NAVIPPRO Roundtable: Abuse Deterrence
Welcome to the September issue of NAVIPPRO Signal. In this discussion, NAVIPPRO experts Simon Budman, PhD; Stephen Butler, PhD; Theresa Cassidy, MPH; Ryan Black, PhD; John Brownstein, PhD; and Deborah Leiderman*, MD, MA, FAAN share their thoughts on abuse deterrence.
What is abuse deterrence and why is it important?
Theresa: Abuse deterrence refers to the ability of a drug formulation to restrict or reduce the potential for abuse of the drug. This is important so that drugs with abuse potential, such as prescription opioid medications, can be readily available to people who need them for a variety of medical conditions. A clear distinction that must be made is that such a formulation would deter abuse, not eliminate it.
Simon: With regard to this definition, one must distinguish between abuse and misuse of a drug. With abuse, one takes the drug with the intention of getting high or for the euphoric effects that the drug causes. Misuse is using the drug for its intended purpose, but in a way that was not prescribed by a health care provider (i.e., taking too much of the drug for pain relief, taking the drug to relieve pain for a condition other than for the condition the drug was originally prescribed for, or accidentally misusing the drug.
Stephen: Most prescription opioid formulations that are currently in the pipeline are being formulated so that they cannot be manipulated for alternate routes of administration. Is “tamper resistant” the same as “abuse deterrent”?
Deborah: This is an important issue in that the designations of “abuse resistant” or “abuse/tamper deterrent” are theoretical or hypothetical characteristics that require empiric validation in the community. The characteristic of “abuse deterrent” could in principle be accomplished in a variety of ways–ranging from pharmacological innovations in the properties of a drug- that is achieving analgesia without euphoriant or rewarding properties–to modified physicochemical properties of a formulation. When drug developers and public health professionals use the term tamper resistance, it usually refers to the physical properties of the drug delivery system which make it resistant to modification from, for example, sustained release to immediate release, solid particle or matrix to solution for injection and so on. Other properties of drug products that theoretically could reduce or deter abuse include pharmacological modifications such as the addition of an opioid antagonist to counter the effects of an opioid agonist drug, if the formulations were modified–perhaps injected–or the dose was substantially increased.
Simon: Abuse deterrence is critical because as opioids are made more available or prescribed more frequently, there is always the risk of increased abuse. A goal of the new abuse deterrent formulations is to cut down on inappropriate use of these drugs.
What are the prominent approaches to measuring abuse deterrence?
Simon: From our point of view, there have been no good models for measuring abuse deterrence.
Stephen: A fundamental challenge in measuring abuse deterrence is proving that something is not happening (i.e., accepting the Null hypothesis). Even if we don′t observe the abuse of a drug, we still cannot prove that it isn′t occurring. How do we design a study to prove that something is not happening?
John: We are faced not only with the issue of answering such a question but also the fact that the situation surrounding abuse deterrence is constantly changing, and that a variety of extrinsic factors affect the abuse of a drug, such as time on the market. Any approach to measuring abuse deterrence needs to take these extrinsic factors into account, and it is the existence of these factors that exemplify the reason why abuse deterrence needs to be examined using real world, epidemiologically-based study.
Simon: As we have seen in the past, it is clear that the question of abuse deterrence cannot be answered via a simple pre-post design. Determining whether or not a drug is abuse deterrent needs to be a dynamic, ongoing process that will have to occur for an extended period of time as conditions change with respect to the abuse of the drug.
Deborah: That is a very important point. Abuse deterrence will be defined by real world experience and “abuse deterrent” will always be a relative characteristic of a product which contains a euphoriant or rewarding drug. Historical epidemiological data will be important in assessing the impact of any new formulation that is developed to replace an (abused) existing drug formulation containing the identical active drug substance. There is no question that determinants of abuse patterns are complex and multi-factorial so that interpretation of the impact on rates of abuse of an opioid analgesic after introduction of a new formulation must take into account other factors such as changes in prescribing patterns for the drug of interest as well as for other products prescribed for the same indication, regional availability, as well as the impact of other interventions such as prescription drug monitoring programs.
Why is an in vivo epidemiological approach so important in measuring abuse deterrence?
John: There is only so much information that can be derived from a clinical trial; abuse deterrence is a broad facet and requires a population view. The issue around abuse deterrence is that it is dynamic and not simply based on a drug′s intrinsic characteristics; several extrinsic factors, independent of the actual characteristics of a drug formulation, such as how much media attention a drug receives also relates to the abuse rates of a drug.
Simon: An ongoing, epidemiologically-based approach is the only approach that will provide data on how people actually abuse these drugs and the implications of such abuse.
Do you believe that abuse deterrent opioids will have an impact on safety and public health?
Deborah: That is the goal, and the theory, but of course it remains to be empirically demonstrated.
Stephen: It is an empirical question. It seems highly unlikely that the development of such drug formulations would have a large effect on the abuse of opioids, which is a phenomenon that has been occurring for thousands of years. These formulations may, however, have an impact on safety and public health, issues that may allow these drugs to be more readily available to pain patients without increasing the potential for abuse.
