March/April 2019

Research Review: Upper Age Limits in Clinical Trials — Research Data Lacking With Older Adults for Evidence-Based Medicine
By KC Wright, MS, RDN
Today’s Geriatric Medicine
Vol. 12 No. 2 P. 30

By the year 2030, the demographics of the United States is projected to reach a historical turning point: People older than age 65 will outnumber children.1

The aging population has created a demand for research evidence to guide clinical practice for older adults, especially those with preexisting medical conditions. Yet one-half of all clinical trials have precise upper age limitations, and others restrict participation of older adults based on indirect exclusion criteria such as comorbid conditions, cognitive impairment, and polypharmacy.2-5

When older people are excluded from clinical trials and other research, how can geriatricians determine the best course of treatment for patients? This has frustrated many providers for years, especially regarding drug research, in which, for example, the average age of the subjects may be 45. How can physicians extrapolate the data for a 75-year-old patient? When many of the patients who have diabetes, heart disease, cancers, osteoporosis, and other illnesses are older than 65, it can be challenging to find relevant evidence-based medicine to implement, leaving some practitioners to make assumptions for care plans.

Clinical Studies Excluding Older Adults
An investigation of phase III and IV randomized clinical trials published in high-impact journals revealed that several practices may limit the relevance of study findings to older people.6 In this review, approximately 20% of clinical trials exclude older adults from participation, based on age criteria alone, and nearly one-half of the remaining trials employ non-age-based eligibility criteria that could disproportionately exclude older adults with complex health status. These trials rarely assessed highly age-relevant outcomes such as functional status and quality of life. Furthermore, results from this review showed that subgroup analyses examining treatment effect by age do not routinely utilize rigorous methodology.

Some clinical trials examining cardiovascular disease over the past decade have specifically focused on the study of elderly persons, but many trials—including those influencing current treatment guidelines—study primarily younger individuals.7-9 Research aimed at measuring exclusion of elderly adults from randomized clinical trials studying drug interventions for ischemic heart disease found that trials across the spectrum of the disease were not adequately enrolling elderly adults.10 In fact, more than one-half of the trials explicitly excluded people based on upper age limits. This research showed that overall, there’s been a slight increase in such exclusions over the past 10 years, in part due to changes in certain trial characteristics. Upper age limits were most frequently set at 75 and 80, resulting in a pronounced drop in the enrollment of participants aged 75 and older, compared with those aged 65 and older.

Although 61% of new cancer diagnoses and 71% of all cancer deaths occur among the elderly,11 studies indicate that people 65 years and older compose only 25% of subjects in cancer clinical trials.12 Research to evaluate the participation of elderly subjects in clinical trials sponsored by the National Cancer Institute and assess how it’s affected by protocol exclusion criteria found that the elderly are underrepresented in cancer clinical trials relative to their proportion of the cancer population.13 Their underrepresentation was more pronounced in trials for early-stage cancers than in those for late-stage cancers. Furthermore, this retrospective analysis found that protocol exclusion criteria based on organ-system abnormalities and functional status limitations are associated with lower rates of elderly participation in cancer trials and almost fully explain the observed underrepresentation of the elderly in these trials relative to their burden of disease.

Considering that ageism was found to be a component of studies related to stroke management,14,15 recent research investigated whether ageism is a feature of study design in osteoporosis management.16 The data showed a distinct difference—two decades—between the mean age of participants in studies of the management of osteoporosis and the mean age of those presenting with hip fractures. This suggests that future research should include a cohort of an age that is more reflective of those most likely to experience the adverse effects of osteoporosis.

Diabetes mellitus is the most common long-term metabolic condition in older people, with 21% of subjects aged 65 and older diagnosed.17 In nursing home residents, the prevalence of diabetes is closer to 33%.18 Diabetes is a source of morbidity and a shorter lifespan as well as a growing cause of disability in older people.19 Despite this, research on the management of diabetes in older adults is sparse, and evidence of a decision-making process is lacking.20 The few clinical guidelines that specifically address diabetes management in older adults show that data on drug treatments in very old populations are lacking.21-23 A more recent study assessing the extent of exclusion of the elderly from ongoing clinical trials regarding diabetes found that 67% of current studies limit the participation of older subjects using an arbitrary upper age limit,24 despite the fact that one-half of the individuals with type 2 diabetes in developed countries are aged 65 and older.25,26 Setting upper age limits in clinical trials is rarely justified, and, in many cases, ethical review fails to highlight this issue.3

