Why are elderly patients under-represented in clinical trials?

Older adults are consistently under-represented in clinical trials, even though they take more prescription medications than any other group. In this two part series, Dr Kiri Granger will explore this under-presentation and outline practical considerations for including older adults in clinical trials.

Read on for session one: the importance of addressing the evidence-practice gap.

Background

Adults aged 65 years and older are the fastest growing proportion of the population worldwide, shouldering a disproportionate burden of chronic diseases (e.g., cancer, cardiovascular disease and dementia) and consumption of prescription drugs, than any other age group. Nevertheless, older adults, especially those aged over 75 years, are chronically underrepresented in clinical trials. Consequently, evidence and knowledge about responses of geriatric patients to medications is inadequate, hindering understanding of the benefit-risk profile of drugs in this population. The FDA are keen to address this evidence gap to ensure age-related efficacy endpoints and adverse events are actively sought for older adults.

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Why does the evidence-practice gap exist?

Scientifically, the general age threshold of >65 years for exclusion of participants in clinical trials is arbitrary and uninformative for the purpose of delineating constructive clinical guidance on treatment decisions. Where Phase I trials may not necessitate representation of older adults with high risk complications, the enrolment of older adults in Phase II and III clinical trials is essential to achieve the goal of confirming dosage, safety, adverse events and effectiveness.

The key reasons for disparate inclusion of older adults in clinical trials are typically due to a combination of challenges and obstacles that both sponsors and older adults face. These include, co-morbid conditions and polypharmacy; both of which may impact attainment of the trial safety and/or efficacy endpoints. Operational challenges tend to include difficulty with recruitment and/or retention, gaining informed consent, economic constraints, communication issues (e.g., hearing difficulties and impaired vision) and physical immobility that can constrain transportation options to clinical sites. Such obstacles lead to restrictions with exclusion criteria based on age and a reluctance to include older adults at high risk of adverse outcomes in clinical trials^[1].

The aging population and pharmacology

Older adults are at high risk for adverse drug reactions because of the pharmacokinetic (PK) and pharmacodynamic (PD) changes associated with aging. For example, hepatic and kidney function can decline in older adults, resulting in impaired absorption, excretion and metabolic clearance of drugs. Furthermore, cerebral blood flow, brain atrophy and changes in neuronal function such as cholinergic neuron loss can result in adverse drug effects on brain function (e.g., cognitive abilities). A study by Gray et al (2015) evaluated the effect of commonly used anticholinergic classes (e.g., tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics) on incident dementia. From a total N=3,434 aged >65 and no dementia at study entry; 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease) over a mean follow-up of 7.3 years^[2].

Overall, older adults are more prone to adverse effects due to PK/PD changes, probable comorbidities and concomitant therapies that can interact with the investigational drug. The adverse effects can be more severe, or less tolerated, and have more serious consequences than in the non-geriatric population^[3].

The Regulatory view

Guidance for industry covers various drug classes believed to be high risk for causing adverse events in older adults. FDA guidelines make reference to the ICH guidance for Studies in Support of Geriatrics^[4] which provides recommendations on special considerations that apply in the design and conduct of clinical trials of medicines that are likely to have significant use in the elderly. These guidelines do not however establish legally enforceable responsibilities; allowing manufacturers to state in the package insert that insufficient numbers of older adults were included in the trials preceding regulatory marketing approval.

A national initiative comprising a stakeholder network of researchers, community advocates, policymakers, and federal representatives strongly advocate practice and policy change recommendations. This includes legal mandates requiring age-related PK disclosures on all labels for all medications (i.e., to improve older adult use labelling), without exception^[5].

Summary

This article has highlighted how the risks involved in including elderly patients in clinical trials pale in comparison to the risks associated with their underrepresentation in these trials.

Next Dr Granger will outline key design considerations when including elderly patients in clinical trials - with a focus on cognitive assessment.