Pain Management and the Opioid Epidemic Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use (2017) / Chapter Skim
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6 Opioid Approval and Monitoring by the U.S. Food and Drug Administration
6 Opioid Approval and Monitoring by the U.S. Food and Drug Administration
Pages 359-422
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From page 359... ...
, helps monitor the use of available opioid products. In this chapter, the committee provides recommendations aimed at improving the FDA's regulation of opioid analgesics, including by informing the agency's development of a framework for opioid approval and monitoring that takes into account the range of benefits and harms associated with the use of opioid analgesics, incorporating both the needs of pain patients and the relevant public health considerations.
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From page 360... ...
Adverse events consistent with other ER opioid analgesics, such as constipation and somnolence, were noted, as were some episodes of study drug diversion and hoarding, despite the particular care taken to minimize such events. The FDA convened an outside expert advisory committee, which voted 11-2 (with 1 abstention)
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From page 361... ...
In making the case for this approach, this chapter begins with an overview of the FDA's current regulatory oversight of prescription drugs. This overview is followed by a discussion of public health dimensions of FDA drug regulation, which includes examples of previous cases in which the agency has successfully incorporated public health considerations into its regulatory decision making and an examination of those public health considerations specifically relevant to the approval and monitoring of opioids.
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From page 362... ...
. These latter studies account for the majority of the spending on drug development, and "are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling."4 While the manufacturer controls the organization and execution of the trials, manufacturers can, and frequently do, consult with FDA staff at various times to receive advice on trial design and outcomes.5 At the conclusion of the clinical trials, the manufacturer submits a New Drug Application (NDA)
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From page 363... ...
This labeling contains, among other things, the drug's approved indications, directions for use, dosing frequency and duration, and route of administration and preparation, as well as clinically significant adverse reactions, safety hazards, or other limitations on its use. The labeling must be revised to include warnings of new, clinically significant hazards as soon as reasonable evidence of a causal association with the drug exists.7 Drug Reformulations Many drugs approved by the FDA are reformulations of previously approved products.
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From page 364... ...
. Application to Opioid Approval The requirement that prescription drugs be subject to prospective clinical trials that provide data on their safety and efficacy is an essential component of the regulatory apparatus that protects patients, allows for collection of rigorous data that can guide clinical practice, and promotes a wellfunctioning prescription drug marketplace by preventing the widespread use of ineffective products.
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From page 365... ...
Based on a pilot program launched in 2008, the Sentinel System allows the agency, through an independent contractor that has established a secure distributed data network, to assess an emerging drug risk using data from a broad array of electronic health care data. While Sentinel has not yet facilitated rapid drug safety assessment and improved regulation, it holds promise for regulatory decisions to be based on big-data tools that help in organizing and evaluating evidence (FDA, 2015a)
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From page 366... ...
. Risk Evaluation and Mitigation Strategies One particularly important type of post-market requirement is a Risk Evaluation and Mitigation Strategy (REMS)
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From page 367... ...
Communicating Drug Safety Information The combination of data from passive adverse event reporting, the Sentinel System, and other surveillance activities conducted by the FDA and manufacturers, together with post-market commitments and requirements, can point to the need to update a drug's labeling. While the FDA can, under certain conditions, require the manufacturer to update the label with new safety information, primary responsibility for keeping labeling up to date for brand-name drugs lies with the manufacturer.12 A boxed warning (also called a black-box warning)
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From page 368... ...
Between 2010 and 2016, 233 Drug Safety Communications were issued (39 in 2010, 66 in 2011, 29 in 2012, 32 in 2013, 16 in 2014, 30 in 2015, and 21 in 2016)
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From page 369... ...
. When an off-label use is particularly risky and non-evidence-based, the FDA can factor this consideration into its post-approval regulatory decisions.
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From page 370... ...
The 2013 Drug Quality and Security Act amended the FDCA to create an electronic, interoperable system to "track and trace" many prescription drugs throughout the supply chain.22 Once fully in effect in 2023, the system will include product identifiers for certain prescription drug packages; information on who handles a drug each time it is sold in the United States; requirements that industry stakeholders investigate products suspected to be counterfeit, substandard, or otherwise illegitimate; and processes for notifying the FDA and others when illegitimate drugs are found.23 Various requirements will apply to drug manufacturers, wholesale drug distributors, repackagers, third-party logistics providers (entities that help coordinate distribution of a drug but never take ownership of it) , and dispensers.
