(T1330-11-62) Regulatory Assessments for In Vivo Pharmacokinetic Abuse Deterrence Studies in Generic Drug Product Applications

Purpose: Abuse and misuse of prescription opioid analgesics have created a serious and widespread public health problem. Development of opioid drug products with abuse deterrence (AD) properties has been a high public priority to address this life-threatening epidemic issue. It is also important that less costly generic versions of those opioid products, which are no less AD than that of its innovator counterpart, are available to patients who need them. Generic opioid products may be manufactured with different excipients and processes which may impact their AD features as compared to the corresponding reference listed drug (RLD) products. The Agency has published both general and product specific guidance (PSG) to aid in the development and approval of generic opioid products with abuse deterrent formulations (ADFs). To date, all in vivo comparative pharmacokinetic (PK) AD studies in Abbreviated New Drug Applications (ANDAs) have been conducted post-publication of the aforementioned guidances. However, some common issues were still identified in the submitted studies. The objective of this project is to categorize these issues and highlight special considerations that are critical for conducting successful in vivo PK AD studies.

Methods: We conducted a survey of currently available data to the Agency from ANDAs for opioid products referencing an RLD with FDA-approved AD labeling. The submission status of in vivo ADF study data and assessment outcomes were examined and captured. Deficiencies for in vivo comparative PK AD studies were identified and divided into five categories: 1) sample manipulation and preparation, 2) drug administration method, 3) study design, 4) data analysis, and 5) other.

Results: Pertinent information from ANDAs submitted from 2010 to 2021 was collected and analyzed. None of these studies was considered adequate in the initial assessment and multiple deficiencies were issued. Among all the deficiencies issued, the most common deficiencies pertained to sample manipulation approaches for the nasal route or patient-relevant chewing conditions for the oral route (43.5%; e.g., lack of information about the equipment used in the sample manipulation) or drug administration method [35.5%; e.g., insufficient evidence to demonstrate that within a given treatment (test or reference), each subject received homogenous drug powder of the same particle size distribution and potency as all other subjects in the same treatment arm]. The less common deficiencies included those related to study design (11.3%; e.g., not following the recommendation in guidance for using opioid antagonist to block the pharmacodynamic effects of the opioid) and data analysis (6.5%, e.g., not providing SAS data for some pAUCs). Other miscellaneous deficiencies were also identified seeking clarification (3.2%; e.g., not providing reasons for study failure).

Conclusion: Our survey indicates that for the in vivo PK AD studies, appropriate manipulation and preparation of the drug samples, drug administration method, and study design are critical elements for study adequacy. Our findings should assist the generic pharmaceutical industry in improving the study design and conduct of these studies, resulting in improved abbreviated new drug application (ANDA) submission quality and shortening the time to approval of safe and effective opioid generic drug products for the American public which are no less abuse deterrent than the corresponding innovator products.

Acknowledgements: The views expressed in this poster are those of the authors and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred.