Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 28
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37Contains Nonbinding Recommendations
The Qualification Phase is generally conducted with only two study treatments: the positive
control to be used in the Treatment Phase (at a single dose known to produce drug liking,
preferably from previously conducted HAP studies) and placebo. If two positive control drugs
are used in the Treatment Phase, each of them should be included in the Qualification Phase.
The Qualification Phase is typically conducted in a double-blind fashion. However, if the
positive control has a very long half-life that could necessitate an extended washout period
between drug sessions, the placebo session may be scheduled before the positive control session
to reduce intersession timing. In such a case, subjects should remain blind to the study treatment
order.
For studies in which an opioid will be administered, it is recommended that subjects undergo a
naloxone challenge prior to initiation of the Qualification Phase (and prior to the Treatment
Phase, if they have left the laboratory unit) in order to demonstrate that they are not physically
dependent on opioids. In a naloxone challenge test, subjects are administered naloxone and
evaluated for 2 hours using the Clinical Opiate Withdrawal Scale (COWS) and vital sign
monitoring. Those subjects who display no signs of opioid withdrawal and have a COWS score
of <5 after each naloxone administration should be considered to be non-dependent on opioids.
Treatment Phase
The Treatment Phase is usually designed as a randomized, double-blind, double-dummy,
placebo- and active-controlled, crossover study.
The study treatments should 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.
In the interests of safety and assurance of successful results, the positive control should be an
FDA-approved drug that is pharmacologically similar to the test drug and scheduled under the
CSA. When the test drug has a novel mechanism of action that presents a difficult selection for
positive control, sponsors should explore and justify use of alternative positive control
candidates that have been shown to be safe and elicit similar psychoactive properties as the test
drug.
The dose(s) of the positive control are ideally selected on the basis of previously-conducted HAP
studies, in which those doses produced positive psychoactive effects indicative of abuse
potential. When the positive control is a drug that has not been evaluated in a HAP study before,
it may be useful to first conduct a separate dose-finding study, to ensure that the dose selected for
the HAP study produces positive subjective responses that differentiate statistically from
placebo.
For regulatory purposes, the doses of a test drug that will be evaluated in human abuse-related
studies should be based on the highest proposed therapeutic dose in humans, as well as a dose 2-
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