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PAINSCAN LITERATURE REVIEW
Issue 1, Volume 3
Abuse-Deterrent Technologies
14 Articles in this Series
Introduction
The effect of a potentially tamper-resistant oxycodone
Commentary: Why Prescribers Need to Adopt Abuse-Deterrent Opioids
Review: The Impact of Abuse-Deterrent Formulations on Prescribing and Abuse
Abuse-Deterrence Guidance Further Highlights Federal Focus
The Burden of Undiagnosed Opioid Abuse Among the Commercially Insured
Reductions in Reported Deaths Following Introduction of Abuse-Deterrent Oxycodone ER (OxyContin)
Abuse-Deterrent Opioids—Evaluation and Labeling
Generic patches containing fentanyl: abuse deterrent evaluation
FDA Advisory Committee Meetings on Abuse-Deterrent Opioids
Regulatory Update: FDA Takes Additional Abuse-Deterrent Steps
Related: At-Risk Patients and Urine Drug Monitoring
Extended-Release Formulations Enter US Market
Development and Impact of Prescription Opioid ADF Technologies
Trends in Opioid Analgesic Abuse and Mortality in the United States

Abuse-Deterrent Opioids—Evaluation and Labeling

Guidance for Industry
2015;online:https://goo.gl/DZxs2R

 

The US Food and Drug Administration (FDA) issued a final guidance for industry titled “Abuse-Deterrent Opioids—Evaluation and Labeling” that offers recommendations on the studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties. It also makes recommendations about how those studies should be performed and evaluated, and discusses what claims may be approved in product labeling based on the study findings.

The FDA states that development of abuse-deterrent opioids is a “high public health priority” and is necessary to address the problem of opioid abuse while at the same time ensuring access to opioids for people with pain. In addition, the FDA notes that abuse-deterrent does not mean abuse-proof, but rather that the risk of abuse is lower with agents that have abuse-deterrent properties than among those without those properties.

The guidance separates abuse-deterrent formulations into categories and describes in detail the premarket and postmarket studies that should be performed on each agent along with recommendations on labeling. Below is a summary of the information provided in the guidance.

Types of Abuse-Deterrent Formulations

The FDA categorizes abuse-deterrent formulations as follows:

  1. Physical/chemical barriers
  2. Agonists/antagonist combinations
  3. Aversion
  4. Delivery system (eg, depot injectable formulations and implants)
  5. New molecular entities and prodrugs (eg, those that require enzymatic activation, different receptor binding profiles, slower absorption into the central nervous system, or other novel effects)
  6. Combination (ie, 2 or more of the above methods in combination)
  7. Novel approaches (ie, any approaches or technologies that do not fall into the above categorizes)

Recommendations for Premarket Studies

Drug development programs should, in most cases, include all 3 of the following premarket study types:

  1. Laboratory-based in vitro manipulation and extraction studies (Category 1)—the goal is to evaluate how easily abuse-deterrent properties can be defeated or compromised.
  2. Pharmacokinetic studies (Category 2)—the goal is to study the in vivo properties of the formulation by comparing its pharmacokinetic profile of the intact medication with a manipulated version (eg, dissolved and injected or crushed and swallowed, snorted, or smoked) as well as compared with the intact and manipulated versions of comparator drugs.
  3. Clinical abuse potential studies (Category 3)—the goal is to assess the impact of the abuse-deterrent properties. The preferred study design is a randomized, double-blind, placebo-controlled crossover study and generally should involve patients who are recreational drug users.

Recommendations for Postmarket Studies

The goal of postmarket studies (Category 4) is to examine whether the abuse-deterrent agent has resulted in meaningful reductions in abuse, misuse, and related adverse clinical outcomes (eg, addiction, overdose, and death).  

Labeling Recommendations

The FDA encourages that labeling include the results of all 4 categories of studies and appropriately characterizes the abuse-deterrent potential of each agent. The labeling should include “a caveat that abuse is still possible.” Given that postmarketing data is typically not available at the time of drug approval, the labeling should include the predictive quality of premarket studies and include findings from any completed postmarket studies.

The FDA noted that these are recommendation and are not legally enforceable responsibilities. The guidance does not include recommendations on the development or testing of generic formulations of abuse-deterrent pain medications, and intends to address these agents in the future.

