Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 24
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37Contains Nonbinding Recommendations
The recommended use of the clinical PK data in designing human abuse-related studies is
described in detail below. The protocols for human abuse-related studies should include a
justification of design elements based on phase 1 and 2 clinical PK data. All PK parameters
utilized should be based on actual measurements, not estimations. When the NDA is submitted,
all clinical PK studies and resultant data that informed the design and interpretation of human
abuse-related studies should be cross-linked.
B. Abuse-Related Adverse Events in Clinical Safety and Efficacy Studies
All clinical safety and efficacy studies should be evaluated for CNS-related AEs that may
suggest the test drug produces effects that will be sought out for abuse purposes. A positive
signal from abuse-related AEs does not inherently mean that a test drug has abuse potential.
However, evaluation of clinical AE data, in conjunction with nonclinical abuse-related data
(chemistry, receptor binding, animal studies), will determine whether a human abuse potential
study should be conducted.
The presence of a euphoria-like response is a key observation in the clinical assessment of
whether a test drug has abuse potential. If euphoria-related AE(s) are reported, it will be
important to further characterize the profile of the abuse-related signals to determine if the drug
is similar to other known drugs of abuse (a stimulant, sedative, hallucinogen, etc.). In the
absence of euphoria-related signals, AEs such as hallucination and dissociative state may also be
indicative of abuse potential. If any of these abuse-related AEs are present, the test drug will
likely need to be evaluated in a human abuse potential study before the FDA can approve it.
Abuse-related AEs should be interpreted in the context of the proposed therapeutic indication of
a drug. Thus, not all CNS-related AEs are equally relevant for purposes of abuse assessment.
For example, an antidepressant that produces “elevated mood” or a sleep aid that produces
“somnolence” in the absence of a clear euphoric signal is not likely to be interpreted from these
AE data alone as having abuse potential. Additionally, even though “dizziness” is listed under
euphoria-related terms, this AE is not by itself indicative of abuse potential. At the time of
publication of this guidance document, a ranking of relevant AEs as signals of abuse risk is not
available, and all AEs are of interest for the Agency to consider in the overall assessment of risk
to the public health. The Agency’s interest extends to information about the timing of the AEs
and the narratives from case report forms (CRFs), which are important in interpretation of the
drug effects.
The list below is a compilation of abuse-related AE terms, related to the drug’s pharmacology, as
provided in the MedDRA (Medical Dictionary for Regulatory Activities) System Organ
Classifications (SOC). We recommend sponsors and applicants use these terms when describing
abuse-related AEs. Each of the lower level terms that are shown are coded on the basis of a
longer list of verbatim terms, words or phrases from a patient or observer. Most preferred abuse-
related terms relate to the drug’s pharmacology and fall under SOC General disorders and
administration site conditions, SOC Nervous system disorders, and SOC Psychiatric disorders.
Below are examples of MedDRA Preferred Terms (PTs), which may provide abuse-related
information about a drug. This list is not exhaustive, however. A MedDRA search should
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