Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 8
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37Contains Nonbinding Recommendations
III.
ASSESSING THE ABUSE POTENTIAL OF A DRUG
This section describes the key decision points in an abuse potential assessment, the types of
abuse-related studies that may be important, the recommended time frame within the drug
development program for conducting such studies, and the organization of abuse-related
information in an NDA submission.
A. Key Decision Points and Recommended Studies in Assessing Abuse Potential
The Controlled Substance Staff (CSS), located in CDER’s Office of the Center Director, has the
central role in CDER in advising sponsors regarding the abuse potential assessment of a drug
product. FDA does not recommend that every drug under development undergo an evaluation of
abuse potential. An evaluation of abuse potential is most relevant for NMEs with CNS activity
that have not previously been assessed by FDA for abuse potential. However, if a drug
substance with CNS activity is already controlled under the CSA and a different dosage strength,
dosage form, route of administration, patient population, or therapeutic indication is proposed
under an NDA or NDA supplement, a modified abuse potential assessment may be necessary
and should be discussed with CSS (see Section III. B).
For NMEs, the decisions regarding whether an abuse potential assessment will be required under
21 CFR 314.50(d)(5)(vii), and what studies should be conducted, as well as the conclusions
regarding a drug’s abuse potential, generally depend on the answers to the following questions
which arise during drug development:
Question 1: Is the new drug (or any major metabolite) active within the CNS?
Drugs with abuse potential almost always have activity within the CNS, so if a new drug or its
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major metabolite(s)
have CNS activity, additional studies will be recommended. Examples of
data relevant to the assessment of whether the drug has activity within the CNS include:
• Chemistry studies (drug structure and ability to pass blood brain barrier)
• Receptor binding studies with the drug and major metabolites at CNS sites
• Second messenger system studies (if available) to identify functionality at binding sites
• Pharmacokinetic studies showing the drug’s relative distribution to and penetration of the
brain
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Our use of the term major metabolite is responsive to the following: “Nonclinical characterization of a human
metabolite(s) is only warranted when that metabolite(s) is observed at exposures greater than 10% of total drug-
related exposure and at significantly greater levels in humans than the maximum exposure seen in the toxicity
studies,” as described in ICH M3(R2) Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical
Trials and Marketing Authorization for Pharmaceuticals (2009), available at:
_Guideline.pdf.
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