Abstract
This cross-sectional study evaluates the risk of exclusion for older adults in randomized clinical trials for treatment and vaccine interventions in coronavirus disease 2019.
Older adults are at greatest risk of severe disease and death due to coronavirus disease 2019 (COVID-19). Globally, persons older than 65 years comprise 9% of the population,1 yet account for 30% to 40% of cases and more than 80% of deaths.2
Unfortunately, there is a long history of exclusion of older adults from clinical trials. In response, the National Institutes of Health instituted the Inclusion Across the Lifespan policy, requiring the inclusion of older adults in clinical trials.3 Thus, we reviewed all COVID-19 treatment and vaccine trials on http://www.clinicaltrials.gov to evaluate their risk for exclusion of older adults (≥65 years).
Methods
Details of our approach, methods, and description of included clinical trials are shown in the eMethods in the Supplement.
Each of the 847 clinical trials was abstracted by at least 1 trained research associate, with reliability checks of all ratings. Age exclusions were identified by viewing all of the eligibility and exclusionary criteria. Specific age exclusions were classified into 5-year categories from ages 55 to 80 years; our focus was on exclusion of the 65 to 80 years age group most affected by COVID-19. Informed consent was waived because all data were deidentified and came from previously published studies.
Results
Table 1 identifies clinical trials by treatment with an exclusion by age. We found large variability in the age exclusions. Among the 847 trials, 195 (23%) included an age cut-off.
Table 1. Age-Based Exclusions by Treatment Type in 847 Clinical Trials.
| Treatment type | No. | Age categories excluded, y | Total, No. (%)a | |||||
|---|---|---|---|---|---|---|---|---|
| ≥55 | ≥60 | ≥65 | ≥70 | ≥75 | ≥80 | |||
| Vaccine | 18 | 3 | 4 | 1 | 0 | 1 | 2 | 11 (61) |
| Stem cells | 38 | 0 | 2 | 3 | 4 | 8 | 4 | 21 (55) |
| Antiparasitic | 14 | 0 | 2 | 2 | 1 | 1 | 0 | 6 (43) |
| Nutraceuticals, vitamins, minerals | 53 | 1 | 2 | 3 | 4 | 5 | 4 | 19 (36) |
| Blood products | 21 | 1 | 1 | 0 | 1 | 1 | 2 | 6 (29) |
| Oxygen | 15 | 1 | 0 | 0 | 1 | 1 | 1 | 4 (27) |
| Antiviral | 74 | 5 | 1 | 2 | 1 | 5 | 5 | 19 (26) |
| Hydroxychloroquine/ chloroquine | 60 | 2 | 2 | 0 | 2 | 3 | 6 | 15 (25) |
| Multimodal | 48 | 0 | 0 | 3 | 2 | 3 | 3 | 11 (23) |
| Immunomodulatory | 144 | 1 | 0 | 4 | 3 | 7 | 18 | 33 (23) |
| Antiseptic | 10 | 0 | 0 | 0 | 1 | 0 | 1 | 2 (20) |
| Nonpharmacologic | 45 | 2 | 1 | 2 | 1 | 2 | 1 | 9 (20) |
| Anticoagulant | 29 | 0 | 0 | 0 | 1 | 1 | 3 | 5 (17) |
| Convalescent plasma | 63 | 0 | 2 | 1 | 2 | 1 | 4 | 10 (16) |
| Antibiotic | 26 | 1 | 0 | 0 | 0 | 1 | 2 | 4 (15) |
| Antihypertensive | 26 | 0 | 1 | 0 | 0 | 0 | 3 | 4 (15) |
| Other drug treatmentsb | 60 | 0 | 0 | 2 | 2 | 1 | 2 | 7 (12) |
| Nitrous oxide | 9 | 0 | 0 | 1 | 0 | 0 | 0 | 1 (11) |
| Anti-inflammatory | 31 | 0 | 0 | 0 | 1 | 1 | 1 | 3 (10) |
| Device | 32 | 0 | 0 | 1 | 0 | 1 | 1 | 3 (9) |
| Prone positioning | 15 | 0 | 0 | 0 | 0 | 0 | 1 | 1 (7) |
| Steroid | 16 | 0 | 0 | 0 | 0 | 0 | 1 | 1 (6) |
| Total all trials | 847 | 17 | 18 | 25 | 27 | 43 | 65 | 195 (23) |
| Phase 3 total | 232 | 3 | 4 | 5 | 2 | 9 | 15 | 38 (16) |
Ordered by percent with age exclusion.
Other pharmacologic treatments indicates drug categories with fewer than 9 clinical trials.
Table 2 displays indirect age-related exclusions preferentially affecting older adults; each trial could have multiple exclusions. The most common age-related exclusion was compliance concerns (213 trials), and 129 of these were related to consent. Next, were broad nonspecified exclusions, specific comorbidities, requirement of technology, and other reasons. A total of 366 (43%) trials had any exclusions, of which 252 (30%) did not have an age-based exclusion. Combining the results of age-based exclusions (Table 1) and exclusions preferentially affecting older adults (Table 2), 447 (53%) trials were considered high risk for excluding older adults.
