In the evolving landscape of clinical research, the incorporation of cognition into the safety profiles of both CNS and non-CNS indications is becoming increasingly critical. This trend gained significant momentum following the US FDA guidance in 2017 that all drug development programs, starting from first-in-human studies, should assess potential side effects on the central nervous system (CNS).
Developing a comprehensive safety and tolerability profile in clinical research is of paramount importance. Including cognitive assessments within trial protocols not only enriches the data to hold the highest standards of patient safety and efficacy for patients and therefore FDA approval it also provides opportunities to further understand the pharmacokinetics and dosage. Overall, including cognition as a primary safety endpoint provides a competitive differentiator to support successful commercialisation.
Assessment of safety and tolerability is crucial in clinical studies, determining the likelihood of progression through phases, and being required by regulators. Many compounds have the potential to detrimentally affect cognitive function. The impact on cognition can be attributed to both a direct effect on the brain (e.g. in antihistamines and anticholinergic medications), and through downstream effects of changes in physiology (e.g. glucose metabolism; hormones, effects on the immune system and other adverse events such as nausea or pain).
This necessitates the objective assessment of cognitive function for drugs that penetrate the blood-brain barrier and those that do not. Beyond early-phase studies, cognitive assessments can be integrated into later phase studies, including post-marketing, which may enable the identification, or elimination, of long-term effects which may not be detected in the timelines of early phase research.
Cognitive safety in CNS trials
In general, any drug that crosses the blood–brain barrier can influence cognition through effects on neurotransmitter systems. This includes many compounds developed for neurological disorders, as well as drugs developed for psychiatric disorders and pain medication.
For instance, in the development for treatments for Parkinson’s disease, while modulators of dopamine may improve motor symptoms, they could produce detrimental effects on specific cognitive processes linked to reward processing or impulsivity1. Such impacts can have a negative effect on ability to function and should be characterised and understood in the context of other clinical benefits.
The need for a cognitive safety profile for new drugs outside CNS
A clear example of the importance of cognitive safety in non-CNS indications is demonstrated in the case of lipid-lowering therapies such as statins. Post-marketing reports of (often) subjective cognitive impairment resulted in the FDA mandating label changes for all statins, listing memory loss and confusion as “non-serious and reversible side effects”, and a requirement for studies of the effect of new lipid lowering drugs on cognition as part of the regulatory submission.
The landmark EBBINGAHUS study of the LDL-lowering drug evolocumab, a PCSK9 inhibitor, became the first trial assessing cognition changes as a primary safety endpoint for this new class of cardiovascular drugs using a brief battery of CANTAB assessments. The study did not observe any impact of lipid lowering on cognition2, a result which has been extended following an open-label study with follow-up of more than five years (Zimerman A., in press)3.
Incorporating cognition as a primary safety endpoint enabled the inclusion of a safety statement of non-inferiority to placebo being included in the drug label, providing reassurance to regulators, clinicians and patients4.
Another therapeutic area with an increasing focus on cognitive safety is oncology. Advancements in oncology, including personalised approaches and immunotherapy have resulted in increased survival for patients. As a result of this improvement in survival, increased attention has been given to the impact of treatment and disease on patient quality of life.
Cognitive function problems, often expressed by patients as “chemo brain” or “brain fog” have a profound impact on quality of life. This is reflected in the selection of endpoints in oncology trials where in the five years leading up to 2023, 85 industry sponsored oncology trials included cognition endpoints, which is a 44% increase on the previous five years, and a more than 500% increase over the 2008-2012 period.
Although this is still a relatively small proportion of the oncology space, demonstrating that therapies can extend lifespan without impairing cognitive abilities is likely to represent a significant competitive advantage, both in oncology and beyond.
Choosing the right partner to achieve regulatory approval for cognitive safety and efficacy
CANTAB, the gold standard in cognitive assessments, is recognised by the industry as a reliable and accurate platform for assessing the effects of drugs on brain health. Cambridge Cognition is becoming the preferred partner for achieving regulatory approval and commercial differentiation for new medicines for both CNS and non-CNS indications.
Establishing a robust safety in clinical research is crucial for regulatory acceptance and gaining a competitive edge. Integrating cognitive assessments into trial protocols not only enhances the quality of collected data but is also important in providing clinically relevant data for physicians and patients.
To learn more about how CANTAB can support your clinical trial, download the document below.
References:
1. O’Sullivan SS, Evans AH, Lees AJ. Dopamine dysregulation syndrome: an overview of its epidemiology, mechanisms and management. CNS drugs. 2009 Feb;23:157-70.
2. Giugliano, R.P., Mach, F., Zavitz, K., Kurtz, C., Im, K., Kanevsky, E., Schneider, J., Wang, H., Keech, A., Pedersen, T.R. and Sabatine, M.S., 2017. Cognitive function in a randomised trial of evolocumab. New England Journal of Medicine, 377(7), pp.633-643.
3. Janik MJ, Urbach DV, van Nieuwenhuizen E, Zhao J, Yellin O, Baccara-Dinet MT, Pordy R, Manvelian G. Alirocumab treatment and neurocognitive function according to the CANTAB scale in patients at increased cardiovascular risk: a prospective, randomised, placebo-controlled study. Atherosclerosis. 2021 Aug 1;331:20-7.
4. Zimerman A, O’Donoghue M, Ran X, Im K, Ott BF, Mach F, Zavitz K, Kurtz CE, Monsalvo ML, Wang B, Atar D. Long-Term Neurocognitive Safety of LDL-C Lowering With Evolocumab: Open-Label Extension Data From FOURIER. Circulation. 2023 Nov 7;148(Suppl_1):A14714-.