Commentary

The FDA released a guide for pharmaceutical industry and others interested in the development of abuse-deterrent, extended-release opioids. This report was released in April 2015 (a prior guidance was released in 2013).1 As the title implies this report is a formalized guide for industry, academics, clinicians, and regulators, with the intent of providing a framework from whence the FDA will evaluate claims of abuse-resistant or abuse-deterrent delivery systems for extended-release opioid analgesics.

The document is necessary for the pharmaceutical industry as it attempts to develop and market extended-release opiates. According to the document, “This guidance is intended to assist sponsors who wish to develop opioid drug products with potentially abuse-deterrent properties and is not intended to apply to products that are not opioids or opioid products that do not have the potential for abuse.” This fits well with the agency’s goal of evaluating drugs.

Unfortunately, the need for such delivery systems has followed, not anticipated a problem. The development of abuse-deterrent technology (ADT) is a priority for the agency. In fact, the agency states in the introduction to the document that it “considers the development of these products a high public health priority.”

The reasons are evident. Abuse of prescription and illegal opiates is costing thousands of lives each year and severely impacting thousands of others. The need for safe and effective drugs that are difficult to abuse is highly desired by the FDA as well as numerous federal and state agencies, and governmental organizations are making a major effort to address this issue.

The report further notes: “FDA believes it is critical to address the problem of opioid abuse while seeking to ensure that patients in pain have appropriate access to opioid products. Moreover, it is important that opioids without abuse-deterrent properties remain available for use in some clinical settings. For example, patients in hospice care and with difficulty swallowing may need access to opioid products that are in solution or that can be crushed.”

The FDA had to develop these guidelines in order to inform industry as well as those who will be working with them to ensure drugs with ADT will be evaluated according to the agency’s expectations. As stated by the FDA: “This guidance explains FDA’s current thinking about the studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties. The guidance makes recommendations about how those studies should be performed and evaluated and discusses how to describe those studies and their implications in product labeling.”

In essence, the agency has had to create a roadmap for industry on how to approach the development of this class of medications. The document spells out the following: the types of delivery systems likely to be considered ADT; the preclinical evaluations necessary to be carried out looking for effects on pharmacokinetics (eg, grinding, solvents, thermal, etc); and studying clinical abuse potential (CAP). This is a relatively new area—frankly, as are essentially all of the studies recommended. And, as if this were not new enough, the FDA describes guidelines forreporting clinical findings.

To date, the FDA has identified several general approaches to abuse deterrence. These are physical chemical barriers; agonist antagonist combinations; aversion techniques; delivery system approached; new molecular entities and prodrugs; combination of the previous listed approaches; and novel approaches to drug or drug delivery. The last category suggests that the FDA is open to novel thinking and strategies to the problem of drug abuse.

Following submission of testing data, the FDA may determine if a drug has abuse-deterrent qualities. Based on preclinical assessment, the drug will be able to include in its label one or more statements that denotes a level of resistance to manipulation or reduction in drug liking. In earlier draft versions of the FDA document, these claims of ADT were referred to as tiers. This language is no longer used in the document. Labeling claims that may be included in the package insert may now include resistance to physical chemical manipulation and reduction in drug liking.

After a drug is approved and marketed, a final assessment for risk of abuse will take place. This may take several years after the medication has been available. These epidemiology studies will be by far the most difficult to conduct. Once a drug delivery system is deemed to be effective at reducing abuse liability, labeling will change enabling the manufacturer to go to clinicians, insurers, and government informing them of this benefit.

There are limits to implementation of the guidelines and these are identified by the agency. One of the major issues noted by the FDA is the lack of guidance on studies of generic drugs: “This guidance also does not address issues associated with the development or testing of generic formulations of abuse–deterrent opioid products.” The FDA does note that it “intends to address that topic in one or more future guidance documents.”

The lack of generic assessment will be important as costs of brand medications may preclude adoption of many of the ADTs. Therefore adoption of ADT formulations will be necessary for all potential patients to avail themselves of this potentially very important technology.

The FDA guidance document is important in aiding clinicians in their understanding of future drug development. It will be an important reference as medications are brought to market for patients with chronic pain.

Reference

1. U.S. Department of Health and Human Services, U.S. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Abuse-deterrent opioids—Evaluation and Labeling-Draft. January 2013. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm334807.htm.

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Generic patches containing fentanyl: abuse deterrent evaluation
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