Establishing performance characteristics for positive control article selection in drug self-administration studies

Area of Science:

• Pharmacology
• Toxicology
• Drug Development

Background:

• Controlled substances (CS) are crucial for nonclinical drug abuse liability (DAL) assessments.
• Current guidelines permit various Schedule I-IV CNS agents as positive controls.
• Not all permissible CS ensure consistent, robust daily intake in animal models.

Purpose of the Study:

• To emphasize the critical factors in selecting an appropriate positive control article for DAL studies.
• To guide sponsors in choosing a control that aligns with the test article's mechanism of action or therapeutic target.
• To highlight that study designs are not standardized and require tailored control selection.

Main Methods:

• Discussion of critical design factors for positive control selection.
• Consideration of stable baseline responding and voluntary intravenous intake in animals.
• Evaluation of CS that can provide efficient, robust, and stable daily intakes.

Main Results:

• The selection process for a positive control article in DAL studies is complex.
• A suitable CS must maintain stable day-to-day responding in animal models.
• The chosen control and dose should offer a balanced, predictive, and scientifically sound comparison.

Conclusions:

• Careful selection of the positive control article is paramount for the scientific validity of DAL studies.
• The choice of control should be tailored to the specific test article and study objectives.
• A well-chosen positive control enhances the predictive value of nonclinical drug abuse assessments.