Deaths from opioid abuse in the U.S. surpassed 16,000 in 2013, quadrupling since 1999. Criticism of the FDA over the opioid abuse epidemic reached a shrill level last year when the agency approved the painkiller Zohydro ER in spite of criticism that it is easily abused.
Months later, the FDA approved a reformulation of the drug designed to be abuse-deterrent. To prepare for the wave of similar candidates in the pipeline, like Pfizer's ($PFE) abuse-deterring, extended-release opioid capsules, the agency just finalized guidance on the evaluation and labeling of abuse-deterrent opioids.
"Development of abuse-deterrent products is a priority for the FDA, and we hope this guidance will lead to more approved drugs with meaningful abuse-deterrent properties," said the director of the FDA's Center for Drug Evaluation and Research, Dr. Janet Woodcock, in a statement. "While abuse-deterrent formulations do not make an opioid impossible to abuse and cannot wholly prevent overdose and death, they are an important part of the effort to reduce opioid misuse and abuse."
Besides preventing patient deaths, an abuse-deterrent label means that a product can be considered for an extended period of marketing exclusivity, typically lasting three years, according to the Regulatory Affairs Professional Society.
The guidance says that there are at least 5 strategies to design abuse-deterrent opioids, all of which involve drug delivery or the creation of novel formulations that house the active ingredient.
They are 1) the deployment of physical and chemical barriers to chewing or crushing, 2) use of a sequestered opioid antagonist that is released upon manipulation of the product to neutralize the addictive chemicals 3) aversion--or the release of irritating chemicals if a product is manipulated, 4) delivery systems for injectable or other non-oral delivery, and 5) the use of new chemical entities such as a prodrug (a formulation in which the main ingredient is administered in an active state and becomes activated inside the body).
Combinations of the strategies can be employed. The guidance also applies to novel approaches that do not fit in any of the 5 categories.
In the guidance, the FDA calls for three types of premarket studies. They are 1) laboratory manipulation and extraction studies to evaluate the strength of the abuse deterring features, 2) comparative pharmacokinetic studies of the formulation in a manipulated and intact state, as well as the intact formulation of other similar drugs. And most importantly, 3) clinical abuse potential studies on recreational drug users.
The guidance describes the last class of studies in detail. They should be randomized, double-blind and placebo-controlled. In addition, the guidance says that a subjective, often numerical, measure known as a "visual analogue scale" should be used as the primary endpoint. The FDA recommends the questionnaire contain a bipolar scale, meaning the two extremes (such as good or bad mood following use) are at both extremes of the scale, with various gradations presented in between.
Other topics discussed in the final guidance include appropriate statistical analysis of the trial results and post-market studies.
In general, the guidance stresses the need to distinguish between and test separately the potential for abuse by various routes of administration. For example, an abuse deterrent label must state the routes of abuse that the product discourages (or does not discourage), such as abuse via inappropriate chewing of the medication (oral administration route) or snorting it (intranasal route).
The Regulatory Affairs Professional Society says another related guidance on the abuse-deterrent qualities of generic opioids is slated to be published soon.