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Inside FDA's Guidance on Generic Abuse-Deterrent Opioids

The agency's focus on creating cheaper, oral opioid products with abuse-deterrent properties may widen treatment access for patients living with chronic pain.
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Prescription opioid analgesics are an important component of modern pain management, but abuse and misuse of these medications have created a serious and growing public health problem. One potentially important step toward the goal of creating safer opioid analgesics has been the development of opioids that are formulated to deter abuse. The US Food and Drug Administration considers the development of these products a high public health priority.

In April 2015, the agency published a Guidance for Industry regarding the evaluation and labeling of abuse-deterrent opioids.1 This guidance explained the agency’s viewpoint about studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties, as well as what language should or could be included in the package insert. The document described seven categories of abuse-deterrent technologies: 1

  • physical/chemical barriers
  • agonist/antagonist combinations
  • aversion
  • delivery system
  • new molecular entities (NMEs) and prodrugs
  • combinations
  • novel approaches.

The 2015 guidance did not address issues associated with the development or testing of generic formulations of abuse-deterrent opioid products. More recently, FDA has noted the importance of developing such products to ensure access to safe and effective analgesics for patients who need them. Therefore, in November 2017, the agency published an updated Guidance for Industry on evaluating the abuse deterrence of generic solid oral opioid drug products.2

This follow-up guidance focuses on formulating generic oral opioid products to incorporate physical or chemical barriers, agonist/antagonist combinations, aversive agents, or a combination of two or more of these technologies. The guidance does not provide testing recommendations for generic versions of opioid drug products incorporating other technologies (ie, delivery system, NME/prodrug, or novel approaches),2 but FDA may provide such recommendations in future product-specific guidance. Further, the agency will continue to assess the state of science and, as novel technologies develop, address them through additional guidance, as appropriate.2

Current Technologies and Formulations

Most abuse-deterrent technologies developed to date are intended to make manipulation more difficult or to make abuse of the manipulated product less attractive or less rewarding. For example, opioids with abuse-deterrent formulations are intended to make certain types of abuse, such as crushing a tablet to snort or dissolving a capsule to inject, more difficult or less rewarding. To date, FDA has approved at least 10 opioid drugs with these properties. It should be noted, however, that current technologies have not yet proven successful at deterring the most common form of abuse—swallowing a number of intact capsules or tablets for the purposes of misuse or abuse.

Moreover, the fact that a product has abuse-deterrent properties does not mean that it poses zero risk of abuse. It means, rather, that the risk of abuse may be lower than it would be without such properties. Because opioid products must, in the end, be able to be delivered to the patient, there may always be some abuse risk.

The uptake of abuse-deterrent opioids among doctors treating patients for chronic pain has been slow. A major reason for delayed adoption has been access to these branded medications. New generic products may widen such availability.

FDA Recommendations for New Product Testing and Comparison

For a pharmaceutical company to develop a generic opioid drug product with abuse-deterrent properties, it must submit an abbreviated new drug application (ANDA) to FDA that references an existing abuse-deterrent medication (ie, the reference listed drug, or RLD). The recent guidance recommends studies, including comparative in vitro and pharmacokinetic studies, to demonstrate that the investigational new product is no less abuse-deterrent than its RLD with respect to all potential routes of abuse.

Bioequivalence

FDA considers a generic medication to be therapeutically equivalent to its RLD when certain conditions are met. For ANDA approval, the agency generally must find, among other things, that the generic product has the following same qualities as the reference product: 2

  • active ingredient(s)
  • conditions of use
  • dosage form
  • route of administration
  • strength
  • labeling (with certain permissible differences).

In addition, the investigational product must be bioequivalent to the RLD and match the methods, facilities, and controls used for the manufacture, processing, and packaging of the product to assure and preserve the medication’s identity, strength, quality, and purity. Furthermore, the inactive ingredients and composition of the generic medication must be demonstrated to be safe under the conditions of use prescribed, recommended, or suggested in the labeling.

Conclusion

Transitioning from the current market, dominated by conventional opioids, to one in which most opioids have abuse-deterrent properties, holds significant promise of a meaningful public health benefit. FDA Commissioner Scott Gottlieb, MD, noted that the healthcare industry must have the potential to improve access to the newer formulations, for appropriately selected and monitored patients, through the introduction of generic competitors.3 Hence, FDA has released guidance on the development of these generic formulations.

 

Last updated on: December 7, 2017
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Abuse-Deterrent Formulations
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