Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 22
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37Contains Nonbinding Recommendations
conditions (e.g., cannabinoids), even when they are known to be taken by humans for their
rewarding effects. Sponsors may propose that a self-administration study is not appropriate,
based on similarity in mechanism of action or behavioral effects to these classes of drugs.
Conditioned Place Preference (CPP). This study evaluates whether a test drug produces
rewarding effects that are demonstrated by an animal’s preference to be on the side of a cage
where it received the test drug, as opposed to the side where it received vehicle. Notably, CPP
differs from self-administration in that it does not measure whether the rewarding effects of a
drug produce reinforcement. It is also not considered to be as sensitive or reliable as self-
administration. The dose of the test drug should produce plasma levels that are equivalent to
and greater than those produced by the proposed therapeutic doses. The positive control is
ideally a scheduled drug in the same pharmacological class as the test drug, with the dose
consistent with that used in published CPP studies. Route of administration is not critical as long
as testing is conducted at T
.
max
4.
Evaluation of Similarity of Effects to Known Drugs of Abuse
Drug Discrimination. This study evaluates whether a test drug produces “interoceptive cues”
(bodily sensations) that are similar to those produced by a known drug of abuse that is scheduled
under the CSA (the training drug). Animals are trained in separate sessions to press one bar in
the test cage after receiving a training drug and the other bar after they receive vehicle, followed
by receipt of a food reward. Animals are typically trained up to a fixed ratio-10 (FR10) schedule
of reinforcement. Once animals reliably associate the interoceptive cues from training drug and
vehicle with correct lever pressing (>80% accuracy), they are given challenge sessions with a
range of doses of the test drug, the positive control, and vehicle. During challenge sessions, if
animals have been trained using FR10, they are allowed to lever press a total of 10 times on
either lever before removal from the test cage. Animals are not typically rewarded during
challenge sessions in order to maintain appropriate associative training.
Animals press the two different levers in the test cage based on the similarity of the interoceptive
cue produced by the test drug to the two separate training conditions. “Full generalization” to
the training drug occurs when the animal lever presses >80% (8 of 10 times) on the lever
associated with training drug. “No generalization” occurs when the animal lever presses <20%
on the training drug lever (e.g., >80% on the vehicle lever). “Partial generalization” occurs in
between these poles. For regulatory purposes, partial generalization between 60-80% suggests
that the test drug produces an interoceptive cue that has some similarity to the training drug. In
order to validate the study, the positive control drug should produce full generalization to the
training drug and the vehicle should produce no generalization to the training drug. If the test
drug produces full or partial generalization to the training drug (a known drug of abuse), it may
have abuse potential.
Drug discrimination is dependent on mechanism of action, so only those test drugs that have
pharmacological activity similar to that of the training drug will likely produce a significant
degree of generalization to the training drug. Thus, if the test drug has a novel mechanism of
action, sponsors may prefer to propose an alternative approach for identifying an appropriate
training drug.
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