For most drugs, the process of developing and obtaining FDA approval of a generic version is simple and well-defined: sponsors must only prove that their product is pharmaceutically equivalent and bioequivalent to the reference listed drug (RLD). No studies of safety or efficacy are needed, since the safety and efficacy of the drug product has already been proven by the innovator product. But what happens in the case of abuse-deterrent opioids, where a would-be generic may be therapeutically equivalent in treating pain, but may not have identical abuse-deterrent properties? Some abuse-deterrent labeling claims, such as demonstrated reduced abuse in the community, cannot be adopted until the analysis of postmarketing data. How can a generic abuse-deterrent opioid have an identical label to the innovator if it has not yet proven its abuse-deterrent properties in the community? Will a generic be required to conduct a clinical abuse potential study as described in the FDA guidance on the Evaluation and Labeling of Abuse-Deterrent Opioids?
While FDA considers this issue, sponsors may be able to gain insight from the way FDA dealt with testosterone gels. Beginning in 2009, FDA became aware of the risk of transferring testosterone from a topically applied gel after adult males would unknowingly transfer testosterone to children, causing adverse events. In FDA’s August 2009 response to a citizen petition from Auxilium Pharmaceuticals, Inc, the NDA holder of Testim (testosterone gel), one of two possible RLDs for testosterone gel, FDA stated that transfer and hand-washing studies were now a requirement for would-be generics of testosterone gel that utilized different penetration enhancers in their formulation. FDA further stated that by requiring in vivo transfer studies these products could no longer be submitted as an ANDA and would have to be submitted as a 505(b)(2) NDA. In October 2010, FDA responded to a similar petition submitted on behalf of Abbott Laboratories, the NDA holders of AndroGel, the other possible RLD for testosterone gel, reaffirming the previous decision of the requirement of the 505(b)(2) pathway. FDA also restated their original sentiment in the Testim response that the requirements for these products may be reconsidered as new information emerges, demonstrated by a change in the study requirements from the 2009 response.
In 2010, the answer seemed very clear: a prospective generic requiring additional clinical studies cannot be submitted as an ANDA. If FDA wouldn’t allow makers of testosterone gel products to file an ANDA as a result of additional study requirements, abuse-deterrent opioids will likely have the same fate. However, FDA demonstrated their evolution on this issue in a draft guidance on testosterone released April 2013 (revised in November 2013) which detailed a partial reversal of their previous decision. The Agency noted that the Office of Generic Drugs will accept an ANDA for a testosterone gel if the product is qualitatively and quantitatively the same (Q1/Q2) as the RLD. That is, an ANDA can be submitted if the product contains the same inactive ingredients and contains them in the same amounts as the RLD, allowing for a +/- 5% error margin.
So what does this all mean for potential generics of an abuse-deterrent opioid? For now, it is not likely that the Agency will accept ANDAs for already approved abuse-deterrent opioids, but will instead require them to pursue a 505(b)(2) NDA pathway. As with testosterone gel, this will probably change with time, after FDA has determined a way to evaluate the implications of abuse-deterrent opioids and develop a pathway for generic versions that assures equivalent abuse deterrence without the requirement of a study in humans. Until FDA’s policy on this issue is solidified, applicants developing abuse-deterrent opioids should prepare to pursue the 505(b)(2) NDA pathway.
Emily Krulewitz is a Researcher at The Weinberg Group, the world’s leading food and drug consulting firm. If you have any questions or thoughts on this blog post or others, please reach out to us by email.