FDA officials and representatives from both the generic and branded drug industries spent two days hashing out next steps for development of abuse-deterrent opioids.

The two topics on the table: reviewing a draft guidance for the development of generic versions of abuse-deterrent opioids, and developing standard in vitro testing methods to characterize a drug's abuse-deterrent properties.

The meeting was in line with FDA's strategic plan for mitigating the opioid epidemic, which it released in February 2016, said Douglas Throckmorton, MD, deputy director of regulatory programs at the FDA's Center for Drug Evaluation and Research. That includes incentivizing the development of "progressively better" abuse-deterrent opioids and supporting a transition to these products, he said.

Throckmorton acknowledged the tension between generic and branded developers, but advocated working together to come up with a solution that benefits all parties.

"If you all came up with a single approach that suits the best product development, we would be delighted and take it very seriously," Throckmorton said. "It would move the field a great deal. It would require careful collaboration, but it's been successful in other fields, like drug-eluting stents, which had a similar challenge but the industry pulled together and made suggestions we all make use of."



FDA released its draft guidance for evaluating generic abuse-deterrent formulations last March, with the goal of ensuring that a generic is no less abuse-deterrent than the brand-name opioid. No generic abuse-deterrent opioids are currently approved.

In general, an ANDA applicant isn't required to provide independent evidence of the safety and effectiveness of the generic drug; instead it relies on the FDA finding that the previously approved product is safe and effective and must demonstrate that the generic is "bioequivalent" to the reference drug, primarily on the basis of pharmacokinetic studies.

Robert Lionberger, PhD, director of the office of research and standards in the FDA CDER's office of generic drugs, noted that the ANDA for any generic abuse-deterrent opioid would cover all routes of abuse: oral, nasal, injected, and smoked. It would also evaluate the drug in comparative in vitro studies and, in some cases, in relevant pharmacokinetic or other studies to show it is no less abuse-deterrent.

But some industry voices -- particularly from the branded industry -- said these assessments did not go far enough. "I am concerned that this draft guidance is not sufficient to ensure that generic versions will be no less abusable than the reference drugs," said Alexander Kraus, PhD, of Grunenthal USA in Morristown, N.J. "It does not do enough to ensure that the generic meets therapeutic equivalence. It can't be based solely on in vitro testing. I encourage the FDA to require not only Category I in vitro tests, but Category II pharmacokinetic and Category III human reference studies as well."

Those Category I in vitro tests for abuse-deterrent opioids have their own issues to be worked out, which was why they were also a focus of the meeting.

Xiaoming Xu, PhD, a senior staff fellow at the FDA's division of product quality, said in vitro testing for abuse-deterrent opioids has not been standardized, making both comparisons with other drugs and overall assessments challenging.

Ideally, that testing should assess each potential route of abuse -- oral, injectable, nasal, and smoking -- starting with simple and gentle mechanical and chemical manipulations, progressing to complex and more destructive manipulations. It should also address mechanisms by which abusers can be expected to attempt to overcome abuse-deterrent properties as well as the ways that patients may alter the formulation to change the amount of of drug that gets released, Xu said.

The challenge is that the design of these experiments is complex: any single product can have more than a dozen possible methods to achieve a desired manipulation; scores of different solvents; different reactions to various temperature conditions; different volumes released, and so on. Indeed, the number of experiments can run into the thousands, Xu added.

The problem garnered unique observations about the automobile industry and coffee grinders. Richard Lostritto, PhD, acting associate director in the office of policy for pharmaceutical quality at FDA's CDER, noted that the auto industry standardized the type of hammer it would use in safety tests; Karsten Lindhardt, PhD, of Egalet Corporation, noted that he's had to buy several different types of coffee grinders to do proper in vitro testing.
"You end up with each material behaving differently," he said. "One grinder may be optimal for one drug but not for another."

Throckmorton acknowledged the tension between developing standardized versus individual tests for these types of analyses: "We've seen that even small changes in some formulations can have a large effect on product performance." Although it was not a point of the meeting, critics at past FDA advisory committee meetings for abuse-deterrent opioids have called for epidemiologic data on whether or not these formulations can actually reduce abuse and the more serious consequences of addiction, overdose, and death.

Also, the meeting did not address patent issues, which generally fall outside FDA's jurisdiction. Although the major opioid drug compounds are now off-patent, it may be many years before patents expire on the specific abuse-deterrence technologies now in use.