The global population of individuals aged 65 and above is experiencing a significant surge, a trend underscored by UN projections estimating 1.5 billion older adults by 2050. This demographic shift is already evident in the US, where the 2020 census revealed that approximately one in six individuals falls within this age bracket. This increase, fueled by enhanced life expectancy worldwide, presents unique challenges and opportunities. Older adults require different health and social support than younger people. Healthy aging is a key priority for this population. With their growing numbers and high healthcare usage, we need to find and implement the best evidence-based practices to address their specific needs and promote their well-being. The goal of this article is to review the status of research in particular Randomized Controlled Trials (RCTS) in older population.
Clinical trials, particularly randomized controlled trials (RCTs), are the cornerstone of evidence-based medicine. They determine the safety and efficacy of new treatments, devices and drugs as wells as shaping healthcare guidelines for generations. However, a critical demographic is consistently underrepresented in these studies: older adults. This disparity has significant implications, especially considering the prevalence of chronic diseases in this population, which is increasing in size.
The Burden of Chronic Diseases in Aging
As we age, the likelihood of developing chronic conditions increases significantly. These conditions, such as cardiovascular disease, diabetes, arthritis, and neurodegenerative disorders, often require long-term management and multiple medications. Older adults often experience multimorbidity, meaning they have two or more chronic conditions simultaneously, further complicating treatment strategies.
Despite the high prevalence of chronic conditions in older adults, there is a significant lack of RCTs investigating these conditions in this population. In a 2015 systematic review analyzing 1,369 RCTs from 2012, researchers discovered a mere 7% inclusion of older adults. While colorectal cancer disproportionately affects older adults, with a median age of diagnosis at 70 years, this demographic is often underrepresented in clinical trials. For example, the MOSAIC trials, which investigated treatments for colorectal cancer, had a median participant age of 60. Furthermore, though two-thirds of cancer patients are older than 65, this age group represents just 25% of those enrolled in cancer trials.These discrepancies highlight a concerning trend where older adults are excluded from research, potentially limiting the applicability of findings to the population most affected by chronic diseases.
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The Problems with Underrepresentation of older adults in RCTs
When older adults are excluded from RCTs, the results may not accurately reflect how treatments will perform in this population. This leads to several problems:
- Lack of Generalizability: Trial results may not be applicable to older adults, who often have different physiological responses to medications due to age-related changes in pharmacokinetics and pharmacodynamics.
- Increased Risk of Adverse Events: Without sufficient data on older adults, there’s a higher risk of adverse drug reactions, drug interactions, and other complications.
- Safety and efficacy of treatment Decisions: Clinicians may lack the evidence needed to make informed treatment decisions for their older patients, potentially leading to undertreatment or overtreatment, which can and unsafe and / or ineffective.
- Exclusion from innovative therapies: Older adults are missing out on the opportunity to benefit from new therapies.
Additionally, older adults represent a diverse population with varying levels of health and functional ability, including fit, vulnerable, and frail individuals; however, most RCTs fail to analyze data for these distinct subgroups, limiting the applicability of findings to specific older adult populations.
In a health policy article published in The Lancet Healthy Longevity in (2023)) , Denkinger, M., et al., emphasized the critical need for including functional measures and frailty assessments in the development and evaluation of medication for older adults. The study highlights a significant gap in research regarding frail older adults, a population that constitutes a large group of patients and major users of medications. The data on this vulnerable group is missing from many clinical trials. This exclusion leads to inadequate assessments of medication compliance and non-adherence, as trials often focus on healthier older adults or exclude frail individuals altogether. Usability studies are recommended to ensure representative cohorts by including frail older adults. Furthermore, the study points out safety concerns for medications used to treat common geriatric syndromes and symptoms, which are difficult to measure due to atypical presentations and inconsistent recording in clinical trials and post-marketing settings. While safety data for older patients are reported separately for regulatory purposes, the study advocates for the same level of attention to be given to data.
Barriers to Including Older Adults in RCTs
Several barriers contribute to the underrepresentation of older adults in RCTs. These can be categorized as follows:
1. Eligibility Criteria
- Strict Inclusion/Exclusion Criteria: Many trials exclude individuals with comorbidities, polypharmacy, cognitive impairment, or functional limitations, all of which are common in older adults.
- Age Caps: Some trials have upper age limits, arbitrarily excluding older individuals.
2. Ethical Concerns
- Vulnerability: Concerns about the vulnerability of older adults may lead researchers to be overly cautious, resulting in exclusion.
