Using Cognition to Guide Decisions on the Safety and Tolerability of Drugs in Clinical Development

July 25, 2019


In clinical trials, changes in performance on cognitive tests can provide a sensitive index of the impact of a drug on the central nervous system (CNS). In such trials, the detection of decline in specific aspects of cognition, or in cognition in general, is important for making decisions about target engagement, maximum tolerated dose and pharmacodynamic profile. Observations of drug-related cognitive decline can also indicate areas for concern with clinical use, such as the potential effects on activities of daily living or the ability to operate a motor vehicle. In children, drug-related cognitive decline can indicate the potential for influence on neurodevelopment.

The clinical relevance of any drug-related cognitive decline, or the absence thereof, can be operationalized and benchmarked using measures of effect size. For example, standardized scores can be compared with those for established sedative-hypnotic and cognitively impairing drugs such as alcohol or benzodiazepines, or with socially relevant challenges such as sleep restriction.

The application of cognitive tests in different experimental designs can provide unique information to guide decision-making in both single ascending dose (SAD) and multiple ascending dose (MAD) studies. The application of cognition can also elucidate the potential for additive or synergistic effects in drug-drug and drug-alcohol interaction trials. Additionally, trials with active controls can confirm the predicted absence of an effect: for example, through the comparison of central versus peripheral anticholinergic drugs.

In later development and post-approval, the assessment of cognition can inform the presence of deleterious effects in the context of long-term follow-up and in larger, more representative samples. In conducting such studies, it is important to derive distinct outcome measures for separate cognitive domains and ensure performance on these tests should remain stable with multiple assessments over short and long retest periods. Most importantly, the sensitivity of cognitive tests to pharmacological interventions is critical.

Featured Speakers

  • Paul Maruff, Chief Science Officer, Cogstate
  • Chris Edgar, Senior Vice President, Clinical Science, Cogstate

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