PRA Health Sciences
PRA Health Sciences

PRA, along with Pinney Associates, presented webinar entitled “Crossing the Blood-Brain Barrier – The Human Element of Abuse Potential Assessment” on July 10, 2018. Please join us to learn more about the requirements for conduct of Human Abuse Potential assessment and clinical abuse potential data integration into the regulatory framework of an 8-Factor Analysis.

Human Abuse Potential

Human Abuse Potential (HAP) studies assess the likelihood that a drug with central nervous system(CNS) activity may be abused. Developers of these drugs rightly focus on physical safety and efficacy first.

The assessment of abuse potential includes in vitro and in vivo nonclinical studies as well as the totality of the clinical data including both healthy volunteers and patient studies. Whilst clinical evidence, vis-à-vis the adverse event profile relating CNS activity observed across studies as well as direct signs of abuse (e.g.: diversion of study drug or withdrawal symptoms upon completion of study treatment), can be highly informative, the HAP study critically informs the drug scheduling process.

PRA, along with Pinney Associates, presented webinar entitled “Crossing the Blood-Brain Barrier – The Human Element of Abuse Potential Assessment” on July 10, 2018. Please join us to learn more about the requirements for conduct of Human Abuse Potential assessment and clinical abuse potential data integration into the regulatory framework of an 8-Factor Analysis.

Human Abuse Potential

For drugs with CNS pharmacology, the 2017 FDA Guidance regarding the assessment of abuse potential of the molecule must be followed. This Guidance stipulates, among other requirements, that chemical manipulation experiments, (ie: “kitchen chemistry”), nonclinical behavioral experiments, and a clinical assessment of abuse potential may be required. Summarizing recent comments by Jack Henningfield of Pinney Associates, “Even drugs that are designed to act peripherally but may have some CNS activity as well as those with no CNS activity but that may result in CNS-related adverse events (e.g.: somnolence, dizziness), may trigger the need for a HAP study.”

The assessment of abuse potential is important to inform drug scheduling by DEA prior to marketing. Both the FDA division responsible for review of the marketing application and the Controlled Substances Staff (CSS), an interdisciplinary review group within FDA, play a critical role providing a scheduling recommendation to DEA. As such, it is critical that sponsors meet FDA requirements for the assessment of abuse potential.

Drugs may fall into six scheduling categories from Schedule 1 (drugs which have no medicinal purpose) to Uncontrolled (drugs with no potential for abuse). Many commonly prescribed opioids for example fall into Schedule II, while some weak stimulants, (eg: phentermine), fall into Schedule IV.

Prior to HAP study conduct, nonclinical studies that may be performed to assess the abuse potential of a drug early in its development include drug discrimination, self-administration, and condition place preference. Drug discrimination studies examine the behaviors of rodents following drug administration as to how similar exhibited behaviors are to a known drug of abuse. Both self-administration and condition place preference studies measure the reinforcing properties of the drug (i.e.: how much drug would the rodent administer itself it had access). These important studies can help define both the dose level and comparator drug in human abuse potential studies. If the totality of the nonclinical data package does not suggest the potential for abuse, a clinical HAP study may not be required.

PRA has conducted numerous HAP studies to assess the relevance of the subjective response to a novel CNS active drug in the context of a known scheduled substance across classes of drugs including opioids, benzodiazepines, stimulants, and cannabinoids. Through direct and indirect interactions with FDA, we have been successful in helping sponsors provide the clinical data required to inform drug scheduling upon marketing approval.

Identifying potential

Two case studies serve to illustrate a broad range of experience:

A drug in development for the treatment of multiple sclerosis that did not exhibit in vitro pharmacology at receptors commonly associated with drugs with known abuse potential was considered by FDA to be “CNS active” by the fact that the primary pharmacology was in the brain. Across previously conducted clinical studies (eg: Phase I and Phase II studies) there had been no overt signs of potential for drug abuse. However, in nonclinical assessments of abuse potential, the drug surprisingly exhibited weak evidence of the potential for abuse. As such, FDA required the sponsor to conduct a full clinical assessment of abuse potential wherein the positive control was identified via nonclinical drug discrimination studies.

On the opposite end of the spectrum, a sponsor with a known benzodiazepine-like molecule conducted a pilot dose-ranging HAP study prior to initiating the full HAP study. Results from the pilot study were adequate to inform potential drug scheduling and thus the study satisfied the FDA Controlled Substance Staff requirements; the sponsor was no longer required to conduct the full HAP study initially requested by the FDA.

Phase I setting

The clinical assessment of abuse potential is conducted in a Phase I research setting wherein recreational drug abusers are recruited to participate in a 6-way crossover study. A recreational drug abuser is an individual who typically uses drugs moderately or occasionally but who is not dependent; most commonly they are poly-drug users.

Prior to being randomized to the cross-over treatment phase of the study, participants must demonstrate the ability to respond appropriately to both placebo and active control administered in a random sequence. This part of the study is called the “drug discrimination” or “qualification” phase. Subjects that qualify, as determined by their response to the question, “How much do you like the drug?” are randomized to the study.

Typically 36 – 42 subjects are required to complete the 6-way cross-over portion of the study, which includes 3 dose levels of the test drug, 2 dose levels of the positive control, and placebo; fewer or more treatment arms may be included. The primary endpoint of HAP studies is the maximal response to “Drug Liking” (i.e.: Drug Liking Emax) for the test drug compared to the positive control and placebo.

HAP study design

The selection of the positive control in HAP studies, which includes a careful consideration of both drug class and schedule, should be agreed upon in advance with FDA CSS, particularly if the test drug represents a novel mechanism of action. Indeed, it is strongly recommended that sponsors consult the FDA CSS during protocol development to see agreement with the selection of positive control, the dose levels of test article to be studied, as well as the primary and secondary endpoints.

Though the outcomes of the Human Abuse Potential study are just one of the many factors that are considered by FDA and ultimately DEA in the scheduling of a drug, the results of the primary outcome measure as well as adverse events in this specific study population may be included in the product package insert language (ie: Section 9 Drug Abuse and Dependence). As such, in combination with the drug scheduling, the Human Abuse Potential can provide important safety and risk information to health care providers when prescribing CNS active drugs.