The US Food and Drug Administration has issued final guidance, General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products, to assist companies in their development of generic versions of approved opioids with abuse-deterrent formulations (ADFs).

The guidance applies to persons that plan to submit abbreviated new drug applications (ANDA) for a generic version of a solid oral opioid drug product that references an opioid drug product with abuse-deterrent properties described in its labeling. The guidance recommends studies, including comparative in vitro and pharmacokinetic studies, that the potential ANDA applicant should conduct and submit to FDA in an ANDA to demonstrate that a generic solid oral opioid drug product is no less abuse deterrent than its reference listed drug with respect to all potential routes of abuse.

“Until we’re able to find new non-opioid forms of pain management for those who need treatment for pain, it’s critical that we also continue to promote the development of opioids that are harder to manipulate and abuse and take steps to encourage their use over opioids that don’t offer any form of abuse deterrence,” said FDA Commissioner Scott Gottlieb in a statement in commenting on the final guidance. 

Opioids with abuse-deterrent formulations (ADFs) 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, the FDA has approved 10 opioid drugs with these properties, according to the FDA. “But their uptake has been slow among doctors who are treating patients in pain,” said Gottlieb in his statement. “The reason for their more limited use is likely multifold. We know there can be a learning curve that comes with new technologies. Some prescribers may not be aware of the existence of these drugs, or may be uncertain of when to prescribe the abuse-deterrent versions. But we also know a significant barrier to use can be price. Because these new formulations are currently only available as brand-name products, they’re inherently more expensive than the numerous non-abuse deterrent formulations that are also available in generic formulations,” he said in the statement.

“Transitioning from the current market, dominated by conventional opioids, to one in which most opioids have abuse-deterrent properties, holds significant promise for a meaningful public health benefit,” said Gottlieb in his statement. “But to transition this market more quickly to the ADFs, and consider permanently withdrawing the older formulations that lack abuse-deterrent features in the event these products were judged to be less safe ‒ there are a number of factors we must consider. One of the factors that the FDA would consider relates to generic access. We must have the potential to improve access to the newer formulations, for appropriately selected and monitored patients, through the introduction of generic competitors.”

In order to support this transition, in November 2017 the FDA issued final guidance, General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products, to assist industry in its development of generic versions of approved ADF opioids. The guidance includes new recommendations about the type of studies companies should conduct to demonstrate that the generic drug is no less abuse-deterrent than its brand-name counterpart. The FDA says it is also taking additional steps beyond the new guidance to help developers of generic ADFs navigate the regulatory path to market as quickly as possible and make the review process more efficient and predictable. For example, it is developing testing methodologies for evaluating complex features, such as abuse deterrence for both brand name (innovator) and generic opioid drug products. In addition, it is also taking an approach for the evaluation and labeling of ADF opioids.

The FDA says it is also advancing new review policies to provide a more efficient pathway for the generic entry of these and other complex formulations. For example, the guidance is intended to assist generic drug developers who meet with the agency to discuss scientific and regulatory issues before submitting their applications. These meetings are supposed to enable the FDA to clarify the agency’s expectations early in the development process with the goal of reducing the time it takes to obtain approval.

The guidance describes seven categories of abuse-deterrent technologies — physical/chemical barriers, agonist/antagonist combinations, aversion, delivery system, new molecular entities (NMEs) and prodrugs, combinations, and novel approaches. This guidance focuses on the general principles for developing and evaluating the abuse deterrence of generic solid oral opioid drug products formulated to incorporate physical or chemical barriers, agonist/antagonist combinations, aversive agents, or a combination of two or more of these technologies. It does not provide testing recommendations for generic versions of opioid drug products incorporating other technologies (i.e., delivery system, NME/prodrug, or novel approaches), but the FDA said it may provide such testing recommendations in future product-specific guidance. Further, the FDA said it will continue to assess the state of science and, as novel technologies develop, and will address them by issuing additional guidance, as appropriate.

Source: FDA (statement) and FDA (final guidance)