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Navigating the FDA Guidance for Nonclinical Abuse Liability Testing

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The goal of this discussion is to help one understand and address the Food and Drug Administration’s Guidance for Industry, “Assessment of Abuse Potential of Drugs”

Drug abuse is the intentional, non-therapeutic use of a drug or substance to achieve a desired psychological or physiological effect.  Abuse potential is a characteristic of a drug that indicates the likelihood that abuse will occur with a product or drug substance.  Not all drugs require the assessment of abuse potential, but it is an important component of some products’ safety evaluation and is necessary for a successful marketing application of some types of new drugs, particularly those with central nervous system activity.  The guidance provides advice on how to determine if your development program should include an abuse liability assessment and the types of studies required.

To determine whether an abuse potential assessment should be conducted, the following questions need to be answered:

Is the new drug or metabolite active within the central nervous system?

This can be determined with chemistry, receptor binding, functional binding assays and pharmacokinetic studies.

If the drug is CNS-active, what are the next steps?

For new CNS-active drugs, the next step would be to design abuse-related nonclinical studies which include evaluation of whether the candidate drug has similarities to known drugs of abuse.  These studies include:

  • drug discrimination studies: investigate subjective or internal effects of the new drug compared with known drug of abuse in a similar class of drugs
  • physical dependence studies: determine if behaviors in nonclinical studies are similar to responses to known drugs of abuse
  • self-administration studies: determine if animals will demonstrate drug-seeking or drug-taking behavior by voluntarily ingesting the drug.  This type of study assesses the primary reward or reinforcing characteristics of a drug.

Should human abuse potential studies be conducted?

Based on results from the nonclinical studies and abuse-related adverse events documented in Phase 1 and Phase 2 clinical trials, the agency may suggest that a human abuse potential study should be conducted.

When should abuse-related studies be conducted?

It is a good idea to understand the chemistry and brain penetrance of the new drug as soon as possible in development.

If the pharmacology and pharmacokinetic data indicate that the drug is CNS-active, abuse liability testing in animals is usually conducted once the therapeutic dose range is determined after completion of Phase 2 clinical trials.

If you need advice about design, conduct, and/or interpretation of abuse liability programs, Aclairo would be delighted to help you in your development program.  Aclairo is committed to delivering independent and objective nonclinical and regulatory advice to the pharmaceutical industry.  Every member of Aclairo’s staff strives to provide our clients with superior advice, analysis, work product and program assistance.

Paul J. Kruzich, PhD, DSP, DABT
Consultant
Aclairo Pharmaceutical Development Group, Inc.

Click to learn more about Aclairo, or view an additional presentation here.

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