Addressing the Issue of Subject Confusion Due to the Use of two Visual Analog Scales in Human Abuse Potential Studies Ling Chen, Ph.D. FDA/CDER/OTS/DBVI www.fda.gov

Disclaimer This presentation reflects the views of the author and should not be construed to represent FDA’s views or policies.

Outline Brief introduction to human abuse potential (HAP) study Abuse potential measures used in HAP studies Example of subject confusion due to two visual analog scales (bipolar versus unipolar) Methods to prevent such confusion Remarks www.fda.gov

Human Abuse Potential Studies The primary objective of a HAP study is to provide information on the relative abuse potential of a test drug (generally a central nervous system (CNS)-active new molecule entity (NME)) in humans. Study subjects are not patients. They are recreational drug users. The design of a HAP study typically includes a Screening Phase, a Qualification Phase, a Treatment Phase, and Follow-up. The Treatment Phase is usually designed as a randomized, double-blind, placebo- and positive-controlled, crossover study. Treatments include placebo, one or two doses of the positive control and at least three doses of the test drug. If the test drug has multiple mechanisms of action that may produce a constellation of abuse-related psychoactive effects, or has a CNS-active major metabolite with a different mechanism of action, it may be appropriate to consider including a second positive control. www.fda.gov

Comparisons Claim for no abuse potential of test drug Study Validation X T1 P Y1 P T2 Y2 T3 Claim for less abuse potential of test drug compared to positive controls Dose response T1 T1 X Y1 T2 Y1 T3 Y2 T2 T3 Y2

Subjective Measures Drug Liking Visual Analog Scale (VAS) – 0-100 Bipolar Scale Question: “Do you like the drug effect you are feeling now?” 0 = “Strong disliking” ; 50 = “Neither like nor dislike”; 100 = “Strong liking” Primary Measure(s) High VAS – 0–100 Unipolar Scale Question: “How high are you now?” 0 = “None”; 100 = “Extremely” Stoned – cannabinoids Hallucinations – hallucinogens Sedation – CNS depressants Stimulated – simulants Secondary measures Overall Drug Liking VAS (bipolar) Take Drug Again VAS (bipolar) Similarity www.fda.gov

Data collection After a single dose administration, subjects will answer many questionnaires at multiple time points. Before the study started, subjects were trained to answer questions for different scales. However, during a treatment session, they may still be confused by scales, especially by bipolar and unipolar visual analog scales. www.fda.gov

Example It was a single-dose, randomized, double-blind, placebo- and positive-controlled crossover study. The primary objective was to evaluate the abuse potential of single doses of test drug (TL, TM, TH) compared to each dose of positive control (CL and CH) and placebo (P) in recreational stimulant users. Forty-eight subjects were randomized to the treatment phase. Of these, 35 subjects completed study. Primary endpoint was maximal score of Drug Liking (Drug Liking Emax). The secondary endpoints were High Emax, Energized Emax, and Good Effects Emax. Note that Drug Liking Emax was on a bipolar VAS, and three secondary endpoints were on a unipolar VAS.

Heat map display by treatment Drug Liking Emax High Emax

Continued… Good Effects Emax Energized Emax

Placebo Response? After carefully examining the data, I found that many subjects were confused by scales (unipolar versus bipolar) in this study. Among 14 subjects who had High Emax greater than 20 to placebo, 10 of these subjects had a High Emax of 50 or 51. Similar situations were also observed for Energized Emax and Good Effects Emax. A score around 50 is a possible response to test drug and positive control. We have no way to know if scores around 50 for these treatments were also due to scale confusion. www.fda.gov

Another issue Calculation of the endpoint Emax Time course profile of placebo for High VAS Data collected at multiple time points. Emax is the maximal score given a period of time. A subject only needs to be confused by the scale at one time point for this response to be the Emax of placebo for this subject. Obviously, training subjects for the scale before the study may not be sufficient to prevent the potential problem of scale confusion.

Serious consequences of “placebo responses” The “placebo responses” would reduce the mean difference between positive control and placebo, hence there may be a risk of failure for the validation test. The “placebo responses” may reduce the mean difference between test drug and placebo, and hence there may be a serious consequence of concluding no abuse potential of the test drug, when it may not be true.

Be Careful with Screen Design Screen for High VAS 1. Move cursor to 0 to begin. 2. Put “Unipolar Scale” on the screen. When subject response is near 50, as a reminder, make the “Unipolar Scale” blink, and allow the subject to change or confirm his/her selection. 3. Properly designing the test screen will improve data quality. www.fda.gov

Using color visual analog scales Drug Liking VAS 0=Strong disliking, 50=Neither like nor dislike, and 100=Strong liking Unipolar High VAS 0=None, and 100=Extremely 50

Remarks Statisticians should examine data quality before performing statistical analyses. Statisticians should also contribute to the improvement of data quality.

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