Use of Causal Framework to Evaluate Effect of Abuse Deterrent Properties of XTAMPZA ER on Opioid Tampering in a Post-Market Setting

Abstract Title: Use of Causal Framework to Evaluate Effect of Abuse Deterrent Properties of XTAMPZA ER on Opioid Tampering in a Post-Market Setting

Background: The US Food and Drug Administration (FDA) guidance on labelling ADF products recommends postmarket studies to assess if there are meaningful reductions in abuse in community settings. In this guidance, categories 1-3 of evaluation focus on the drug product properties and whether the drug itself can be tampered with by individuals to whom it is prescribed in a controlled setting. Category 4 of the guidance shift to studies in a postmarket setting, focusing on person-centric behaviors such as occurrence of abuse and individual’s overall proclivity to tamper with drugs. To achieve category 4 labelling, the ADF should reduce abuse in the community, suggesting that an ADF must alter trajectories of individuals drug use behavior and reduce tampering broadly. XTAMPZA^® ER (Collegium Pharmaceuticals, Inc.) is an extended-release (ER) ADF of oxycodone utilizing the DETERx technology, which was approved in 2015 and available in 2016 with categories 1-3 label claims for abuse deterrence.

Purpose/Objectives: It is essential to assess effectiveness of any ADF technology outside controlled settings, where tampering behavior is more complex than tampering with individual drugs and the drug effect may differ based on a person’s history.  For example, it is likely that altering a person’s established behavior would be more challenging than preventing initiation in a person with no prior experience with tampering. Tampering is a common abuse method to increase or change the physiological effect of the drug; this behavior was the focus of the study irrespective of whether the tampering attempt was perceived as successful by the tamperer. The goal of this study was to assess whether exposure to XTAMPZA ER reduced tampering of oxycodone utilizing the formalized guidance and causal theory as frameworks for study design.

Method: Data from an observational cross-sectional surveillance study of the general adult population administered in 2022, the Survey of Non-Medical Use of Prescription Drugs Program, was used to estimate the confounding adjusted odds of tampering after exposure to XTAMPZA ER as compared to: other extended-release (ER) oxycodone and single entity immediate-release (SE-IR) oxycodone. The tampering outcome was defined as use by snorting, smoking, or injecting of either XTAMPZA ER or comparator. Average treatment effect among the treated was estimated using inverse propensity score weighting combined with survey weights in a regression for generalizable results. A directed acyclic graph (DAG) was used to identify covariates. After evaluation of the DAG, confounders identified included demographic variables (race, ethnicity, socioeconomic status proxies, age, and sex), clinical indicators (pain history and mental health), and other substance use indicators (severity of drug use, obtainment of diverted ER oxycodone outside healthcare professionals, and illicit opioid use).

Results: Among 59,041 individuals in the general population, 10 of 117 (8.5%) reported tampering of XTAMPZA ER. This was larger proportionally than other ER oxycodone (113/2,267; 5.0%) and SE-IR oxycodone (142/1,880; 7.6%). Individuals who used XTAMPZA ER had more non-medical use of other oxycodone products, and more severe drug use markers despite similar health histories. After adjustment,  the odds ratio of tampering with any form of oxycodone among those who used XTAMPZA ER compared to users of ER oxycodone was not statistically significant (1.32; 95% CI: 0.56-3.10). Similarly, odds ratio compared to users of SE-IR oxycodone was not significant (2.17;  0.91-5.18).

Conclusions: Our analysis provides direct evidence in accordance with FDA guidance for labelling of an ADF product, XTAMPZA ER, and utilized a causal framework. The analysis assessed whether there was a concurrent reduction in abuse behaviors by tampering associated with use of XTAMPZA ER in a post-approval setting. Tampering of oxycodone products by individuals using XTAMPZA ER was rare and similar to individuals using other oxycodone products. We identified the possibility of preferential prescribing of XTAMPZA ER to patients at higher risk. Given the extensive co-use with other oxycodone products and abuse history observed in individuals using XTAMPZA ER, it is notable that an individual’s exposure to another ER oxycodone product did not result in higher tampering in this XTAMPZA group. This real-world evidence utilized an approach to quantify and adjust for the factors and experiences that influence an individual’s drug use. This evidence, alongside prior mechanistic and parallel evidence, constitutes a more complete picture of ADF use in a post-approval setting. One area not examined in this study was potential effect modification in individuals without severe drug use histories; in this study this population was unmeasured. This method is transferrable to other product claims for real world effectiveness.

References: Center for Drug Evaluation and Research. (2015). Abuse-Deterrent Opioids – Evaluation and Labeling: Guidance for Industry. Food and Drug Administration, U.S. Department of Health and Human Services. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/abuse-deterrent-opioids-evaluation-and-labeling

LABEL: XTAMPZA ER- oxycodone capsule, extended release. U.S. National Library of Medicine. Accessed 18 May 2023, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b0a5ded2-8ee2-49ca-a86c-2b28ae40f60c

Ridgeway G, Kovalchik SA, Griffin BA, Kabeto MU. Propensity Score Analysis with Survey Weighted Data. J Causal Inference. Sep 2015;3(2):237-249. doi:10.1515/jci-2014-0039