The Importance of Using Cognition as an Endpoint in Clinical Trials

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Establishing a robust safety and tolerability profile is essential in clinical development. Integrating cognitive assessments into trial protocols enhances the understanding of drug effects, ensuring the highest patient safety and efficacy standards, which are critical factors for FDA approval. Additionally, these assessments offer valuable insights into pharmacokinetics and optimal dosage. This article explores the growing importance of incorporating cognitive evaluations into the safety profiles of drugs developed for central nervous system (CNS) and non-CNS indications.

Cognition as a safety endpoint

In 2017, the FDA issued guidance recommending that all drug development programs, beginning with first-in-human studies, evaluate potential CNS side effects, including drowsiness, agitation, and dizziness.¹ This directive has led to the inclusion of cognitive assessments as an important safety endpoint, significantly enhancing the scope of safety profiles of new drugs. The approach has emerged as a competitive differentiator, supporting the successful commercialization of novel therapies.

Assessing the safety and tolerability profile of a drug or treatment is crucial for regulatory approval and determining its potential to progress through the various phases of clinical development. Many compounds can adversely affect cognitive function through direct impacts on the brain, as seen with antihistamines and anticholinergic medications, or downstream physiological changes, such as altered glucose metabolism, hormonal imbalances, immune system effects, and other adverse events like nausea or pain.

Medication-induced cognitive issues can significantly impact well-being and daily functioning. They affect processes like seeing, hearing, reacting, processing, remembering, and responding. These disruptions can affect productivity, hinder people's communication and ability to use technology, and even impair their navigation in unfamiliar places. Additionally, they pose severe risks in tasks such as driving or operating machinery.

This requires objective cognitive assessment of all drugs, whether they penetrate the blood-brain barrier or not and whether they are meant to treat CNS indications or not. Integrating cognitive assessments into later-phase clinical studies, including post-marketing trials, can help identify or rule out long-term effects that may not be apparent during early-phase research.

Understanding the cognitive safety profile for all medications

Any drug crossing the blood-brain barrier can affect cognition by influencing neurotransmitter systems. This can impact the ability to perceive, process, understand, and store information, make decisions and produce appropriate responses. This risk is present in many compounds developed for neurological, psychiatric, and pain-related conditions. For example, while dopamine modulators used in Parkinson's disease may improve motor symptoms, they can also negatively impact cognitive processes related to reward processing or impulsivity.² These effects can impair overall functioning and must be carefully characterized and understood in the context of the drug's other clinical benefits.

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 cognitive assessments. The study, which followed a total of 1974 patients for a median of 19 months, did not observe any impact of lipid-lowering on cognition,³ a result which has been extended in an open-label study with a follow-up of more than five years.⁴ Incorporating cognition as a primary safety endpoint enabled the inclusion of a safety statement of evolocumab’s non-inferiority to placebo being included in the drug label, providing reassurance to regulators, clinicians, and patients (see Repatha package insert).³ A similar drug, the PCSK9 inhibitor alirocumab, was also assessed for cognition using CANTAB in a 96-week Phase IV safety study of 2086 patients, and it also achieved noninferiority to placebo.⁵

The impact of oncology treatments on cognition

Oncology is another therapeutic area with a growing emphasis on cognitive safety. Advances in personalized approaches and immunotherapy have significantly improved patient survival rates. Consequently, there is now a greater focus on the impact of both treatment and disease on patients' long-term quality of life, including cognitive function. While a new drug may be lifesaving, ensuring it doesn’t negatively impact cognition is critical. This information is vital for physicians when discussing the potential benefits and risks with their patients.

In cases where there are several possible drug options, understanding the risks and potential benefits is incredibly useful, especially how they may impact a patient’s life. This knowledge can differentiate one drug from another in terms of what is most effective for the individual patient. It is essential to grasp the risk-benefit profile across these different areas fully.

Cognitive function issues, commonly referred to by patients as "chemo brain" or "brain fog," can also significantly affect quality of life. This growing concern is evident in the selection of endpoints in oncology trials. Between 2018 and 2023, 85 industry-sponsored oncology trials included cognition endpoints, representing a 44% increase from the previous five years and a more than 500% increase compared to the 2008-2012 period.

While this remains a relatively small segment of the oncology field, proving that therapies can extend lifespan without compromising long-term cognitive abilities will likely offer a significant competitive advantage in oncology and other therapeutic areas.

Incorporating assessments

Cognitive assessments broadly evaluate an individual’s information processing capacity, including concentration, memory, and control. From a safety perspective, several key areas should be assessed to ensure a comprehensive evaluation of cognitive function. These include reaction time to stimuli, accuracy of responses, effectiveness of memory retention, processing speed, and the ability to maintain attention on a task over an extended period. Thoroughly assessing these aspects can help us better understand how a drug may impact cognitive abilities.

In cognitive safety studies, the sensitivity and comprehensiveness of these assessments and resulting measurements are crucial, especially when the results hinge on statistically nonsignificant findings. Even in a well-powered study, using an insensitive or improperly applied assessment tool can lead to misleading results.

Sensitive, standardized cognitive assessments that have proven effective in detecting cognitive impairment are essential. These tools should also offer high test-retest reliability and minimal practice effects to ensure accurate results. While self-report questionnaires are common, they often fall short, as individuals may lack insight into their cognitive abilities, only documenting the most apparent impairments. Digital assessments are targeted to measure more specific cognitive domains. These assessments produce more data points and reduce noise, making them highly sensitive.

Objective measurements can evaluate reaction time in milliseconds, provide quantitative assessments of attention, and measure memory by tracking errors made during testing. These cognitive functions can be precisely quantified through computerized assessments, allowing for a comprehensive and objective analysis of a drug's impact on cognition across a broad range of functions.

It is, however, important to select the right tests for the specific study population. A test that is too easy or difficult can compromise sensitivity due to boundary effects, leading to skewed or incomplete data. Careful consideration must be given to choosing appropriate and effective cognitive assessments for each study.

Final thought

Cognitive impairment is increasingly recognized as a significant potential side effect of various medications. Yet, many drug development programs still overlook the importance of incorporating sensitive cognitive assessments, potentially missing a competitive advantage for their therapies. These assessments must be scientifically validated, highly sensitive, and precise to ensure that new treatments are safe and effective. By targeting specific cognitive domains and correlating results to neural networks, these tools can provide objective measures of cognitive function, offering invaluable insights for regulators, clinicians, patients, and their families. As the demand for more comprehensive safety profiles grows, integrating cognitive evaluations will continue to be a key differentiator in the successful development and commercialization of new therapies.

Kenton Zavitz, PhD, director of clinical affairs, Cambridge Cognition

References

1. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluating-drug-effects-ability-operate-motor-vehicle
2. 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.
3. 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.
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-.
5. 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.