# Presentation: 357900

## Objectives of a Drug Abuse Potential Human Laboratory StudyMichael Klein, Ph.D.Controlled Substance StaffCDER/FDA

** **
- DIA Session on *Statistical Considerations in Human Drug Abuse Potential Studies, *Washington, D.C. June 30, 2005
**The views expressed in this talk represent the opinions of the presenter, and do not necessarily represent the views of the U.S. Food and Drug Administration.**

## NDA RequirementsUnder FD&C Act

- All data pertinent to abuse of the drug
- Proposal for scheduling under the Controlled Substances Act
- Data on overdose

**21 CFR § 314.50 (5) (vii)**

- If potential for abuse exists, the following _must be included in the NDA_:

## Abuse Liability Assessment

- Includes data from pre-clinical studies, INDs, and NDA phases
- Based upon a comprehensive evaluation of available data on:
- Chemistry
- Pharmacology (Preclinical & Clinical)
- Pharmacodynamics & Pharmacokinetics
- Adverse Events Reported in Clinical Trials
- Epidemiological Data
- Comparisons to pharmacologically similar  drugs

## Pre-clinical Pharmacology

- Pharmacological characterization
- Receptor binding
- Animal behavioral studies
- Reinforcing effects (self-administration)
- Discriminative effects (drug discrimination)
- Physical dependence (withdrawal)
- Tolerance

## Human Pharmacology

- From clinical trials evaluation of AE profiles for evidence of abuse liability
- Systematic categorization, tabulation, analysis of AEs for stimulant, mood elevation, sedation and psychotomimetic events
- Prospective evaluation of withdrawal AEs after abrupt discontinuation of treatment - “drug liking”
- From human pharmacology studies
- Subjective & Mood Effects
- Cognitive & Performance Impairment

## The Human Abuse Liability Study

- A pharmacology study that provides unique information
- Applies to CNS drugs: opioids, stimulants, depressants, cannabinoids, and hallucinogens
- Surrogate measure of abuse potential, not a measure of actual abuse

## Objectives of the Study 

- Provide information on the relative abuse potential of new drugs in humans
- Predictive of the likelihood of abuse by recreational drug abusers
- Predictive of the extent of drug diversion & illicit street sales if the new drug becomes available to the drug abuse community

## Study Considerations

- Evaluates measures following repeated single dose administrations over a period of time, depending on the time-course of the drug’s effects
- Doses range from minimally effective to supratherapeutic
- Conducted in recreational drug abusers
- Other abuse-related data in patient & *normal *populations exposed to the drug therapeutically may be retrievable from other parts of the NDA

## Primary Review Questions

- Is the study being conducted appropriately?
- Is the appropriate population studied?
- Is an appropriate positive control selected?
- Are the right doses being studied?
- For safety?
- For assessment of abuse potential?
- Have the appropriate outcome measures been selected?
- Does the study have adequate statistical power?

## Typical Trial Design

- Double-blind, placebo controlled, within-subject or complete crossover design
- All subjects are tested with all drug conditions
- Trial involves responses to single dose administrations
- Drug conditions typically involve placebo, multiple doses of the new drug and comparison drug
- Sequence of conditions is usually mixed (e.g. Latin Square) or randomized
- N typically = 10 -14.  Up to 40 or more in recent cases
- Subject & staff who interact with subject don’t know the sequence of substances that are administered

## Controlled Laboratory Settings

- Closed residential unit preferred
- Subjects stay overnight following administration each drug
- Subjects with histories of drug abuse considered unreliable and have greater dropouts or missed visits
- Sleep, nutrition & carryover effects from recent abuse are hard to control in outpatient studies & may lead to greater variability in outcome or increased rates of AEs
- Prevention of other drug use
- Safety concerns
- High doses administered.
- Possible drug carryover effects

## Subject Population

- Conducted in subjects with extensive drug abuse histories
- Subject population is at-risk for abuse
- Subjects show reliable increases in reports of liking and readily self-administer these same drugs
- Subject population provides ratings of drug experiences:
- Ratings of drug high
- Estimated value on street
- Overall drug effect
- Similarity to specific classes of known drugs of abuse.
- Subjects with drug abuse histories are believed to provide extremely low false positive rates relative to placebo
- Subjects selected for an abuse liability evaluation _must _test unequivocally positive for the positive control

## Selection of Positive Control

- Test drug is compared with a standard drug (*positive control*) under identical assay conditions
- For assay of abuse liability
*Positive control* should have measurable abuse liability previously established through experimental studies and epidemiological data
*Positive control* is usually a drug of abuse in the same pharmacological class as the test drug
- Additionally, the *positive control* may have the same medical indication as the test drug
- Interpretation of results of an abuse liability evaluation is easier if the *positive control* & test drug have similar onset & duration

## Positive Control: Dose Range Selection

- Selection of doses must be justified
- Ideally, more than one dose of the positive control is tested, spanning a range of doses that produces effects ranging from little to moderate or high
- Limits of sensitivity of the assay to lower doses are determined
- Slopes of the dose-effect functions across different measures are measured
- Positive control should demonstrate dose-related, statistically significant increases on the primary measures of abuse liability
- Failure to demonstrate significant increases with the positive control invalidates the assay

## Test Drug: Dose Range Selection

- Dose Run-up Pilot Study in drug abuser population:
- Empirical basis for dose selection
- Selecting maximum doses of the test drug &  matching doses between test drug & positive control
- Provides an opportunity to evaluate & modify procedures in subsequent dose-effect studies
- Supra-therapeutic doses of test drug are usually tested:
- Drug abusers inevitably sample high doses
- Tolerant to behavioral or physiological effects
- Under-report magnitude of subjective effects
- Doses of the test drug selected should produce comparable effects to the positive control highest dose

## Selection of Outcome Measures

- Familiar with all measures, vocabulary & specific questions
- Procedures easily learned & rapidly completed by subjects
- Good reproducibility
- Assessment intervals should be adequate to characterize onset, peak, and offset of effects

## Outcome Measures: Most directly related to likelihood of abuse

**Ratings of Liking**
- “do you like the the drug?”
- “good effects,” “bad effects”
**Disposition to take the drug again**
- “degree to which you would like to take the drug again,”
- “estimate of street value of the drug,” “Next Day Questionnaire” given 24 hours after drug administration
**Street Value & Drug vs. Money Choice Behavior**
- Subject can choose various $ amounts or more drug

## Outcome Measures: Interpreting the likelihood of abuse

**Drug identification**
- Subjects categorize effects of the test drug as similar to one of 14 different classes of psychoactive drug
- Drug Classes: opiate, antipsychotic, muscle relaxant, stimulant, barbiturate, hypnotic, hallucinogen, benzodiazepine, alcohol, cocaine, marijuana, phencyclidine, antidepressant
**Subject-rated side effects**
- Side effects of drug class may be relevant to abuse
- For example, Opioid effects include the following: itching, sweating, upset stomach, nodding, talkativeness, sluggishness

## Outcome Measures: Measures of drug effect typical of drug class

**Subject-rated strength of drug-effect**
**Behavioral & cognitive performance**
**Observer-rated measures**
**Physiological effects**
**Assessment of mood state changes using Profile of Mood States (POMS)**
**The Addiction Research Center Inventory (ARCI)**

## Conclusions

- The abuse liability assessment of a new drug is based upon a composite analysis of chemistry, pharmacology, clinical data, and the perceived public health risk that the drug presents; one study alone is not considered sufficient for the abuse liability assessment.
- Data from the human abuse liability study make a useful contribution to the development of product labeling, drug scheduling recommendations, and risk management programs.