14 July 2020
Guidance for including elderly patients in clinical trials
Older adults shoulder a disproportionate burden of chronic diseases and consumption of prescription drugs. Nevertheless, older adults, especially those aged over 75 years, are chronically under-represented in clinical trials. In this two part series, Dr Kiri Granger explores the risks of under-presentation and outlines guidance for including older adults in clinical trials. Read on for session two: key design considerations when including elderly patients in clinical trials, with a focus on cognitive assessment.
Why is it important to include elderly patients in clinical trials?
On average, older adults carry 60% of the national disease burden but only represent approximately 32% of participants in Phase II and III clinical trials. Cardiovascular diseases (CVDs) are the number one cause of death globally, taking an estimated 17.9 million lives each year; and for diagnosed individuals, 65% are older than 65 years of age. Despite these statistics, only 42.5% of CVD participants enrolled into clinical trials are older than 65 years and 12.3% older than 75 years. Clinical trial participation of these older adult populations is also low in research on cancer, Alzheimer’s disease, arthritis, epilepsy and many more.
In a world where people are living longer (elderly population expected to increase to >2BN by 2050), there is an undoubtable expectation that treatments will cure an individual or at least improve their quality of life. To deny older adults the opportunity of optimal or appropriate treatment due to the inadequacies of clinical trial representation, runs counter to the precepts of medical practice and could even be considered unethical. To aid much-needed access to new treatments, clinical trials should fairly represent older adults, particularly when they are the intended recipient age group of the medication under investigation. This will ultimately provide sufficient data about the positive and/or negative effects of treatments in older adults and better guide geriatricians in their prescribing decisions.
Planning for your clinical trials: What should be considered?
The inclusion of elderly patients in clinical trials is undoubtedly important but there are methodological considerations in doing so. A key example is the appropriate assessment of both pharmacokinetic (PK) profiles with your investigational medicinal product (IMP) and pharmacodynamic (PD) endpoints for geriatric (vs non-geriatric) participants.
To ascertain adverse central nervous system (CNS) events that might be clinically important for the patient and provide understanding of clinical outcomes in at-risk older adults; cognitive function and functional status, in particular, should be considered during trial design.
Drug developers, regulators, physicians and patients are increasingly interested in measuring and monitoring cognitive function as part of a drug’s Safety Profile and Risk Management Strategy. For example, in 2012 the US FDA issued a warning that statins or drugs that lower cholesterol might be associated with impaired cognitive function. This environment led to the design and completion of a multi-national Phase III clinical study of evolocumab, the first-to-market of a new class of monoclonal antibody drugs designed to specifically lower LDL cholesterol. Cognitive function was evaluated using CANTAB assessments of reaction time (RTI task), episodic memory (Paired Associates Learning task; PAL) and working memory/executive function (Spatial Working Memory task; SWM). The data generated in this study resulted in language added to the evolocumab package insert that states ‘in EBBINGHAUS (NCT02207634), a substudy of 1974 patients enrolled in the FOURIER trial, REPATHA was non-inferior to placebo on selected cognitive function domains as assessed with the use of neuropsychological function tests over a median follow-up of 19 months’.
Some compounds to be considered higher risk of adverse CNS events, particularly on cognitive function, are those that:
- Cross the blood brain barrier
- Modulate brain neurotransmitter systems
- Indirectly affect the CNS (e.g., Non-CNS drugs that modulate cardiovascular, respiratory, immune, glucose functions)
Facilitating inclusion of elderly participants using remote-based trials
Decentralised clinical trials offer a positive step change for facilitating the appropriate inclusion of older participants, particularly for Phase II and Phase III programmes aiming to confirm the safety and/or efficacy of their investigational medicinal product (IMP). Conducting a clinical trial remotely allows participants to take part in research from the comfort of their own homes; with a recent survey supporting 74% of older adults prefer this option over in-clinic visits.
A 2019 study conducted by Eli Lilly assessed the feasibility of self-administered at home cognitive testing, using the CANTAB platform in testing in healthy controls and cognitively impaired individuals (aged 60-76). Eleven cognitive assessments were completed twice, with an average of two weeks between testing sessions with reported >85% compliance across both groups. These results support the capability of older participants to successfully self-administer cognitive tests at home, without prior familiarization of the tests or oversight by an administrator/rater.
With over 55,000 active interventional clinical trials, the industry is increasingly looking to decentralise trials, particularly in the face of the Covid-19 outbreak. It is critical that high-quality research continues to advance clinical drug development programmes.
Age based stratification
With an adequate sample size, data should be collected for various age groups (e.g., <65, 65-74, 75-84, and >85) to assess the consistency of the treatment effect and safety profile in these patients with the non-geriatric patient population. Regulators are typically flexible in their approach to clinical trial design and statistical analysis, thus a trial design with stratification based on age is recommended to evaluate benefits vs risks amongst older adults. Furthermore, an intent-to-treat (ITT) population that consists of all enrolled patients in a randomised controlled trial can be compared against a modified ITT (mITT) population consisting only of the patients under e.g., 75 years of age. Here, the mITT can comprise the primary analysis with subsequent ITT analysis to provide the relevant and necessary safety and efficacy information about all patients.
Equitable participation in clinical trials on the basis of age is vital to advance medical knowledge and test the safety and efficacy of new treatments that are generalizable to aging populations. Ideally, clinical trials designed with not just chronological age in mind but also physiological age would further aid evaluation of the safety and efficacy of drug therapies by reducing potential bias in the inclusion of ‘heathier older adults’ than the average older-age population.
 World Health Organization: Cardiovascular Diseases (https://www.who.int/health-topics/cardiovascular-diseases)
 Bourgeois et al. Exclusion of elderly persons in randomized clinical trials of drugs for ischemic heart disease. Journal of the American Geriatrics Society 2017;65(11):2354-2361.
 Herrera et al. Disparate inclusion of older adults in clinical trials: Priorities and opportunities for policy and practice change. American Journal of Public Health 2010;100:S105-S112.
 World Health Organization: Ageing and Health (https://www.who.int/news-room/fact-sheets/detail/ageing-and-health)
 Giugliano et al. Cognitive function in randomized trial of evolocumab. The New England Journal of Medicine 2017;377:633-43. ADD reference to Repatha package insert
 Earl et al. Better ways of assessing cognitive health. Brisbane: National Seniors 2017.
 Maljkovic et al. At home cognitive testing (CANTAB battery) in healthy controls and cognitively impaired patients: A feasibility study. Alzheimer’s and Dementia 2019;16(7):P440, AAIC
 MedCity News
 FDA Draft Guidance. Inclusion of older adults in cancer clinical trials. March 2020.