Simon: The development of these abuse deterrent formulations is a massive public health experiment. As these products become more difficult to be abused, might more people start to abuse heroin? It is hard to imagine that the development of these formulations will change abuse in our society and what long-term impact these new abuse deterrent formulations may have is an open question. Certain routes of administration may decrease for a particular product and this may have an impact on the transmission of various blood-borne pathogens, for example. Our hope would be that these drugs could intervene in the downhill course that some abusers follow when they move from oral ingestion to chewing to snorting to injecting and so on. This is still an empirical question and one that can only be answered over time.
Stephen: There is also a possible downside to these formulations in that prescribers may misinterpret the safety of an abuse deterrent-designated drug. It needs to be clear to health care professionals that these drugs would still be powerful and problematic medications.
Deborah: Absolutely right, and that is a significant concern. If physicians did not adhere to principles of appropriate prescribing and modified their practices based upon the perception of reduced risk of these drug products, this could be viewed as an unintended consequence of product labeling. That is why there needs to be a cautious, step-wise approach to labeling of these modified formulations. It is important to emphasize that one of the goals in developing these putative “abuse resistant” formulations is not only to make them more difficult in practice to abuse or misuse, but also to decrease the attractiveness of prescription opioid products for abuse, particularly by adolescents and new initiates.
Simon: It is true that if these drug formulations prove to be abuse deterrent, that it might become necessary for all drugs within that particular class to be abuse deterrent. This might prevent drug abusers from transitioning from one prescription opioid formulation to another to avoid the abuse deterrent mechanism. The real goal of all of these abuse deterrent efforts is to keep opioids readily available to those with chronic pain who need them and minimize the risks of abuse. We are all interested in that as a goal.
How can we really know if a drug is abuse deterrent?
John: We don′t know if that can be answered at the moment or possibly ever. The potential abuse deterrence of a drug needs constant monitoring and one thing we could ask is whether a drug is not abuse conducive by making a comparison between the abuse deterrent formulations with non-abuse deterrent counterparts.
Theresa: There is no zero risk. It will be the weight of evidence over time that will give us some indication of whether a drug is not abuse conducive.
Ryan: The better question to be asking may be not whether a drug is going to be abuse deterrent but rather to look at the data from multiple sources and determine whether or not the drug is actually being abused.
Stephen: That is the dilemma. This situation of not being able to “prove” abuse deterrence puts the regulatory agency in a difficult situation. The Agency is going to be asked to “reward” pharmaceutical companies for putting the effort and time into developing these abuse deterrent drugs which puts them in a bind of having to make a designation or labeling decision on something that might prove to be problematic in the future.
Simon: It is also clear that incentives need to be in place for the drug companies to produce these abuse deterrent formulations. Also, the designation of abuse deterrence is temporal and should be assessed on a continuous basis.
Deborah: The FDA is on record as stating that it encourages and wants to see the development of abuse deterrent medications, particularly in the analgesic arena. However, what would constitute sufficient and relevant data to earn such a designation and what would need to be demonstrated is not entirely clear. The answer may be that such labeling may rely upon post-approval community-based epidemiological studies after sufficient marketing experience–that is, that the designation of abuse deterrent–perhaps in contrast to tamper-resistant–may not be granted at the time of initial approval.
Can you discuss the DETER model a bit and where things stand with it?
Simon: We at Inflexxion developed this approach to address the issue of measuring abuse deterrence. DETER, or Dynamic Evaluation and Timely Estimates of Rx Opioid Routes of Administration and Abuse Deterrence, is being developed as a real world, dynamic approach to monitor the abuse potential of prescription opioids. As we stated throughout our discussion, it is clear that in addition to being based in epidemiological study, and being dynamic, such an approach will need to be ongoing and provide real-time data, and it must be able to derive information from multiple sources. One aspect of DETER, the Abuse Deterrent Adjusted Measurement Model, or ADAMM, monitors abuse rates within a population of substance abuse treatment clients; this is important because it is this population of drug abusers that are going to be eager to get their hands on a new drug formulation in order to manipulate it for alternate routes of administration. Through the development of ADAMM it was clear that certain covariates, such as availability of the product and how long any particular product has been on the market, would have to be taken into account in order to create an “even playing field” for comparisons between formulations. We have been conducting a number of studies to test and clarify the model in order to make this approach available to pharmaceutical companies. DETER also has an Internet Monitoring component, called iPOST for Internet-based Prescription Opioid Surveillance Technology. The iPOST component helps us learn how people try to thwart an abuse deterrent mechanism and how this information spreads. Additionally, we′re developing methods to help determine the attractiveness of a drug both pre- and post-launch of the formulation, called Rx Opioid Attractiveness Measure (ROAM).
Deborah: The DETER approach has the potential to be enormously useful as it would study the real-world issues associated with a product and (hypothesized) abuse deterrence compared to the more traditional studies conducted during pre-market development of a new drug product.
*The views expressed by Deborah B. Leiderman, M.D. are her own and do not represent current or past policies of the FDA.
National Association of State Controlled Substances Authorities
2008 NASCSA Educational Conference
October 21-25, 2008
Fort Lauderdale, FL
National Association of Drug Diversion Investigators
19th Annual Education and Training Conference
November 11-14, 2008
Nashville, TN
Founding Sponsors
The NAVIPPRO™ team would like to recognize the continued sponsorship of founding sponsors: Alpharma Pharmaceuticals LLC. and Endo Pharmaceuticals.
