Top 4 reasons to measure the cognitive safety of new therapeutics
Posted on 23 October 2015 in Clinical Trials
Cognition is essential for the intake, interpretation and storage of information about the world around us and how we then use that information to interact with our environment.
The pharmaceutical industry is becoming increasingly aware that side-effects of medications for both central nervous system (CNS) and non-CNS diseases could include cognitive impairment, but how can measuring the cognitive safety of new therapeutics during clinical development add value to the clinical program?
Product specialist Linda Hermans reviews the top 4 reasons to measure cognitive safety for new compounds:
1. Changing regulatory environments
Due to the increasing awareness of the effects that drugs can have on cognition, regulators are continuing to place more importance on the inclusion of objective cognitive safety assessments in clinical trials conducted by pharmaceutical companies. Both European and U.S. regulatory bodies have issued guidance documents around conducting clinical safety reviews, and the FDA guidance even specifically states that:
“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.1”
These sorts of environmental changes are causing sponsors to more often consider the benefits of measuring the potential impact their compound may have on everyday cognitive functioning. And while cognitive dysfunction is typically associated with central nervous system (CNS) disorders, this also applies to drugs being developed for non-CNS diseases. Recent FDA guidance documentation called for the evaluation of potential adverse effects of all new treatments for both CNS and non-CNS indications on an individuals’ memory, attention and reaction time2.
Results of post-marketing studies can also influence regulations, as demonstrated in 2012 when the FDA mandated warnings on all statin labels following a study that revealed adverse effects of statins on cognitive functions, such as memory loss, altered mood and sleep disruption3,4.
2. Time-cost benefits
Measurements of cognitive safety early in the drug development process can be highly beneficial for sponsors. Objective assessments can facilitate faster and more informed decision making about whether or not to advance a new compound from both an efficacy and safety perspective by detecting “off-target” effects on cognition early on, thereby minimizing the risk of costly late-stage failure.
Furthermore, determining a compound’s cognitive safety profile can facilitate accurate determination of dose response relationships as well as the selection of safe dose ranges (including titration) for later drug development. This can help optimize drug effectiveness and avoid the detection of detrimental effects to cognition at later-stage development.
3. Differentiating label claims
Competition within the pharmaceutical industry is fierce and sponsors are often looking out for additional label claims that can be used to differentiate their drug from the others already on the market or in development.
Often particular drug classes or mechanisms of action are associated with cognitive side-effects that are of concern and any approved drug within that class requires a warning on the label, such as the earlier example of statins. However, demonstrating an absence of adverse cognitive effects as a result of having conducted objective cognitive assessment as part of a regulatory submission could avoid this class labelling, thus differentiating a new drug from the competition.
Label claims regarding cognition are commonplace for CNS treatments, but sponsors specialising in therapeutics for non-CNS disorders are increasingly turning towards conducting cognitive safety and tolerability assessments in clinical trials with a view to being able to make unique labels claims on their products.
4. Assessment of the risk-benefit ratio
The assessment of a drug’s cognitive safety and tolerability profile during the development process can contribute to the evaluation of its balance of therapeutic efficacy and safety risks in relation to the target indication, also known as the benefit-risk assessment.
To measure this relationship, regulatory bodies typically rely on qualitative measures and expert opinions during drug registration or post-marketing surveillance. Whilst there are currently no quantitative methods systematically being used by regulatory bodies, both the EU and US authorities are showing increasing interest in such benefit-risk measures. Methods such as cognitive safety profiling using computerized testing platforms can provide sponsors with data to further support their submissions to regulators. For example, a drug with a safety profile of risk of adverse effects that includes statistically significant memory impairments may be accepted in oncology, but its use for less severe disorders or young populations may be questioned.
Dr Kenton Zavitz presented at the World Drug Safety Congress on cognitive safety assessments and the need to closely and fully monitor cognitive effects in clinical trials, watch it here.
Cambridge Cognition has experience in supporting pharmaceutical and biotech companies evaluate new drugs in clinical studies with CANTAB cognitive assessments for over 30 years.
1 FDA Review Guidance, 2005: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review
2 FDA Review Guidance, 2015: Evaluating Drug Effects on the Ability to Operate a Motor Vehicle.
3 http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm#references and http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm293623.htm
4 Sahebzamani, F. M., Munro, C. L., Marroquin, O. C., Diamond D. M., Keller, E. & Kip, K E., (2014), Examination of the FDA warning for statins and cognitive dysfunction, Journal of Pharmacovigilance, 2:4