacked explicit authority to require studies solely to examine drug efficacy.

The SUPPORT Act generally amends the FD&C Act to clarify FDA's authority to require postmarket studies and trials for certain drugs that may have reduced effectiveness over time. The Act also expressly authorizes FDA to compel drug manufacturers or others to make drug labeling changes based on new information related to reduced effectiveness. Finally, the SUPPORT Act calls on FDA to issue guidance on its new authority.

Agency Guidance to Promote Development and Use of Nonaddictive and Nonopioid Analgesics

To encourage development of new, nonaddictive therapies that treat chronic pain or opioid addiction, the SUPPORT Act directs FDA to hold at least one public meeting and subsequently to issue nonbinding guidance to assist industry stakeholders and health care providers. The meetings and guidance may address, among other things, (1) circumstances under which the agency considers misuse and abuse of controlled substances in reviewing a new drug or device; (2) use of novel clinical trial designs and real-world evidence and patient experience data to develop nonaddictive medical products; (3) standards for, and development of, opioid-sparing data to include on medical product labeling; and (4) application of breakthrough therapy designation for nonaddictive medical products intended to treat pain or addiction.

Additional FDA Enforcement Capabilities

The SUPPORT Act provides the HHS Secretary with additional enforcement tools to address the opioid epidemic. For instance, under new Section 5569D of the FD&C Act, if the Secretary determines that there is a "reasonable probability that a controlled substance would cause serious health consequences or death," the agency may order manufacturers, importers, distributors, or pharmacists to immediately cease distributing these drugs. Parties subject to the order must have an opportunity to consult with FDA prior to issuance of the order and an informal hearing. Following this hearing, the Secretary may (1) vacate the order based on inadequate evidence to support the order; (2) continue the order ceasing distribution of the drug until a specified date; or (3) amend the order to require a recall. However, if the Secretary determines that recalling a controlled substance presents a greater health risk than not recalling it, the order may not include a recall or a cessation of distribution.

The SUPPORT Act addresses the agency's enforcement role with respect to drug importation as well. In collaboration with U.S. Customs and Border Protection, FDA is authorized to inspect, detain, and refuse entry to imported drugs, devices, food, and other products under its jurisdiction. Recently, FDA Commissioner Scott Gottlieb and others have highlighted challenges associated with diverted opioids or illegal drugs that enter the United States through international mail facilities, including inspecting the high volume of items passing through these facilities and procedural difficulties relating to whether a particular product violates the FD&C Act and may be refused entry or destroyed. The SUPPORT Act is intended to streamline the process of refusing entry to diverted or illegal drug products. Among other things, the Act directs the Secretary (acting through the FDA Commissioner) to coordinate with the Secretary of Homeland Security on customs and border protection activities relating to illegal controlled substances and drug imports, including at international mail facilities. The Act also requires the HHS Secretary to work with the Homeland Security Secretary and the Postmaster General of the U.S. Postal Service to provide that import facilities, in which FDA operates, have certain facility and technology upgrades.