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From page 371... ...
. Propelled by the unrelenting increase in opioid-related deaths in the United States, one element of the FDA's Opioid Action Plan, launched in 2016, is to expand the REMS for opioids to incorporate pain management, include a broader range of health care professionals involved in the management of patients with pain, include IR opioid analgesic manufacturers, and evaluate approaches for implementing mandatory pain management education for prescribers (FDA, 2017e)
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From page 372... ...
Developed by Purdue Pharma after the FDA provided suggestions and comments, it collects this information through regular surveys of individuals entering or being assessed for SUD treatment, experts in SUD, and law enforcement agencies, as well as analysis of exposure calls to poison control centers pertaining to misuse and diversion of licit and illicit drugs, including prescription opioid analgesics (Cicero et al., 2007)
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From page 373... ...
Decision Making About Scheduling The CSA allows the DEA to place a drug temporarily in Schedule I when it believes the drug may pose "imminent hazards to public safety." The substance may be retained in Schedule I for up to 3 years, after which it must be removed or permanently scheduled.27 The DEA has used this temporary scheduling authority for more than 35 synthetic drugs since 2002. Most recently, the DEA has used it to place several synthetic opioids temporarily in Schedule I.28 26 Kentucky Settlement, http://ag.ky.gov/pdf_news/purduepharmaoxycontin.pdf (accessed June 27, 2017)
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No prescription refills permitted. Schedule Substances in this Prescriptions may III: products containing not III/IIIN schedule have be written, oral, more than 90 milligrams a potential for or transmitted by of codeine per dosage unit abuse less than fax.
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From page 375... ...
Drug Enforcement Administration requirements, and are also subject to any additional state-level regulations. bAn exception also exists for hospice care programs, where Schedule II controlled substances may be prescribed via telephone or fax.
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From page 376... ...
, and (8) above, as well as any other relevant scientific or medical considerations.33 The FDA may require the drug's manufacturer to provide relevant data pertaining to its abuse potential as part of the NDA requirements.34 The FDA's recommendation is binding on the DEA, although any specific scheduling recommendation is not.35 If the FDA has recommended that the drug be controlled as a scheduled drug, the baton passes to the DEA administrator for consideration of the above eight factors in the context of appropriate scheduling.36 The FDA and the DEA thus play different roles in their evaluation pursuant to the CSA.
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From page 377... ...
When the FDA undertook a review based on the eight factors listed earlier in 2008, it paid special attention to how rescheduling might affect prescribing practices. It found, for example, that rescheduling might result in the need for additional physician visits, that prescribers might then opt for oxycodone rather than hydrocodone combination products since they were in the same schedule, and that patients might receive inadequate pain relief (FDA, 2012)
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From page 378... ...
. The reclassification of hydrocodone combination products in 2014 has provided a natural experiment with which to study the effect of moving a drug to Schedule II.
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From page 379... ...
First, the CSA requires explicit trade-offs between the effects of regulatory decisions on legitimate medical use and the harms associated with misuse and OUD. Second, the rescheduling of hydrocodone combination products reveals the diverging perspectives of the FDA and the DEA in exercising regulatory judgment on these issues and the inefficiency thus produced.
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From page 380... ...
The committee also believes that this framework can be adapted to specifically integrate public health considerations, and can be incorporated into a much more comprehensive approach to gathering and reviewing the available information and making decisions accordingly to guide the FDA's regulation of opioids. As described below, the FDA routinely considers broader public health goals in its assessment of drugs, and the committee believes there is a growing public health mandate to apply this flexibility in certain ways to the approval and oversight of opioids.
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From page 381... ...
products, antibiotics, and prescription acetaminophen products further illustrate that the FDA is able to integrate, and has integrated, public health considerations into its drug approval and withdrawal decisions pursuant to its existing authority under the FDCA. In addition, this integration of public health considerations into regulatory decisions has encompassed decisions regarding the content that must be in drug labeling and REMS requirements.