Challenges of Inclusion
There is a bias in the study of drugs of particular relevance to the geriatric population, mainly with trials being sponsored by industries that aim for the drug to be marketed, giving more value to efficacy and internal validity than to effectiveness and safety.27 This leads to exclusion of older adults with complex illnesses and multiple diseases common in clinical practice. Inclusion and exclusion criteria should be clear and simple and aimed at limiting the number of participants who are considered ineligible because of comorbidity or concomitant medications. Older people may have difficulties participating in multiple study visits, such as barriers to transportation. Data collected on subjects may vary depending on whether the information is self-reported or proxy derived. Obtaining informed consent from older participants who may be cognitively impaired or have mental health issues may be difficult.28 Attrition and data collection can be significant issues when clinical trials are performed in older adults with multiple comorbidities and multiple medications. It’s also critical that outcomes that are relevant to older adults are defined with validated measures. Strategies to manage obstacles in clinical trials with older adults can be addressed in both the study design and execution.29,30

Regulating Study Criteria for Inclusion of Older Adults
Even though proportionate participation of the elderly in trials may not be desirable or feasible, it’s important to determine the factors that influence elderly participation in trials and to ensure that older adults have access to trials. Quantifying gaps and identifying the types of trials most likely to exclude older people from clinical studies may inform policies addressing research needs. Historically, the FDA has been aware of the relevance of obtaining information concerning the efficacy and safety of new drugs in older adults. In 1989, the FDA released regulatory guidelines for the study of drugs likely to be used in the elderly.31 In 1998, the approval of the geriatric labeling rule by the FDA guaranteed that safety and effectiveness data of a new drug in relation to age and the appropriate dosage requirements will be reported.32 Despite the FDA’s commitment to promote the inclusion of older people in clinical trials, there’s still widespread exclusion.5

The National Institutes of Health (NIH) has implemented the Inclusion Across the Lifespan Policy to “ensure individuals are included in clinical research in a manner appropriate to the scientific question under study so that the knowledge gained from NIH-funded research is applicable to all those affected by the researched diseases/conditions.”33 This applies to any grant applicant, effective January 25, 2019, and requires applicants to clarify any justifications for age-based exclusion criteria. According to the NIH Office of Extramural Research, in order to comply with this policy, applications or proposals must adequately address age-appropriate inclusion or exclusion of individuals in the proposed project. Scientific review groups will assess each application or proposal as being “acceptable” or “unacceptable” with regard to age-related inclusion and will evaluate plans for conducting the research in accordance with this policy. After award, recipients/offerers are expected to report deidentified individual-level age data in progress reports. The NIH Office of Extramural Research also added that as with other policies, NIH program staff will monitor adherence to this policy during award and conduct of research and will manage the NIH research portfolio to comply with the policy.

Although NIH’s new inclusion policy sounds like a promising solution to reduce ageism in research, others suggest that the FDA needs to require pharmaceutical companies and device manufacturers to include older adults in clinical trials when they apply for FDA approval of a product. According to Susan Peschin, president of the Alliance for Aging Research (AAR), a nonprofit organization “dedicated to accelerating the pace of scientific discoveries and their application to vastly improve the universal human experience of aging and health,”34 NIH’s new policy sets a good precedent for government-funded medical research to move away from age limits and encourage greater participation in clinical trials by older adults. That said, Peschin notes that the NIH only devotes about $4 billion of its $37 billion annual budget to clinical trials.35 Yet private industry invests about $90 to $100 billion per year in research and development,36 although their studies will not be affected by this policy. The AAR believes that the FDA must be given statutory authority by Congress to mandate a certain percentage of older adult clinical trial participation, for example, in conditions that disproportionately affect the older adult population. Peschin adds that eliminating age limits doesn’t mean older adults will be enrolled in clinical trials; rather, there must be an equal focus on recruitment efforts to ensure participation.

The AAR is also advocating for policy changes to incentivize health care providers to discuss clinical trials with their older adult patients. Furthermore, the AAR suggests that another provider incentive under Medicare could be the new Quality Payment Program. To educate older patients about clinical trials, the AAR offers health care providers an educational video, Pay It Forward: Volunteering for Clinical Trials, which provides an overview for patients of how the trials work, their importance, and what to expect when volunteering.

Summary
The design of clinical trials that include older adults more typical of those seen in clinical practice is vital. Common research practices such as appropriate design for inclusion, outcomes, and methods of rigor should be addressed in order to expand and strengthen the evidence guiding policy and treatment decisions for complex, older patients. Researchers who have examined the evidence for inclusion of older adults in clinical trials suggest opportunities for the FDA, funding agencies, and research investigators to improve evidence by increasing representation of these individuals in clinical studies.

— KC Wright, MS, RDN, is a freelance writer who advocates for healthy lifestyles and sustainable food systems at www.wildberrycommunications.com.

References
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