Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 21
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37Contains Nonbinding Recommendations
that of the proposed therapeutic route. Given that the Irwin test is a safety pharmacology study,
it will usually include a comparison with vehicle but will not usually include a positive control.
Motor Performance Tests. These tests evaluate the ability of a test drug to interfere with normal
motor functioning after acute administration. Some of these tests may overlap with measures
evaluated in the Irwin study. Examples of these tests include observations of locomotor behavior
in a test cage (including stereotypy), ability of an animal to maintain itself on a rotating rod
(rotarod performance), ability to turn over when an animal is placed on its back (righting reflex),
observations of muscle tone (tail suspension test), and ability for an animal to maintain itself on
an elevation (inclined plane test). These tests may be conducted as part of the safety
pharmacology evaluation of a drug and may provide relevant information about behavioral
similarities of a test drug relative to known drugs of abuse.
3.
Evaluation of Rewarding Drug Effects
Self-Administration Study. This study evaluates whether a test drug has rewarding properties
that are sufficient to produce reinforcement (i.e., the likelihood that an animal will repeatedly
self-administer the test drug after initial exposure). Animals are first trained to press a bar in the
test cage in order to receive a food reward, using a schedule of reinforcement that typically
increases over the training period from FR1 to FR10. After animals consistently bar-press in
response for food, they begin to receive an intravenous dose of a known drug of abuse (training
drug) as the reward, instead of food. They are also tested with vehicle to ensure that bar-pressing
is not maintained for a substance without rewarding properties. Once animals stably bar-press
(self-administer) the training drug, they are then allowed to self-administer intravenous doses of
the test drug.
If the test drug produces a high level of self-administration compared to vehicle, there is a good
probability that the drug will produce rewarding properties in humans that are supportive of drug
abuse. The intravenous route of administration should be used in order to optimize the temporal
association between active lever-pressing and immediate drug effects. The doses of the test drug
should be fractions of the doses that produce plasma levels similar to those produced by the
human therapeutic dose. This is done to allow for the repeated administration of the test drug
without the risk of immediate overdose, and to prevent immediate satiation from a single dose,
which would obscure the ability to assess reinforcement.
Any drug of abuse that is scheduled under the CSA may serve as the animal training drug for the
self-administration study. However, in order to validate the study, a positive control drug should
produce self-administration levels in challenge sessions that are statistically significantly
different from vehicle. The ideal positive control drug is in the same pharmacological class as
the test drug and is scheduled under the CSA. The dose of the positive control should be
consistent with that used in published self-administration studies. When the test drug has a novel
mechanism of action, the positive control drug may be one in the same therapeutic class or one
that produces similar behavioral effects. The appropriate negative control is vehicle.
Certain classes of drugs with hallucinogenic properties do not typically produce animal self-
administration (e.g., 5HT2A agonists), or are only self-administered by animals under limited
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