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From page 382... ...
Since the agency already incorporates these issues into its decision making in various contexts, integrating public health considerations into its regulation of opioids -- including its approval decisions on new opioids -- would be consistent with both its past practice and a generally accepted understanding of its statutory authority. Examples of the FDA's Taking a Public Health Approach to Regulation Example 1: Testosterone Products In 2009, the FDA received a series of adverse event reports of children who had not been prescribed testosterone gel suffering serious side effects after inadvertent exposure to the products.
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From page 383... ...
To accomplish the second goal, the REMS requires a prescriber–patient agreement form in which the prescriber documents that she or he has counseled the patient on the risk that TIRF products pose to children and on proper storage, and in which the patient documents that she or he understands this information. In sum, the FDA has considered the risks of the use of TIRF products by unintended patient populations in its approval and labeling decisions, as well as in the design of the REMS, for these products.
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From page 384... ...
The precautions section also provides specific guidance for physicians in counseling their patients about the proper use of antibiotics. Additionally, the 21st Century Cures Act, enacted in 2016, amended the FDCA to create an approval pathway for antibiotic drugs intended for patients with unmet medical needs that would require the drugs' labeling to caution prescribers that the drug is intended only for a limited population."53 Example 4: Prescription Acetaminophen Products Acetaminophen is an active ingredient in many prescription combination drug products for pain, such as hydrocodone/acetaminophen (Vicodin)
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From page 385... ...
In particular, in explaining its rationale for planning to withdraw approval of prescription acetaminophen products that did not comply with the new maximum dosage unit strength, the agency pointed to some conventional individual health considerations, including the lack of evidence suggesting that the benefits of the higherstrength products outweigh their risks and the need to establish a larger margin of safety because of uncertainty about the precise toxicity threshold for different patient populations. But the agency also discussed various public health considerations.
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From page 386... ...
are used legally and regularly to great benefit beyond the individuals to whom they are prescribed, and sometimes must be administered to the individuals to whom they were prescribed by other persons. As discussed in Chapter 4, an approach to opioid regulation that actively takes public health considerations into account also requires the recognition that actions taken with respect to one opioid will affect the use and misuse of other opioids, opioid derivatives, and forms of pain management and consideration of the social system shaping use of those drugs.
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From page 387... ...
Finally, the social system surrounding opioids is a key driver of the committee's recommendations in this report. Integrating public health considerations into regulatory decision making helps in considering distributional effects of those decisions over time.
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From page 388... ...
This integrated framework needs to facilitate informed regulatory decisions throughout a drug's life cycle, and include built-in periodic monitoring of each decision's consequences instead of decisions being treated primarily as self-contained events. If correctly formulated, this integrated framework will minimize mistakes and allow the community to recover expeditiously from any that are made.
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From page 389... ...
Approval or withdrawal of a prescription opioid on the legal market can affect levels of use of black market opioids such that the total net effect on mortality may be very different from the apparent effect if one considers only outcomes directly related to the approved or withdrawn opioid. Indeed, one survey found that roughly three-quarters of people who used heroin in the past year misused prescription opioids first, and seven of ten people who used heroin in the past year also misused prescription opioids over the same period (Jones, 2013)
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From page 390... ...
, and may never be given the illicit nature of most opioid misuse. However, sound regulatory decisions need not overlook important benefits and risks just because they are difficult to quantify.
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From page 391... ...
Another challenge is to weigh the risks avoided by tighter regulation of an opioid against the pain, functional limitations, and other adverse effects experienced by patients who would benefit from that drug if its access were not restricted. The FDA's current approach informally weighs the available measures of pain utilized in clinical trials against estimated increases in misuse and OUD and the derivative risks.
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From page 392... ...
Stage 1: The Clinical Development Stage The FDA can first intervene to implement a new approach to opioid regulation after the submission of the IND application. During the investigational clinical trial period that follows submission of an IND application, crucial data currently are collected on the drug's pharmacodynamics, safety, and efficacy for intended users, but data also could be collected on its potential public health consequences.
