Human Abuse Potential Studies: Subject Selection and Study Design

1. Human Abuse Potential Studies: Subject Selection and Study Design Roland R. Griffiths Johns Hopkins University School of Medicine Science of Abuse Liability Assessment: Public Workshop Sponsored by NIDA, FDA, & CPDD Disclosure: I serve as a consultant to various pharmaceutical companies on abuse liability assessment. Much of my research on abuse liability assessment has been supported by NIDA grant R01DA03899.

2. Overview of the classic acute abuse potential trial in recreational drug users [FDA Draft Guidance] The human abuse potential study consists of pharmacology assessments that provide unique information relevant to central nervous system-active drugs, especially opioids, stimulants, depressants, cannabinoids, and hallucinogens. The objectives of such studies are to provide information on the relative abuse potential of a new drug in humans and to contribute to predicting the likelihood of abuse when the drug becomes available. The studies are typically conducted in a population experienced in using drugs recreationally after sufficient data related to safety and efficacy in a patient population have been acquired.

3. Abuse Potential vs. Abuse Liability • The draft guidance makes the point that the terms abuse potential and abuse liability have been usually used interchangeably • However, the term abuse liability can refer to two types of assessment that are both relevant to a final scheduling decision under the CSA • Liability forabuse = Abuse potential • Liability of abuse = refers to the adverse consequences of abuse • The standard abuse liability trial lends itself to concurrently assessing a range of behavioral, cognitive, and physiological measures (e.g. balance, memory, coordination) that can provide information about possible toxic consequences of abuse and overdose

4. Features of the classic acute dose-effect abuseliability trial 1. Subject population 2. Study site 3. Typical trial design characteristics 4. Positive control comparison drug 5. Range of doses of the positive control comparison drug Range of doses of the novel compound, including high supratherapeutic doses

5. Subject population • The most preferred population consists of subjects with histories of polydrug abuse including drugs from the same pharmacological class as the novel compound • Face validity: drug abusers are the actual criterion population whose behavior laboratory studies seek to predict (vulnerability to abuse is not spread evenly within the general population) • Increased sensitivity/Reduced noise: Drug abusers can meaningfully rate drug effects and categorize drug effects relative to drugs of known abuse potential • Reduced false negatives: Drug abusers are less likely to provide false negative results than subjects without histories of drug abuse

6. Subject population (continued) • The subject population must be one in which the positive control comparison drug tests unequivocally positive • Studies can be done in nonabusers, but there are significant limitations • studies with abused barbiturates, benzodiazepines and opioids have shown that nonabusers generally do not report liking or show self-administration of these compounds; in contrast, drug abusers show reliable increases in reports of liking and readily self-administer these same drugs • One approach for identifying subjects for abuse potential studies who do not have extensive polydrug abuse histories has been to pre-screen volunteers with a test dose of a standard abused drug; volunteers who report liking the standard compound are eligible

7. Subject population (continued) • The FDA guidance indicates that exclusion criteria should include a diagnosis of current abuse, current substance dependence, and current treatment for a substance-related disorder • This is overly restrictive • The threshold for meeting current abuse in DSM-IV is quite low; excluding these individuals would severely limit the available subject population and perhaps compromise the validity of the trial • Volunteers with current physical dependence usually should be excluded. However, there are circumstances in which current physical dependence might be desirable (e.g. to determine whether a novel opioid can precipitate withdrawal in physically dependent individuals) • Excluding for current substance dependence or even current treatment is likewise debatable

8. Study site • Studies should be conducted in a controlled clinical laboratory setting with staff who are knowledgeable about drug abuse and nonjudgemental • The ideal setting is a closed residential drug abuse pharmacology research unit which provides stable day-to-day routine and minimizes the opportunities for confounding by concurrent drug abuse • These studies can also be conducted on an outpatient or ambulatory basis with subjects reporting to the clinical laboratory and providing a drug-free urine prior to drug administration

9. Typical trial design characteristics • A double-blind, placebo-controlled, complete crossover design • The FDA draft guidance explicitly recommends a specific Latin-square design (Williams Design) -- although Latin-square designs are common in this type of research, alternative designs should be considered on a case-by-case basis • Sample sizes in published trials have varied from 10 to 40 subjects (need sufficient power to detect differences in primary endpoints) • Acute effects of a range of doses of the novel compound are compared to a range of doses of a reference compound of known positive abuse potential • Each session involves assessment of a single dose of drug or placebo; intervals between test sessions are typically one to several days • 5 times the t1/2 of the most slowly eliminated drug in the study

10. Typical trial design characteristics (continued) • Within each session, measures are evaluated repeatedly to characterize onset, peak, and duration of drug effects • Outcome measures include: • multiple measures reflecting abuse potential (e.g. liking) • measures to verify the equivalency of the novel and standard compounds on some relevant dimension of biological activity • measures can also be added to concurrently assess behavioral, cognitive, and physiological outcomes that may provide information about possible toxic consequences of abuse or overdose

11. Selection of an appropriate positive control comparisondrug If possible, the positive control compound should be an abused drug from the same pharmacological class as the novel compound The positive control and novel compound should have similar onset times and durations of action If possible the positive control compound should be used for the same medical indication proposed for the novel compound  Consideration may be given to including a negative control comparison compound from the same class which is behaviorally active but not abused

12. Selection of an appropriate range of doses of the positive control comparison drug Ideally, three dose levels of the positive control compound are included, spanning a 3- to 8-fold range of doses, and producing effects ranging from little to moderate or high Within the study, the positive control compound should demonstrate dose-related statistically significant increases on the primary measures of abuse potential -- failure to do so invalidates the assay  Testing a range of doses of the positive control compound determines the limits of sensitivity of the assay to lower doses which is critical to concluding an absence of abuse potential for the novel compound  Testing a range of doses of the positive control compound permits comparison of the slopes of the dose-effect functions across different measures -- such comparisons may be important to concluding that the novel compound has less abuse potential

13. Selection of a range of doses of the novel compound, including high supratherapeutic doses • Evaluation of high doses of the novel compound is critical to the validity of the trial -- it must be assumed that drug abusers will inevitably sample high doses and the effects of these doses will determine whether or not the drug engenders abuse -- drug abusers tend to be remarkably insensitive to drugs of abuse (possibly reflecting behavioral or physiological tolerance development and/or a disposition to significantly under-report magnitude of drug effects) -- in determining the highest dose of the novel compound to be tested the planned therapeutic dose of the compound is only very marginally relevant

14. Selection of a range of doses of the novel compound, including high supratherapeutic doses (continued) • A dose run-up pilot study is useful for selecting maximal doses and matching doses between the novel and comparison compound • If possible, the high dose of the novel compound should be selected that will produce comparable effects to the highest dose of the positive control comparison compound on one or more objective measure