Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 23
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37Contains Nonbinding Recommendations
5.
Evaluation of Physical Dependence and Withdrawal Behaviors
Physical Dependence Study. This study evaluates whether chronic administration of a drug at
therapeutic plasma levels produces a withdrawal syndrome upon drug discontinuation. This
assessment may be conducted in animals at the conclusion of a toxicology study or in a dedicated
study. Drug administration should typically occur for at least four weeks at stable doses that
produce plasma levels similar to those produced by therapeutic (and possibly supratherapeutic)
doses. Withdrawal is preferentially initiated in animals through abrupt drug discontinuation,
although tapered drug discontinuation and antagonist precipitation may provide additional safety
information. Behavioral observations should begin several days before drug discontinuation and
continue daily for at least 7 days or for a duration equivalent until the test drug is eliminated. A
standardized checklist of expected withdrawal behaviors for pharmacological drug classes should
be used. Different pharmacological classes of drugs tend to produce different withdrawal
syndromes (although there can be overlapping responses). These withdrawal signs often are
opposite to the signs observed during drug administration (e.g., benzodiazepine withdrawal may
produce hyperactivity and seizures, while stimulant withdrawal may produce hypoactivity and
sleep). In order to validate the study, a positive control (a scheduled drug with known abuse
potential, preferably in the same pharmacological class as the test drug) should produce
withdrawal behaviors that are greater than those produced by vehicle.
Although physical dependence should be assessed during the safety evaluation of a drug, it is
also considered to be part of the abuse potential assessment because of the role aversive
withdrawal can play in maintaining abuse of certain classes of drugs. Also, dependence liability
is a factor FDA must consider when recommending whether a drug should be controlled under
the CSA.(see 21 U.S.C. 811(c)(7)). Additionally, the scheduling placement of a drug with abuse
potential under the CSA includes consideration of its ability to induce physical or psychological
dependence, relative to other scheduled drugs (see 21 U.S.C. 812(b)).
V.
ABUSE-RELATED DATA FROM HUMAN STUDIES
Abuse-related data can be obtained from numerous human studies, including a human abuse
potential study, human studies that evaluate cognition and performance, abuse-related AEs from
clinical studies, and human physical dependence studies.
A. Use of Clinical Pharmacokinetic Data in Human Abuse-Related Studies
Pharmacokinetic data that are generated during phase 1 and 2 clinical studies with the test drug
are important in appropriately designing and interpreting data from human abuse-related studies.
The main PK parameters for this purpose are C
, T
, time to onset of drug effects, and T
for
max
max
½
the parent drug and any major CNS-active metabolites (>10% of parent concentration). Other
elements, such as AUC
, bioavailability, and CNS concentration and drug clearance, may be
0-∞
important, depending on the drug product. Human pharmacokinetic data may be useful in
determining relative passage of the test drug into the brain.
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