Why monitor Cognition in Drug Development?
Posted on 6 July 2015 in Clinical Trials
Detecting adverse effects on cognitive function can be vitally important for:
- determining dose response relationships and selecting safe doses for later phase development (including the need for titration);
- detecting off-target effects;
- assessing the risk/benefit ratio in relation to the target indication;
- differentiation from competitor drugs in relation to cognitive outcome.
The human brain has over 100 billion nerve cells, each of which may have up to 10,000 connections with other nerve cells. This makes for an incredibly complicated organ. Cognition is defined as mental processes relating to the input, storage and control of information. We need cognitive abilities to take in information about the world around us, interpret it, store it, and interact safely with our environment.
How do we measure cognition?
Cognitive assessment refers to the objective measurement of distinct cognitive abilities, such as working memory, inhibition, cognitive flexibility, and executive planning.
Cognition can be measured using a variety of methods, each varying in their level of objectivity and sensitivity. CANTAB computerized cognitive tests benefit from being language and culture independent, using abstract visual stimuli and automated test administration to minimize subjectivity caused by cultural bias or rater variance. As well as being objective, CANTAB assessments provide sensitive measures of cognition, with tasks linking directly to specific neural systems such as executive function, attention, episodic memory, and visual perception.
Cognitive assessment provides us with insight into human behaviour and how this relates to underlying brain circuits and neurochemical systems. From work across species, we know that the brain can be thought of in terms of several distinct circuits, which are regulated by neuromodulators including dopamine, serotonin, norepinephrine, and acetyl choline.
Genetic and environmental factors affect brain function across the whole lifespan. Cognitive assessment provides an accessible and straightforward method for studying the effects of genetic and environmental factors on brain function in health and in disease. This can have profound implications in terms of public health and disease models.
In which conditions can cognitive impairment occur?
Cognitive testing is also critical in understanding and treating a range of different disorders. Here are just some of the disorders that have been studied in relation to cognitive problems including psychiatric disorders, neurological conditions, genetic disorders, and medical conditions:
Mild cognitive impairment
Traumatic brain injury
While some of these examples are well known to be linked with cognitive conditions (such as Alzheimer’s disease, or schizophrenia), other examples might be more surprising. Identifying cognitive impairments is important because they represent potential treatment targets to optimize everyday functioning of those affected.
Clinical trials in drug development are then able to use cognitive assessments to characterize the cognitive properties of their compounds, measure cognitive efficacy of different interventions and identify unwanted side effects, such as sedative effects of medication. Moreover cognitive assessments can help detect effects that might be desired, such as reversing or ameliorating cognitive deficits in people with impairment, or even cognitive enhancement in healthy individuals.
CANTAB cognitive tests on an iPad (from left to right): Paired associates learning test of episodic memory; reaction time test; visual analogue scale for measuring subjective patient characteristics.
Accelerating development of safe and effective drug treatments
Monitoring cognition in drug development is highly beneficial to the sponsors of the drug. Providing a more holistic profile of their compound and its cognitive properties can ultimately accelerate informed decision making during the course of drug development.
Benefits of objective and sensitive cognitive assessment in drug development include:
- Facilitates faster and more informed decision making on whether or not to advance a new compound from both an efficacy and safety perspective
- Provides accurate recommendation of dose selection (including titration), which optimize drug effectiveness and avoid detrimental effects
- Helps with the selection of appropriate patient populations for Phase II and III studies
- Enables sponsors to differentiate their product from the competition
- Helps determine effect of cognition based on treatment of underlying disease
Gaining approval from regulators
Objective quantitative cognitive safety and tolerability testing is increasingly becoming a critical part of the review process for regulators.
Drug developers, regulators, physicians and patients are becoming increasingly aware of the impact a drug can have on cognitive function, leading to a growing interest in measuring and monitoring cognitive function as part of a drug’s safety profile and risk management strategy.
Both in Europe and the US, the regulatory bodies have issued guidance on conducting clinical safety reviews and, more recently, attention from these regulatory bodies has turned towards the assessment of a drug’s impact on cognitive functioning. The guidance states that studies that include objective measurements of cognitive safety should be given greater authority.
“Beginning with first-in-human studies, all drugs, including drugs intended for non-CNS indications, should be evaluated for adverse effects on the CNS including measures of reaction time, attention, and memory.”
FDA Review Guidance, 2015: Evaluating Drug Effects on the Ability to Operate a Motor Vehicle.
“Some categories of adverse events, such as decreased cognitive function, are notoriously difficult to detect without special efforts. If the database includes special studies intended to identify these events, they should generally be given more credence than non-targeted studies, which tend to substantially underestimate rates.”
FDA Review Guidance, 2005: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review.
Improving outcomes throughout clinical development
Clinical trials would benefit from cognitive safety and efficacy assessments throughout all stages of clinical development.
Cambridge Cognition has experience in supporting pharmaceutical and biotech companies improve outcomes in clinical studies with CANTAB cognitive assessments for over 30 years.