On March 24, 2016, the U.S. Food and Drug Administration (“FDA”) published a draft guidance concerning studies for ANDA applicants to demonstrate the abuse deterrence of their generic solid oral opioid drug products. This draft guidance offers ANDA applicants principles for how to test certain abuse-deterrent aspects of a generic solid oral opioid drug product in order to show that it is no less abuse deterrent than the reference-listed drug (“RLD”).
FDA focuses this draft guidance on four of the seven categories of abuse-deterrent technologies described in the FDA guidance, Abuse-Deterrent Opioids – Evaluation and Labeling, which are physical or chemical barriers, agonists/antagonists, aversive agents or combinations of these tactics. FDA reviewed these four categories of abuse-deterrent technology for its generic testing recommendations for the following routes of opioid drug abuse: injection (parenteral route), ingestion (oral route), insufflation (nasal route) and smoking (inhalation route). In addition, FDA notes that it may provide testing recommendations on the three remaining abuse-deterrent technologies categories (delivery system, new molecular entities and prodrugs, and novel approaches) in the future.
The principles offered by FDA for testing generic solid oral opioid drug products involve testing the proposed generic product (“T product”), the RLD product (“R product”) and a control product (“C product”). The general principles for evaluating the abuse deterrence of a generic solid oral opioid drug product are:
- Tier-based approach to testing, where the abuse-deterrence evaluation of the T product begins with simple, gentle manipulations of the product and progresses to substantially more destructive mechanical and chemical manipulations (see Appendix 1 of the draft guidance for recommendations on mechanical manipulations and Appendix 3 for different levels of solvents that may be used for chemical manipulations) until the R product’s abuse deterrence is defeated or compromised, or the T product is shown to be less abuse deterrent than the R product (seeFigure 1 of the draft guidance for an example of a tier-based approach);
- Evaluation of abuse deterrence, where the ANDA applicant should identify the R product’s abuse deterrence for all routes of opioid drug abuse using the tier-based approach and (1) provide a summary of its assessment that the RLD has no abuse deterrence for a given route and why there is no need to test its T product in comparative studies and (2) base its evaluation of the T product’s abuse deterrence on its best understanding of the R product, the potential routes of abuse and specific measures meaningful to the evaluation of abuse by those routes;
- Use of control, where the C product—a non-abuse-deterrent version of the R product with the same active pharmaceutical ingredient (“API”) as the R product—is used in connection with testing the abuse-deterrent properties of the R product when appropriate, such as with extractability studies;
- Identification of discriminatory study conditions, where the appropriate parameters for each test for abuse deterrence for each route of abuse should be selected and should lie within the range specified in Appendices 2–5 of the draft guidance; and
- Comparison of R and T products, where the appropriate statistical comparisons on the R product and the T product should be conducted for each route of abuse as recommended in Section VIII and as shown in Appendices 2–5 of the draft guidance.
FDA recommends in vitro studies for its suggested tier-based testing. In cases where in vitro studies may not be applicable in abuse-deterrent testing, FDA notes that other types of studies may be available, such as pharmacokinetic (“PK”) studies. Finally, FDA suggests abuse-deterrent testing for T products of varied strengths if an ANDA applicant is seeking approval of generic solid oral opioid drug products of varied strengths.