Randomized Clinical Trial Should Represent Those We Treat: Strategies to Improve the Representativeness of Elderly Patients in Clinical Trials
The landscape of cardiovascular disease (CVD) is shifting: patients are older, have a greater burden of co-morbidities, and have a challenging combination of adverse social determinants. There is growing public acknowledgement of this demographic change, yet, as highlighted by a recent editorial by Skolnick and Alexander1, the medical profession and pharmaceutical industries have been slow to respond.
The recognition of a growing burden of older adult patients is not new. In 1989, the Food and Drug Administration (FDA) set out nonbinding guidelines on strategies to ensure that older patients achieve adequate representation in clinical trials. In 1992, a workshop hosted by the American College of Cardiology attempting to address the issue of an aging population, recognized that not only is CVD the predominant cause of morbidity and mortality in older adults, but the profile of patients has shifted to encompass predominantly older patients. Despite this, almost two decades later, older adults continue to be disproportionally excluded from randomized controlled trials. An analysis of 251 ongoing heart failure trials in the World Health Organization Clinical Trials Registry suggested that over a quarter have explicit age based cut-offs.2 The editorial by Skolnick and Alexander1 addressed that the use of exclusion criteria such as related comorbidities, medication use, visual or hearing limitations, further reduce the ability of the elderly to participate in clinical trials. Nearly half of all older patients have three or more concurrent illnesses.3 The difficulties in enrolling these patients becomes compounded as substantially more older patients may have to be screened to enroll one into a trial.4 This results in a pragmatic concern of rapidly enrolling patients into a clinical trial. Clinical trialists may also conflate legitimate clinical concern with more subjective feelings of what is best for the older adult.5 The lack of clinical evidence makes therapeutic decision-making particularly challenging. Older adult patients, who are often at the highest risk of adverse outcomes, may stand to gain the most benefit from therapeutic interventions; however, the potential for harm may also be exaggerated.
Guideline recommendations have been a poor way to encourage the enrollment of older adult patients in randomized clinical trials. Using the direction of other special populations, Skolnick and Alexander propose several solutions. The National Institutes of Health sponsored trials have targeted enrollment tables for sex, race, and ethnicity; similarly, age based target enrollments can be adopted by federal regulators. Furthermore, similar to dedicated offices such as the Office of Women's Health, Office of Minority Health, and Office of Pediatric Therapeutics, congress could create an Office of Geriatric Health and Aging within the FDA. This would allow for dedicated dosing protocols, data collection, and trial monitoring ensuring that the needs of the elderly patients are being represented.
Another strategy involves incentivizing the patent protection extensions. Drug development is an expensive process due to high attrition of potential products as they proceed through laboratory, animal, and human trials. Patent exclusivity provides a unique opportunity to increase knowledge in older adult patients and gives companies an incentive to conduct dedicated studies in this population. The Pediatric exclusivity rule of 1997 allowed for a six month patent extension for conducting studies in children, which resulted in a significant increase in the pediatric labeling of drugs.6 A 'Geriatric Rating Category' analogous to the Pregnancy Categories can be used to emphasize safety or risks associated with drug therapy in the elderly; such a system may help distinguish a drug from its competitors.
When dealing with older patients, clinical trials can consider using an adaptive design or dose adjusted design. Older patients constitute a large and growing proportion of ST-elevation myocardial infarction (STEMI) patients, yet they have been under-represented or even excluded from reperfusion trials due to fear of excessive risk of hemorrhage. The Strategic Reperfusion Early after Myocardial Infarction (STREAM)7 trial randomized 1,892 patients with STEMI who presented within three hours of symptoms and were unable to undergo primary PCI within one hour to undergo primary percutaneous coronary intervention (PCI) or fibrinolytic (tenecteplase) therapy. The mean age of patients randomized to the fibrinolytic arm was 59.7 years, with a standard deviation of 12.4 years. An increased risk of intracranial bleeding was recognized in patients above the age of 75 years after one fifth of planned enrollment had occurred, leading to a halving of the tenecteplase. Before dose amendment, there were three (7.1%) of 42 elderly patients with intracranial hemorrhage (ICH). No ICH occurred in the 93 elderly patients who received half-dose tenecteplase post-amendment. The median extent of ST-segment elevation resolution (≥50%) and proportion of patients with ≥2 mm in the electrocardiogram lead with greatest ST-segment elevation was comparable in elderly patients pre-amendment and post-amendment (63.2% vs 56.0% and 43.6% vs 40.0%, respectively).8 Such results demonstrate that even in interventions which are thought to be a high risk of bleeding such as thrombolysis, evaluation of such therapies can be conducted in older patients. However, trial investigators or data safety monitoring board members must be actively evaluating and assessing outcomes in the older adult trial participant throughout the duration of the trial.
Finally, given the age demographic in North America and most high-income countries, the definition of what is considered elderly may also need to be re-evaluated. As life expectancy has increased, the proportion of adults over the age of 65 has significantly increased. Furthermore, in disease states such as heart failure, those over the age of 65 form the overwhelming majority. This raises the question of whether one can call patients elderly from a medical standpoint when they form the majority of the population with the disease. While age cut-offs are arbitrary, age cut-offs of 75 years maybe a more appropriate reflection of those whom we would consider to be a vulnerable cohort.1
While challenging, patients, payers, clinical trialists, and medical industry need to be more inclusive of older adults. A dialogue needs to take place on how to enhance the representativeness of clinical trials for the older adult. Only then can physicians begin to practice more evidenced based medicine in this vulnerable population.
- Skolnick AH, Alexander KP. Older Adults in Clinical Research and Drug Development: Closing the Geriatric Gap. Circ Cardiovasc Qual Outcomes 2015;8:6313.
- Cherubini A, Oristrell J, Pla X, et al. The persistent exclusion of older patients from ongoing clinical trials regarding heart failure. Arch Intern Med 2011;171:5506.
- Wolff JL, Starfield B, Anderson G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med 2002;162:226976.
- Masoudi FA, Havranek EP, Wolfe P, et al. Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure. Am Heart J 2003;146:2507.
- Gurwitz JH, Goldberg RJ. Age-based exclusions from cardiovascular clinical trials: implications for elderly individuals (and for all of us): comment on "the persistent exclusion of older patients from ongoing clinical trials regarding heart failure". Arch Intern Med 2011;171:5578.
- Li JS, Eisenstein EL, Grabowski HG, et al. Economic Return of Clinical Trials Performed Under the Pediatric Exclusivity Program. JAMA 2007;297:4808.
- Armstrong PW, Gershlick AH, Goldstein P, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med 2013;368:137987.
- Armstrong PW, Zheng Y, Westerhout CM, et al. Reduced dose tenecteplase and outcomes in elderly ST-segment elevation myocardial infarction patients: Insights from the Strategic Reperfusion Early After Myocardial infarction trial. Am Heart J 2015;169:8908.
Keywords: Aged, Clinical Trials Data Monitoring Committees, Comorbidity, Electrocardiography, Emotions, Fear, Heart Failure, Intracranial Hemorrhages, Life Expectancy, Morbidity, Motivation, Myocardial Infarction, Percutaneous Coronary Intervention, Pharmaceutical Preparations, Randomized Controlled Trials as Topic, Registries, Tissue Plasminogen Activator, Vulnerable Populations, Women's Health, Geriatrics
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