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From page 393... ...
should utilize a comprehensive, systems approach for incorporating public health considerations into its current framework for making regulatory decisions regard ing opioids. The agency should use this approach, in conjunction with advisory committee input, to evaluate every aspect of its oversight of prescription opioid products in order to ensure that opioids are safely prescribed to patients with legitimate pain needs and that, as actually used, the drugs provide benefits that clearly outweigh their harms.
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From page 394... ...
, a remarkably low number given the number of investigational drugs being tested during those years. A clinical hold, if needed, could be issued as soon as possible after the IND was submitted or after the FDA received new information about ongoing opioid development trials, thereby reducing disruption for manufacturers and clinical trial enrollees.
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From page 395... ...
. Drugs receiving faster reviews also have more spontaneous reports of drug- elated adverse events (Lexchin, 2012; Olson, 2008; r Reaves, 2009)
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From page 396... ...
Box 6-3 contains the committee's recommendations to the FDA for the clinical development stage. Stage 2: Drug Approval The next major intervention point for the FDA in its regulation of opioids is the time of market authorization, when it is considering an NDA for a new opioid molecule or formulation.
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From page 397... ...
Recommendation 6-3. Ensure that public health considerations are ad equately incorporated into clinical development.
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From page 398... ...
, used when making approval decisions on applications for new opioids, new opioid formulations, or new indications for approved opioids.
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From page 399... ...
Complete response letters traditionally are not made public, but recent research has shown that manufacturers' press releases often misstate the reasons for disapproval. Because of the significant public health concerns associated with opioids and the need to be able to evaluate the FDA's new regulatory TABLE 6-4 Example of an Adapted Benefit-Risk Framework for Approval of Opioid Products Evidence and Conclusions and Decision Factor Uncertainties Reasons Characteristics of Opioid How Opioid Fits Among Currently Available Pain Treatment Options Benefits Observed in Clinical Trials, Overall • Benefits to patients • Public health benefits Risks Observed in Clinical Trials • Risks to patients • Public health risks Predicted Benefits/Risks to Families of Patients Predicted Benefits/Risks to Society, Overall • Special communities • Subpopulations Diversion Potential Predicted Effects on Use of Other Opioids or Illicit Drugs Risk Management, Overall • Potential for off-label use • Advertising/promotion
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From page 400... ...
The U.S. Food and Drug Administration should commit to increasing the transparency of its regulatory decisions for opioids to better inform manufac turers and the public about optimal incorporation of public health considerations into the clinical development and use of opioid products.
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From page 401... ...
This step would include identifying the specific characteristics of the drug and the health problem at issue, available information about the drug, alternative treatments that are available, and plausible regulatory actions and their poten tial consequences. This stage would be aimed at identifying the information needed for a regulatory decision.
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From page 402... ...
Thus, it would be important to actively solicit the perspectives of prescribers and patients who are independent from the pharmaceutical industry in developing an optimal REMS. Development of an optimal opioid REMS also could be facilitated through collaborations between the FDA and other relevant government agency stakeholders, such as the Substance Abuse and Mental Health Services Administration, National Institute on Drug Abuse, U.S.
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From page 403... ...
As the committee proposes in Recommendation 6-5, the FDA should engage in active surveillance of data on the use and misuse of approved opioids. This surveillance might include monitoring of new data that emerge from post-market commitments or requirements or the REMS program, which could be acted on efficiently and integrated with spontaneous adverse event reports and other observational data conducted through the Sentinel System.
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From page 404... ...
Just as the FDA should move to incorporate public health considerations in its approval-related decisions for opioid drugs, it should incorporate such considerations into its review of industry promotional strategies for these products. Requiring that advertising of a drug explicitly mention these public health considerations might be necessary for the advertising of approved opioids to be considered accurate, truthful, and not misleading.
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From page 405... ...
Steps to this end should include use of Risk Evaluation and Mitigation Strategies that have been demonstrated to improve prescribing practices, close active surveillance of the use and misuse of approved opioids, periodic formal reevaluation of opioid approval decisions, and aggressive regula tion of advertising and promotion to curtail their harmful public health effects. More specific actions under this recommendation might include the following • Maximizing the use of REMS with elements to assure safe use, boxed warnings, and other available risk communication methods in an evidence based way to help influence safe and appropriate prescribing and dispens ing practices.
