Methodological Advances in Evaluating Abuse Deterrent Opioid Analgesics
The Methodological Advances in Evaluating Abuse Deterrent Opioid Analgesics is a visionary research and dissemination project intended to advance the science of studies of opioid analgesics by leveraging emerging advances in data connectivity and establishing new standards for methodological rigor, with a focus on abuse deterrent formulations.
The overall project goal is to develop and disseminate new “open source” epidemiologic tools to facilitate evaluation of abuse deterrent formulations (ADFs). The methodologic products from this project will be made available to the research community, in the expectation that researchers will apply them to improve the quality of studies in the area of opioids.
The project comprises three inter-related sections: Theory, Practice, and Lived Experience.
The project is co-led by the University of North Carolina 
(Injury Prevention Research Center, the Department of Epidemiology at the Gillings School of Global Public Health ) and the University of Kentucky (College of Public Health , College of Pharmacy , Kentucky Injury Prevention Research Center , Institute for Pharmaceutical Outcomes and Policy ), with other collaborators coming on board in Fall 2019.
This project is supported by the U.S. Department of Health and Human Services’ Food and Drug Administration .
Study 1: Surveys of Clinical and Pharmacy Practice Involving ADFs
Lead: Dr. Patricia Freeman, University of Kentucky (Project Years 2018-2020)
This study will provide information on key factors that influence ADF prescribing and dispensing to better understand the context of ADF utilization in clinical practice. It will also evaluate pharmacists’ derivation of days’ supply and determine validity of days supply calculations to assist in the interpretation of PMP data. The use of scientific trainees further reduces costs.
Study 2: Timely Monitoring of PMP-Linked Mortality Data
Lead: Dr. Terry Bunn, University of Kentucky (Project Years 2018-2020)
Establishment of a novel near real-time opioid mortality surveillance system based on multiple linked data sources, which can be conceptualized as an automated, prospective real-time all-cause mortality registry study for all patients in the state receiving opioids. This is an unprecedented technological advance in pharmacoepidemiology. Monthly data analysis will provide up-to-date observations and identify potential trends associated with overall opioid dispensing and mortality. This effort in KY can serve as a model for other states to enhance national opioid mortality monitoring.
Study 3: Informing the Choice of Comparators
Lead: Dr. Shabbar Ranapurwala, University of North Carolina (Project Years 2019-2020)
In this study, we evaluate and compare methods for the confounding by “indication”, the expected likelihood that patients receiving ADF opioids have different risk profiles for experiencing overdose/abuse outcomes than patients prescribed traditional opioids. Since an individual’s risk for misuse of opioids likely changes over time, time-varying models will be deployed to quantify the importance of time-dependent adjustment. Advancing methodologic rigor of methods for controlling for confounding by indication is critical to achieving valid results from large administrative databases. We will also conduct validation studies (for exposure and outcome, using both ICD-9 and ICD-10 codes) and create tools for quantitative bias analysis that can be used to improve the scientific quality of PMR studies. This work will quantify the impact of bias in PMR studies, thereby informing the degree to which the federal agencies can depend on these studies for policy formulation.
Study 4: Accuracy of Mortality Outcomes in Linked Claims Data
Lead: Dr. Michele Jonsson Funk, University of North Carolina (Project Years 2019-2021)
The development and validation of an algorithm to distinguish disenrollment (out-of-hospital death versus other types of disenrollment) addresses a major limitation in claims-based studies. These methodological advances will 1) enable a broad array of research for which mortality is an outcome of interest, 2) improve the efficiency of studies for which data on cause of death is necessary but too costly to obtain for the full study population, and 3) address a pervasive bias in studies of outcomes for which mortality serves as a competing risk. This effort will produce tools to overcome practical limitations for claims-based PMR studies of overdose to link to external mortality registries.
Study 5: ADF Tampering and Excipient Harm
Lead: Dr. Alex Kral, Research Triangle Institute (Project Years 2019-2021)
Studies of excipient harms and tampering with ADFs have been limited. This will be the first long-term US ethnography focused on ADF tampering and excipient harms of opioid analgesics with people who inject drugs.
THEORY
Led by the University of North Carolina at Chapel Hill (UNC), these studies will apply pharmacoepidemiology theory to the practice of ADF evaluation, with the goal of developing and gathering feedback on open source tools that will assist in advancing the science of this field, for both ADF and non-ADF opioids. Specific issues of focus are the choice of comparators and confounding by “indication”, use of tools for addressing misclassification and quantitative bias analysis), and identifying out-of-hospital deaths in claims data.
PRACTICE
Led by the University of Kentucky (UKY), these studies will provide insight on practice- level decisions that impact how ADFs are prescribed and dispensed, focusing on motivators of physician choice in ADF prescribing and pharmacists experience with ADF dispensing. Additionally, the pioneering electronic linkage of Prescription Monitoring Program (PMP), mortality, toxicology, and claims data in Kentucky will be leveraged to examine issues in the validity of epidemiologic studies utilized real-time individual-level mortality data.
LIVED EXPERIENCE
Understanding the lived experience of opioid patients and people who use drugs is critical to comprehending the role of ADFs in society. Led by the Research Triangle Institute (RTI) International and run in conjunction with the Urban Survivors Union (USU) in Greensboro, NC, a health advocacy organization, this study will use ethnographic methods to provide much-needed data on ADF injection and excipient harm.