Guidance For Industry - Assessment Of Abuse Potential Of Drugs - U.s. Department Of Health And Human Services - 2017 Page 34
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37Contains Nonbinding Recommendations
In humans, discontinuation of many CNS-active drugs produce drug withdrawal symptoms
indicative of physical dependence, including headache, anxiety, nausea/vomiting, tremor, chills,
decreased concentration, agitation/irritability, sleep disturbances, and mood changes. However,
different pharmacological classes of drugs may produce unique withdrawal symptoms that are
often opposite to the responses produced during drug administration. For example, opioids may
produce constipation during drug administration but diarrhea during drug discontinuation, while
amphetamines may produce mental acuity during administration but cognitive impairment during
drug discontinuation.
The Agency recognizes that physical dependence does not inherently indicate that a drug has
abuse potential. Indeed, some drug classes (such as beta-blockers and monoamine reuptake
inhibitors) that are known to produce physical dependence are not abused and are not scheduled
under the CSA.
The assessment of physical dependence in humans does not typically involve a dedicated study.
Instead, physical dependence is usually assessed at the conclusion of a phase 2/3 clinical efficacy
study through a monitored discontinuation period. Use of abrupt drug discontinuation rather
than tapered discontinuation, or precipitated withdrawal through antagonist administration, is
generally preferable in order to produce naturalistic conditions under which patients stop taking
medication. The duration of observation during drug discontinuation should persist for a period
equivalent to at least 5 half-lives of the test drug when the drug has been fully eliminated.
A human physical dependence evaluation may include:
• Use of drug class-specific withdrawal scales
• Use of disease-specific scales for evaluation of potential symptom rebound
• Assessment of AEs before and after drug discontinuation
• Use of VAS assessing withdrawal symptoms and mood states
• Use of daily diary by study subject
• Collection of physiological measures and vital signs
• Blood sampling for association of pharmacokinetics and withdrawal signs/symptoms
When clinical efficacy studies with the test drug are conducted in a vulnerable population, or
when abrupt discontinuation of a test drug may pose a safety concern due to return of disease
symptoms (e.g., seizures in study subjects with epilepsy or psychotic responses in subjects with
schizophrenia), a dedicated physical dependence study conducted in healthy controls may be
recommended. In the design of such a study, the highest proposed therapeutic dose can be tested
in comparison to placebo (with evaluation of withdrawal AEs and relevant scales). If the abrupt
withdrawal of the drug is likely to cause serious AEs in healthy subjects, an animal physical
dependence study may be sufficient. For a drug with a novel mechanism of action, an animal
physical dependence study should be conducted prior to a human study, to obtain information
about which signs and symptoms should be monitored during drug discontinuation in a human
study.
A sponsor should propose and justify all design elements of a physical dependence study.
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