Final Guidance on Abuse-Deterrent Opioid Generic Drug Testing Arrives – High Burden of Proof!

FDA published its final guidance on General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products (here) as perhaps a Thanksgiving present to the generic drug industry.  The theme throughout the document is “[i]f the summary in section 9.2 [of the RLD labeling] indicates that FDA has concluded that the product has properties that are expected to (or have been shown through postmarketing studies or trials to) deter abuse, in addition to other testing that may be needed to support the ANDA, the potential ANDA applicant should evaluate its proposed generic drug to show that it is no less abuse-deterrent than the RLD with respect to all of the potential routes of abuse.”(emphasis added)

The document describes the in vitro and in vivo testing the FDA expects in order to be able to approve an abuse-deterrent generic product equivalent to the reference listed drug (RLD). The testing outlined is, of course, in addition to the usual information that must be included in an ANDA. The guidance does not answer the question as to whether the generic product can be better or have more abuse-deterrent properties than the RLD.

The FDA has approved various products as NDAs where the sponsor has not successfully demonstrated to the Agency’s satisfaction that its product does actually deter abuse.  In such instances the NDA product does not contain information in its label about abuse deterrence.  FDA notes in the guidance that “if the labeling for R [reference] product does not describe any abuse-deterrent properties, the testing recommendations in this guidance are not applicable.” In such cases, the question of whether the FDA will approve a generic to the NDA product remain unanswered.  There are several products where ANDAs have been languishing at OGD or where the Agency has been reluctant to ascribe RLD status for an NDA product in such a situation. In addition, it is not clear what the Agency would do if it approved generics for such an NDA and the NDA sponsor later obtained abuse-deterrent language in labeling after conducting additional testing.

On the other hand, the guidance is clear that “[w]here the labeling for R product describes properties expected to deter abuse, a comparative evaluation of the abuse deterrence of T [test] product relative to R product for all potential routes of abuse should be conducted according to the following general principles:

  • “Tier-based approach to testing” – This tier-based approach allows for hierarchical testing, evaluating abuse-deterrent properties under progressively more challenging conditions.
  • Performance-based evaluation of abuse deterrence “- While formulations and exact mechanisms of abuse deterrence do not have to be the same, the performance of the test and reference products should be comparable. “For example, the measure that is expected to be the most meaningful for evaluation of abuse by injection is the percentage of opioid drug substance extracted from the product under various test conditions.”
  • “Most effective manipulation”– Appendix 1 of the guidance provides different methods of manipulation and describes which may be the most effective method to determine equivalence of the test and reference products.
  • “Sample selection after physical manipulation” – “At a minimum, the two extreme forms of a drug product (i.e., the intact and most effectively manipulated form) should be selected for evaluation in each relevant tier.”
  • “Comparing T and R products in extraction studies” – Again, Appendix 1 of the document provides recommendations as to which extraction methods to use for each tier of testing.
  • “Statistical comparison of T and R products” – There is an extensive section describing the expected statistical approach to evaluating the comparative testing.

It should be noted that, while this guidance document does provide significant direction to proposed sponsors of abuse deterrent generic versions of corresponding RLDs, the Agency makes it clear that in some cases the sponsor should still seek advice and guidance on specific testing requirements from the FDA prior to conducting some studies.

The guidance document also contains various appendices that described FDA expectations when evaluating abuse for various route of abuse:

  • Ingestion (oral route)
  • Injection (parenteral route)
  • Insufflation (nasal route)
  • Smoking (inhalation route

These appendices go into fine detail regarding testing requirements for each route of abuse.

In general, there is now a plan for approving generic products with abuse-deterrent properties and characteristics of the RLD if the generic is at least as abuse-deterrent as the RLD.  The hurdle, however, appears to be set very high.  Given that there has not been a single generic abuse-deterrent product approved to date, the question is when and if a generic sponsor will be able to meet these stringent requirements.  The penultimate question may be, when could a generic product even be marketed when facing new listed patents on the RLDs being approved?