Talking with Dr. Judy Staffa, PhD, RPh, who is the Associate Director for Public Health Initiatives in CDER’s Office of Surveillance & Epidemiology.
Determining the real-world impact of opioid analgesic formulations with properties designed to deter abuse is key to understanding how these particular products may be helping to curb the opioid abuse epidemic. However, there are limitations in how relevant post-market data are currently obtained and interpreted. In July 2017, FDA held a public workshop, titled, Data and Methods for Evaluating the Impact of Opioid Formulations with Properties Designed to Deter Abuse in the Postmarket Setting: A Scientific Discussion of Present and Future Capabilities, to exchange ideas about how to measure and track the effectiveness of these particular products.
Workshop participants agreed that the quality of the available post-market data needs to be improved, so we can better interpret the results of studies using these data. To further that goal, FDA recently awarded contracts to two companies, Denver Health and Hospitals Authority (RADARS) and Inflexxion, Inc., that will help us determine how to collect more scientifically valid data, as well as improve our interpretation of existing data. The results of this work will be shared publicly, which will facilitate better research on ADFs and other aspects of drug abuse in the United States.
Judy Staffa, PhD, RPh, Associate Director for Public Health Initiatives in CDER’s Office of Surveillance & Epidemiology, further describes the issue, and discusses the current methods and challenges associated with measuring the impact of opioid analgesic formulations with properties designed to deter abuse.
- First, let’s clarify what is meant by the phrase “properties designed to deter abuse.” What is an opioid formulation with these properties, and what is it not?
Abuse deterrent formulations (ADFs) of opioid analgesics have been specifically formulated to make manipulation for abuse by specific routes, such as intranasal (snorting) or injection more difficult or less rewarding through those routes. They are designed to make it harder for people to manipulate the products, but they are not “abuse-proof,” and they do not prevent addiction. This last point is particularly important. Because the product still has to deliver the opioid to provide the analgesic effect, prescribers must be aware that all of the risks and adverse effects for that product remain, including the risks for overdose, death, and addiction.
- How are ADFs tested before they are approved and enter the marketplace?
Prior to the approval and marketing of any ADF, it must undergo a series of in vitro and in vivo studies. For instance, in vitro studies, also known as Category 1 studies, determine the effects of physical and chemical manipulation of the product, including any resistance to crushing, and whether the product can be dissolved, or if the opioid can be extracted for the purpose of injection. Category 2 studies are pharmacokinetic studies. They examine the amount of opioid that can be absorbed from a product that is manipulated for oral or nasal abuse. Category 3 studies are human abuse liability studies. They measure the effects of manipulated product by the oral or nasal routes of administration, including the amount of “high,” how much the drug is liked, and to what extent the person would want to take the drug again. These studies typically compare the new product to an already approved product. All ADFs currently marketed have successfully undergone these types of pre-market studies, and their labeling information is based on these data.
The challenge we face now is that none of the ADFs on the market have been definitively shown to deter abuse in the real world where reliable data can be hard to find, and where many different factors influence which drugs people choose to abuse.
- What are some challenges associated with evaluating ADFs after they enter the market?
All of the sponsors that market ADFs have post-marketing requirements, or PMRs, to evaluate whether their product actually decreases abuse and related adverse outcomes in the real world, outside of the controlled environment of the pre-market testing. The sponsors are all in various stages of conducting these studies, but they face many challenges, in part because existing data sources have substantial limitations.
For example, some potentially valuable data are based on surveys of individuals who are entering or are being assessed for treatment for substance use disorders. From these data, we can try to determine what products or substances they have been abusing and through which routes, but these data sources are limited to people who are referred to or seek treatment in those centers. Moreover, not all treatment centers in the United States are included in these data sources, and we do not know if the ones that are included are representative of certain regions, populations, or types of centers. We also do not know how individual responses may be influenced by the phrasing of questions, or the order in which the questions are asked.
- What are some of the other outcomes of the July 2017 workshop?
The intention of the meeting was to gather a diversity of experts from different fields that would not normally interact, and to stimulate conversation about best practices in evaluating the real-world effectiveness of ADFs. For example, we had experts who study substance abuse behaviors; epidemiologists from the Centers for Disease Control and Prevention who collect data on the nation’s health, including reportable diseases like HIV; survey statisticians; and traditional pharmacoepidemiologists who study other drug safety issues, all exchanging ideas. The participants at the workshop confirmed that we are tackling a complex and difficult problem that will not be solved easily. We will need to work together and think in different ways to address it. We hope that innovative and creative collaborations addressing the opioid crisis will arise from some of these conversations, including ways to improve the design of studies and timely data collection to support these studies. As an agency, we look forward to working with others to address the challenges in this area, as well as initiating our own efforts, as evidenced by our funding of this new research to better understand and improve available data resources. If we all do our part to move this science forward, we can make a difference.
More information about the July workshop, including an issues paper, a list of participants, and presentations, is found here.