Table 2. Indirect Age-Related Exclusions by Treatment Type in 847 Clinical Trials.
| Treatment type | No. | Broad, nonspecified | Specific comorbidities | Compliance concerns | Requiring technology | Other reasons | No. (%)a | |
|---|---|---|---|---|---|---|---|---|
| Any indirect age-related exclusion (1 per study) | Combined age and indirect exclusion | |||||||
| Vaccine | 18 | 11 | 9 | 9 | 1 | 1 | 7 (39) | 18 (100) |
| Stem cells | 38 | 18 | 1 | 15 | 0 | 0 | 9 (24) | 30 (79) |
| Antiparasitic | 14 | 3 | 6 | 4 | 0 | 0 | 4 (29) | 10 (71) |
| Nutraceuticals, vitamins, minerals | 53 | 10 | 4 | 9 | 3 | 2 | 13 (25) | 32 (60) |
| Blood products | 21 | 3 | 2 | 4 | 0 | 0 | 8 (38) | 14 (67) |
| Oxygen | 15 | 2 | 1 | 6 | 1 | 1 | 6 (40) | 10 (67) |
| Antiviral | 74 | 22 | 8 | 20 | 0 | 2 | 22 (30) | 41 (55) |
| Hydroxychloroquine/ chloroquine | 60 | 10 | 5 | 14 | 4 | 3 | 20 (33) | 35 (58) |
| Multimodal | 48 | 13 | 4 | 11 | 1 | 1 | 14 (29) | 25 (52) |
| Immunomodulatory | 144 | 35 | 5 | 33 | 0 | 2 | 43 (30) | 76 (53) |
| Antiseptic | 10 | 0 | 2 | 2 | 1 | 0 | 4 (40) | 6 (60) |
| Nonpharmacologic | 45 | 2 | 6 | 15 | 4 | 1 | 16 (36) | 25 (56) |
| Anticoagulant | 29 | 5 | 2 | 5 | 0 | 0 | 10 (34) | 15 (52) |
| Convalescent plasma | 63 | 7 | 1 | 11 | 0 | 1 | 11 (17) | 21 (33) |
| Antibiotic | 26 | 4 | 3 | 6 | 2 | 0 | 8 (31) | 12 (46) |
| Antihypertensive | 26 | 3 | 2 | 6 | 1 | 0 | 6 (23) | 10 (38) |
| Other drug treatmentsb | 60 | 8 | 1 | 13 | 0 | 0 | 12 (20) | 19 (32) |
| Nitrous oxide | 9 | 4 | 0 | 4 | 0 | 0 | 5 (56) | 6 (67) |
| Anti-inflammatory | 31 | 10 | 3 | 7 | 1 | 0 | 14 (45) | 17 (55) |
| Device | 32 | 2 | 2 | 13 | 1 | 3 | 13 (41) | 16 (50) |
| Prone positioning | 15 | 0 | 1 | 3 | 1 | 0 | 3 (20) | 4 (27) |
| Steroid | 16 | 2 | 0 | 3 | 0 | 0 | 4 (25) | 5 (31) |
| Total all trials | 847 | 174 | 68 | 213 | 21 | 17 | 366 (43) | 447 (53) |
| Studies without age exclusion | 652 | 119 | 31 | 157 | 16 | 12 | 252 (39) | NA |
| Phase 3 total | 232 | 48 | 12 | 52 | 2 | 4 | 100 (43) | 115 (50) |
| Studies without age exclusion | 194 | 38 | 6 | 42 | 1 | 4 | 77 (40) | NA |
Abbreviation: NA, not applicable.
Total without overlap (1 per trial). Counts can exceed 100% except where indicated.
Other pharmacologic treatments indicate drug categories with fewer than 9 clinical trials.
In 232 phase 3 clinical trials, 38 (16%) included age cut-offs and 77 (33%) had exclusions preferentially affecting older adults; thus, 115 (50%) were considered high risk for excluding older adults. Of 18 vaccine trials, 11 (61%) included age cut-offs, and the remaining 7 had broad nonspecified exclusions; thus, 100% were considered high risk for excluding older adults.
Discussion
Our findings indicate that older adults are likely to be excluded from more than 50% of COVID-19 clinical trials and 100% of vaccine trials. Such exclusion will limit the ability to evaluate the efficacy, dosage, and adverse effects of the intended treatments. We acknowledge that some exclusions for severe or uncontrolled comorbidities will be essential to protect the health and safety of older adults. However, caution must be taken to avoid excluding otherwise eligible participants for reasons that are not well-justified. A limitation of this study is that we did not conduct detailed review of every study protocol; thus, we were unable to fully evaluate the appropriateness of all comorbidity exclusions.
Our concern is more than theoretical. Even without stated age-based exclusions, several recently published clinical trials of COVID-19 treatments had young age ranges, such as 1 recent study4 with a median age of only 40 years, meaning there would be no or few participants over age 75.
If the older age group is excluded from vaccine trials, efforts to ensure effectiveness, titrate dosage or frequency, and assess adverse effects in the group most vulnerable to COVID-19 will not be possible. Antibody responses to vaccines may decrease with age, and can improve with increasing antigen levels, adjuvants, or repeated dosing.5 Some have argued that only vaccination of younger populations is needed to achieve herd immunity (67% level of immunity),6 and therefore, vaccination of older adults is not essential; however, the high level of immunity required, coupled with the fact that many settings (eg, nursing homes) are comprised nearly exclusively of older adults, highlights the imperative for their inclusion in COVID-19 vaccine trials.
With advanced preparation, staff training, and aging expertise, enrollment of older adults is feasible, allowing COVID-19 clinical trials to be as relevant and inclusive as possible.
eMethods
References
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Associated Data
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Supplementary Materials
eMethods