- Informed Consent: Obtaining informed consent from individuals with cognitive impairment can be challenging, raising ethical dilemmas.
- Balancing Risk and Benefit: Evaluating the risk-benefit ratio for older adults with multiple health issues can be complex.
- Design of RCT. Designing RCTs where older adults are excluded is an ethical concern.
3. Logistical and Practical Challenges
- Transportation and Accessibility: Older adults may face difficulties traveling to trial sites or participating in lengthy study procedures.
- Time and Burden: Participating in a trial can be time-consuming and burdensome, especially for individuals with functional limitations.
- Recruitment Difficulties: Recruiting older adults can be challenging, particularly those with cognitive impairment or limited social networks and communication problems
- Cost: Additional testing or monitoring may be required for older adults, increasing the overall cost of the trial.
4. Investigator and Sponsor Biases
- Perceived Complexity: Researchers may perceive older adults as a complex and challenging population to study.
- Fear of Increased Adverse Events: Sponsors may be concerned about increased adverse event rates in older adults, potentially delaying or complicating drug approval.
- Lack of Awareness: Insufficient awareness of the importance of including older adults in trials may contribute to their exclusion.
The Path Forward: Regulations and Standards
The FDA has also taken steps to address this issue. They have issued guidance documents encouraging the inclusion of older adults in RCTs, particularly Phase III trials, which are crucial for determining the safety and efficacy of new treatments before they are marketed.
Specifically, regarding phase III trials, the FDA is strongly encouraging the following:
- Representative Sampling: Trials should aim to include a representative sample of older adults, reflecting the population who will ultimately use the treatment.
- Age-Stratified Analysis: Data should be analyzed by age subgroups to identify potential differences in treatment effects.
- Pharmacokinetic and Pharmacodynamic Studies: Specific studies should be conducted to assess how age-related changes affect drug absorption, distribution, metabolism, and excretion.
- Consideration of Comorbidities and Polypharmacy: Trials should consider the impact of comorbidities and polypharmacy on treatment outcomes
Furthermore, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a key player in promoting global standards for pharmaceutical development, including clinical trials. The ICH’s efforts are crucial for achieving international harmonization and ensuring that clinical trials are conducted in a way that prioritizes the safety and efficacy of medications for all populations, including older adults.
In one of its statement, ICH stated that “not all potential differences in pharmacokinetics, pharmacodynamics, disease-drug interactions, drug-drug interactions, and clinical response that can occur in the geriatric population can be predicted from non-geriatric populations”. The ICH develops harmonized guidelines, aiming to create consistent standards across different regions, reducing duplication and promoting efficient drug development. This contributes to ensuring trials prioritize safety and efficacy for all, including older adults.
Moving forward, a collaborative effort involving researchers, clinicians, regulatory agencies, and patient advocacy groups is essential to ensure that older adults are adequately represented in clinical trials. By overcoming the barriers to inclusion, and by following the guidance provided by groups such as the ICH, we can generate robust evidence that supports safe and effective healthcare for our aging population.
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Reference
- Denkinger, Michael et al. The Lancet Healthy Longevity, Volume 4, Issue 12, e724 – e729 December 2023
- Breekhuizen K. etal. Characteristics of randomized controlled trials designed for elderly: A systematic review. PloS ONE.2015; 10(5):1-8.
- Anna Mańko, Anna Raczkiewicz, Andrzej Górski, Jan Borysowski, Piotr Wiland. Exclusion of older adults from randomized controlled trials in rheumatoid arthritis, Rheumatology, Volume 63, Issue 3, March 2024, Pages 672–679.
- Kadambi S, Loh KP, Dunne R, Magnuson A, Maggiore R, Zittel J, Flannery M, Inglis J, Gilmore N, Mohamed M, Ramsdale E, Mohile S. Older adults with cancer and their caregivers – current landscape and future directions for clinical care. Nat Rev Clin Oncol. 2020 Dec;17(12):742-755.
- van Eijk, E., van der Spek, Y.M., van Deudekom, F.J.A. et al. Temporal changes in characteristics and external validity of randomized controlled trials in older people from 2012 to 2019. BMC Geriatric 23, 324.
- Guidance for Industry: E7 Studies in Support of Special Populations: Geriatrics. Questions and Answers.,” February 2012, ICH. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e7-studies-support-special-populations-geriatrics-questions-and-answers
