Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 19
ADVERTISEMENT
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37Contains Nonbinding Recommendations
toxicological properties of the test drug. Recreational drug users tend to use drugs at doses that
are multiples of the medically-recommended dose, so abuse-related studies in animals typically
test doses that produce C
levels that are equivalent to, as well as at least 2-3 times greater
max
than, the C
produced by the highest proposed therapeutic dose. (This principle does not apply
max
for a self-administration study, see below). If a test drug has partial agonist activity at a site
associated with abuse potential (where higher doses tend to produce antagonist activity, while
lower doses produce agonist activity), evaluating decrements in dose may be more appropriate
when assessing the abuse-related properties of the drug, if the therapeutic indication relies on
receptor antagonism.
Control Groups. Abuse-related studies should include a positive control drug group and vehicle
group for comparison with the test drug group. In order for a study to be considered valid, the
positive control group should produce results that are statistically significantly different from the
vehicle group to establish that the study has “assay sensitivity” (i.e., the ability to demonstrate
that an abuse signal can be produced under study conditions, to ensure that the abuse potential of
the test drug can be determined). Although unscheduled psychoactive drugs are sometimes
proposed as a “negative control”, they are unlikely to fulfill this condition because they have not
typically undergone a thorough abuse potential assessment. Thus, for animal studies, we expect
that the only appropriate negative control will be vehicle. The drug selected as the positive
control should be in the same pharmacological class as the test drug, whenever possible, and
should be scheduled under the CSA. The dose of the positive control is typically based on a dose
utilized in published abuse-related studies, to ensure adequate abuse-related behavioral responses
in the specific animal test. For a test drug with a mechanism of action that is novel or does not
correspond to a drug currently controlled under the CSA, the Agency will consider sponsor
proposals for an alternative positive control. This may be a drug that has a therapeutic indication
or behavioral profile that is similar to the test drug, even if the mechanism of action is different.
The statistical evaluation should compare the test drug to both the positive control and vehicle.
Timing of Data Collection. Data collection in animal behavioral studies should occur at T
,
max
with additional measurements made before and afterward to ensure full characterization of the
test drug. Since T
is determined by route of administration, data from animal PK studies
max
should inform the time points at which observations are made. The time to onset will be
dependent on the specific animal behavior being evaluated, since various responses may occur at
different times while the drug is active.
Of special interest is the role of tolerance in determining study time points. The direct
evaluation of tolerance is not typically required for an abuse potential assessment in animals.
However, sponsors should be aware of whether the pharmacological mechanism of a test drug is
associated with the development of tolerance. If so, this should influence the timing of the
behavioral training and testing, so that drug exposure is not frequent enough to induce tolerance.
When the possibility of tolerance is not controlled, a negative result in the test often cannot
confidently be interpreted as failing to show a signal of abuse. For test drugs with novel
mechanisms of action, the likelihood of preventing the development of tolerance is increased if
drug testing is conducted no more frequently than every other day.
16
ADVERTISEMENT
0 votes
Related Articles
Related forms
Guidance For Industry And Food And Drug Administration Staff - U.s. Department Of Health And Human Services - 2012
Legal
Department Of Health And Human Services Family Medical Leave/family Illness Leave Request Form
Business
Form Nih 2762-3 - Undergraduate Scholarship Program (ugsp) - Academic Enrollment Certification And Service Obligation Deferment Request - U.s. Department Of Health And Human Services
Legal
Form Acf-196t - Administration For Children And Families - U. S. Department Of Health And Human Services
Legal
Related Categories
Parent category: Legal