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From page 406... ...
would require additional regulatory resources. The cost of such interventions could be accounted for without additional legislation as part of the FDA's discretionary budget until the next reauthorization of the Prescription Drug User Fee Act, at which time the user fees applied to NDAs could be adjusted to account for the additional costs of adequate oversight of the prescription opioid market.
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From page 407... ...
. Patients also would not need to be concerned that the OSI process would affect the cost of opioids as long as sufficient numbers of generic manufacturers were producing the opioid formulations remaining on the market at the conclusion of the OSI review.
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From page 408... ...
In the case of these agents, REMS and other restrictive post-approval prescribing systems might do more harm than good by making them less available to patients and providers. The public health considerations relevant to approval of these drugs are therefore quite different from those outlined in this chapter and would not fit well under the proposed approach for opioid regulation.
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From page 409... ...
The recommendations offered to the FDA in this chapter are intended to balance manufacturers' ability to introduce new opioid products that hold promise for pain management with the agency's obligation to manage the risks posed by opioids, which extend beyond risks to individual patients. In line with the FDA's public health authorities, mission, and practice, these recommendations focus on incorporating public health considerations into the entire life cycle of drug development to create a safer prescription opioid marketplace.
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From page 410... ...
should utilize a comprehensive, systems approach for incorporating public health considerations into its current framework for making regulatory decisions regarding opioids. The agency should use this approach, in conjunction with advisory committee input, to evaluate every aspect of its oversight of prescription opioid products in order to ensure that opioids are safely prescribed to patients with legitimate pain needs and that, as actually used, the drugs provide benefits that clearly outweigh their harms.
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From page 411... ...
One important implication is that the evidence necessary to demonstrate safety and efficacy for opioid products will necessarily broaden, and this will affect the traditional FDA review and approval process at multiple points. Specific considerations to meet these needs may extend beyond the protocolized setting of traditional clinical trials to encompass use of data from less traditional sources, such as online forums.
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From page 412... ...
Steps the FDA could take to implement Recommendation 6-4 might include issuing a guidance document that outlines opioid-specific clinical development considerations, or releasing summary versions of complete response letters for opioid products to inform the public about the public health considerations that the FDA has determined would preclude marketing approval.
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From page 413... ...
Steps to this end should include use of Risk Evaluation and Mitigation Strategies that have been demonstrated to improve prescribing practices, close active surveillance of the use and misuse of approved opioids, periodic formal reevaluation of opioid approval decisions, and aggressive regulation of advertising and promotion to curtail their harmful public health effects. Evidence on the effectiveness of the current REMS for opioids is conflicting and limited, and the REMS may provide a false sense of risk mitigation.
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From page 414... ...
Recommendation 6-7. Apply public health considerations to opioid scheduling decisions.
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From page 415... ...
2014. Schedules of controlled substances: Placement of hydrocodone combination products into Schedule II.
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From page 416... ...
2012. Drug Safety and Risk Management Advisory Committee (DSaRM)
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From page 417... ...
2016c. New safety measures announced for opioid analgesics, prescription opioid cough products, and benzodiazepines.
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From page 418... ...
2012. Curbing the opioid epidemic in the United States: The Risk Evaluation and Mitigation Strategy (REMS)
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2014. Measures to quantify the abuse of prescription opioids: A review of data sources and metrics.
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From page 420... ...
Opioid Post-Marketing Study Requirements Main Study Objective Research Schedule Quantify the serious risks of misuse, Final Protocol Submission: 11/2015 abuse, and addiction associated with (completed) long-term use of opioid analgesics for Study Completion: 10/2019 management of chronic pain.
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From page 421... ...
Final Report Submission: 06/2017 Conduct a clinical trial to estimate the Final Protocol Submission: 11/2014 serious risk for the development of (completed) hyperalgesia following the long-term use Trial Completion: 02/2019 of high-dose ER/LA opioid analgesics Final Report Submission: 08/2019 for at least 1 year to treat chronic pain.
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