FDA Releases Draft Guidance on Evaluating Abuse Deterrence of Generic Solid Oral Opioid Drugs

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The draft guidance outlines ways applicants can test for abuse deterrence in solid oral opioid drugs.

FDA released draft guidance on abuse deterrence for solid oral opioid drugs in March 2016. The draft guidance, titled General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products, is intended for those submitting abbreviated new drug applications (ANDAs) for generic opioid drugs with abuse deterrent properties.

According to the National Institute on Drug Abuse, it is estimated that 2.1 million people in the US abuse opioid prescription pain relievers, resulting in addiction and, in some cases, death. The institute says the number of unintentional overdose deaths has more than quadrupled since 1999. In the past year, US regulatory agencies have prioritized addressing prescription drug dependence. Sylvia M. Burwell, secretary of the Department of Health and Human Services, released a targeted initiative on the topic in March 2015, and Robert Califf, PhD, FDA’s deputy commissioner, called for a “sweeping review” of FDA opioid policy in February 2016.

FDA released its Opioids Action Plan in early February 2016, stating a plan to combat opioid abuse, dependence, and overdose. In the plan, FDA said it had plans to “fundamentally re-examine the risk-benefit paradigm for opioids.” Releasing draft guidance on the abuse-deterrent formulations (ADF) was a “high priority” for the regulatory agency, which said it hoped the guidance would spur more generic ADF development.

Draft Guidance Recommendations
FDA defines abuse deterrence in opioid drugs in seven distinct categories. These categories include physical/chemical barriers, agonist/antagonist combinations, aversion, delivery system, new molecular entities (NMEs), prodrugs, and combinations and novel approaches. FDA recommends that ANDA applicants follow a tiered approach when conducting comparative in-vitro studies of generic solid oral opioid products. The guidance suggests following tiered levels of solvents in chemical manipulation tests to determine the possibility of extraction of opioid for oral abuse. FDA says level one tests should be conducted with water; level two with commercially available food-grade vinegar, 0.2% baking soda, 40% ethanol, and carbonated drink; and level three with cooling oil, isopropyl alcohol acetone, 0.1 N HCl, and 0.1 H NaOH.

In cases where there are no reliable in-vitro testing methodologies, FDA suggests using pharmacokinetic (PK) studies to evaluate the abuse deterrence of the generic product in comparison to the reference. FDA also says the “applicant may provide supportive data to demonstration compositional proportionality across difference strengths of R [reference] and T [generic] products as justification for not conducting studies” to evaluate strengths.


FDA outlines a tier-based approach for comparing abuse deterrence in generic opioid drug products. These steps involve comparing the percentage of opioid extraction between a reference product, generic product, and control. The guidance notes there may be times where the tier-based approach “cannot adequately capture the complete profile” for the generic product due to inclusion of novel inactive ingredients, use of new technology, and formulation design.

The guidance also provides a detailed outline for ways solid oral opioid products may be mechanically manipulated using household equipment, in addition to ways they may be abused through injection, insufflation, inhalation, and oral ingestion. The agency provides testing methods to combat these types of abuse through comparison of reference and generic products, allowing applicants to more accurately determine abuse deterrence.

Source: FDA