The Ongoing Push For Human Abuse Liability Studies In The EU

By Lynn Webster, MD, VP of scientific affairs, PRA Health Sciences

Medications containing psychoactive properties must be tested for their abuse potential before their introduction to the market. Human Abuse Liability (HAL) studies use clinical procedures that were initially developed in the United States. Clinical abuse potential studies are one category of study required by the U.S. Food and Drug Administration (FDA) ahead of bringing to market medications with abuse-deterrent properties. The goal is to gain an understanding of the true abuse potential of drugs that affect the central nervous system, producing psychoactive properties like sedation, euphoria, or other mood changes.

HAL study subjects are primarily experienced recreational non-dependent users of drugs. Subjects are selected who prefer to abuse drugs from the same pharmacologic class as the test drug. The study is performed in a controlled laboratory setting, preferably a closed residential unit. The investigators collect a number of study endpoints, including whether the patient likes the study drug and would take it again. At the same time, the tested drug should not impose a new serious safety risk on a potential patient who takes medications as directed.

However, European nations have had little experience in developing and applying these techniques. In fact, regulations for marketing medications with abuse potential have been laxer in Europe, leading some to question whether more thorough testing could have forestalled some difficulties with addiction, diversion, and other societal harms.

An editorial written by Jordi Camí and published in the British Journal of Addiction stated:

Many psychoactive drugs have been marketed in Europe five or 10 years earlier than in the U.S. In some cases, the dependence potential of new substances has become evident after the drugs have been made available to the public. It seems logical to ask if adequate pre-marketing testing on abuse liability in humans would have contributed to reducing the control-related problems of some drugs already available in Europe. (Br J Addict. 1991 Dec;86(12):1525-6)

A significant moment for European guidelines occurred in 1990 when a meeting was held in Barcelona to develop a consensus statement and recommendations on clinical testing of drug abuse liability. A renewed interest in HAL testing in Europe has grown in part from the 1998 study of selective serotonin se-uptake inhibitors (SSRIs) in relation to physical dependence, withdrawal reaction, and inappropriate long-term use by the Committee for Proprietary Medicinal Products (CPMP) as requested by the European Commission. This issue received much scrutiny in the public domain, as the available clinical data did not suggest SSRIs cause dependence. However, the result was a call for more research and ongoing evaluation of emerging data.

This work led to the publication in 2006 of non-clinical guidelines to investigate the dependence potential in medicines by the European Medicines Agency. Currently, the European Union (EU) requires a number of preclinical studies to address self-administration, drug discrimination, psychomotor tests, tolerance, physical dependence, and various pharmacokinetic and pharmacodynamics properties.  However, EU regulatory guidelines lack specific discussions related to abuse deterrent formulations (ADFs) and do not require laboratory study in human recreational abusers or healthy drug-naïve subjects. Furthermore, countries vary in the steps necessary to place the drug in an appropriate regulatory schedule. The time it takes to schedule a new drug depends on whether the country has a rapid classification system, and whether the decree must be approved by governing bodies or signed by one official, among other particulars.

It is understood that no single study or series of studies definitely profile the abuse potential of a drug. But the results may provide rich data, illustrating improvements in physiochemical properties related to abuse liability. As such, the results of HAL studies may guide risk-benefit assessments and decisions relating to drug approval, scheduling, prescribing information, and educational information for the consumer and risk management programs.  A well-designed HAL study, which includes proper subject selection, dose of control agents, powering, study environment, subject training, and well-selected primary and secondary endpoints, may also provide critical information on the differentiation of the tested drug from others in the same category.

When misused, drugs with psychoactive properties can lead to tremendous personal and societal costs. It is hoped that ADFs can restore a balance wherein physicians may focus more on the patient with an indication for the medication and less on the person at risk for abusing the drug.

There is some evidence this is already occurring. In the United States, the reformulation of OxyContin, released in 2010by Purdue Pharma, was associated with a significant reduction in past-month abuse (45 percent in January to June 2009 versus 26 percent in July to December 2012, P<0.001), according to research published in JAMA Psychiatry. Although ADFs will not completely solve the problem with opioid misuse, they may be one valuable component, in addition to wider availability of substance-abuse treatment and education of pain-care providers and patients. The HAL study is an important step in the process.