Addressing the Challenges of Abuse Liability Testing – Meeting Regulatory Requirements and Study Design

Addressing the Challenges of Abuse Liability Testing – Meeting Regulatory Requirements and Study Design

Identifying clinically useful compounds and developing a novel drug treatment to improve human health has many rewards. But with increasing press about the growing abuse of prescription medications and potentials for physiological or physical dependence, regulatory agencies around the world have taken note.

Called abuse liability testing, this stage of drug development was first officially recognized in 1970 with the U.S. Controlled Substances Act. Since then, many iterations and guidelines have been developed to determine a compound’s potential for abuse.

Abuse liability studies are very important because they are required by the regulatory agencies in U.S., Europe, and even Asia for setting the scheduling of new chemical entities that come into the marketplace.

There have been cases where a pharmaceutical company wanted to register a new chemical entity, but hadn’t completed sufficient abuse liability testing and experienced delays within the approval process. As any drug developer knows, delays in regulatory decisions translate into setbacks on moving into the marketplace while the patent clock is ticking.

Typically, preclinical abuse liability studies take place in Phase II of clinical development and are best served by aggregate data collected from three studies: Drug Dependence, Drug Discrimination, and Self Administration. Each can be performed in parallel, but if done consecutively, the downstream studies benefit from previous results.

Study design starts with examining the triggers of the treatment to see how it affects central nervous system activity, especially if it is considered a “high priority indication,” such as a treatment for pain, attention-deficit/hyperactivity disorder (ADHD), or insomnia. The abuse liability team at Covance studies the target or mechanism of action, pharmacokinetics data, and characterizes the active metabolites, based on the target population.

They also look at the blood level data and duration of how long a treatment acts. This is critical in trying to design a study to determine if or when to pretreat, as well as calculate the number of replicates needed. Based on all this information, the client is advised on the particular studies to run.

Another design consideration is determining the species to use, either rodents or non-human primates. The preference from many perspectives would be to use rodents, but in some cases they may not be sufficient to characterize the compound. This depends on the mechanism of action (MOA) of the drug.

One must first determines whether the MOA occurs in both rodents and primates, or if the receptor for the effect is only present in primates. Because the metabolites profile can differ across species, if a significant metabolite in humans doesn’t appear in the rodents, this will affect the species choice in the study design.

Once the pre-planning is complete, the first study of drug dependence takes about 2-4 weeks. It determines if discontinuing the treatment shows signs of withdrawal, by looking at both behavioral and physiological parameters before, during, and after treatment.

The drug discrimination study then compares the test compound to a reference compound, such as amphetamine, a drug with known response. The animal model is trained to respond on a lever to receive food and discriminate between the test compound and the reference to see if the test elicits a similar response when substituted with the reference. Can the animal model reliably discriminate between the two treatments? Drug discrimination testing provides valuable insights into the potential for abuse.

Finally, the self administration study assesses abuse liability by again comparing the test compound to a reference compound, such as cocaine. Similarly, the animals tested in self-administration are trained to respond on a lever for the intravenous administration of the reference compound, which is then substituted for the test compound. The study compares the rate of responding for both compounds, as they can choose to press the lever to deliver more of the compound. If the animal continues to press it, then there is a high likelihood that the compound will be abused.

As a specific example, I contributed to a published study that detailed the abuse liability testing of a compound intended to treat ADHD in children. Because this compound had a central nervous system affect, it was evaluated in three types of abuse liability studies, including therapeutic competition and a dependence study.

The results of the study were encouraging: the withdrawal symptoms were minimal; the compound was not reliably self-administered, meaning that animals would not work to get it. As a result of the data, the compound was considered to not have a strong liability for abuse and was put in the marketplace as a non-scheduled treatment for ADHD.

If a compound is considered “scheduled,” it affects many factors in the market. Scheduling requires specific labeling, dictates specialized record keeping, has restrictions on distribution, and sets dispensing limits.

The process for abuse liability testing is involved, but choosing a partner is paramount. You need a team with lots of experience running studies along with knowledge of drug development. From study design to testing to reporting, my team at Covance can comfortably surmount the challenges associated with abuse liability testing and ensure a straightforward regulatory preparation.

For more information about how Covance can help you develop successful Lead Optimization Pharmacology & Toxicology strategies please contact us or visit our website for more information: www.covance.com/discovery.

This entry was posted in Drug Development, Lead Optimization and tagged , , , , , , by Mary Jeanne Kallman. Bookmark the permalink.

About Mary Jeanne Kallman

Mary Jeanne Kallman has over 22 years of pharmaceutical industry experience in safety pharmacology and neuroscience. She spent 17 years at Eli Lilly in various roles including research adviser and group leader for safety pharmacology. She is a recognized leader in the development of abuse liability and risk assessment strategies and has served as President of the Safety Pharmacology Society as well as the Chair of the pHRMA/PSLC technical working group on abuse liability and she is currently co-Chair of the Cross Company Abuse Liability Consortium. In her present position as Director of Nonclinical Global Neuroscience at Covance Inc., she provides leadership for the neuroscience strategy across all Covance sites for delivering all central nervous system evaluations. She is engaged in the identification and development of preclinical models for evaluation of pharmaceutical compounds and specifically in the delivery of neuroscience strategies for drug abuse assessment.