Imagine the end of the pandemic — with new cases and deaths trending down towards zero — a time we are all eagerly anticipating. Key to achieving this goal will be the development of effective treatments and vaccines. Yet, based on a research study my team and I have conducted, older adults, particularly those in their 70s and 80s, may be systematically excluded from the clinical trials necessary to develop and test them.
And yet, those same people are the group hardest hit by the pandemic. Adults 65 and older currently account for 40% of the hospitalized cases and over 80% of the deaths related to COVID-19.
A History of Excluding Older Adults From Clinical Trials
Unfortunately, there is a long history of exclusion of older adults from clinical trials, such as those for heart disease, cancer and diabetes. In fact, this reality resulted in the National Institutes of Health instituting a policy in 2018 requiring inclusion of older adults in clinical trials in order to obtain federal funding.
Our results demonstrated that older adults are highly likely to be excluded from 53% of 847 COVID-19 clinical trials that qualified for detailed review.
Given this new policy, along with the demographic realities of COVID-19, the imperative for including older adults in the coronavirus vaccine clinical trials seemed clear. However, the early clinical trials have largely failed to include them.
I became very concerned that in the rush to find effective drugs and vaccines for COVID-19, older adults might be pushed to the side and excluded from clinical trials, either purposefully or inadvertently.
To explore this possibility, I undertook a study with my research team to review all of the 1,000+ COVID-19 clinical trials registered at Clinicaltrials.gov (as of June 1, 2020). We wanted to see whether people over 65 would be excluded either directly, based on age criteria, or indirectly, based on exclusions that would tend to affect older adults. The study team included Benjamin Helfand of the University of Massachusetts Medical School; Margaret Webb, Sarah Gartaganis and Lily Fuller of Hebrew SeniorLife and Dr. Churl-Su Kwon of the Icahn School of Medicine at Mount Sinai.
Findings From My Team’s Research Into COVID-19 Vaccine Trials
Published Sept. 28, 2020 in JAMA Internal Medicine, our results demonstrated that older adults are highly likely to be excluded from 53% of 847 COVID-19 clinical trials that qualified for detailed review.
Of these, 23% had an age-based cutoff; an additional 30% had an indirect exclusion, such as a comorbidity or lack of technology (like internet or smartphone), that would be more likely to affect older adults.
Importantly, older adults are highly likely to be excluded from 100% of 18 vaccine trials — 61% for an age-based cutoff and 39% for an indirect exclusion.
Finally, in a separate review of 232 Phase III clinical trials, which are intended to include older adults, 50% are still likely to exclude them either due to age (17%) or for indirect reasons related to their age (33%).
Coronavirus vaccine makers have not said much about enrolling people 65+ other than they’re trying to include them in their big, current, Phase III trials.
Yet there are reports that they’re not succeeding in including many older adults and diverse populations.
One New York Times reader, commenting on a Times story about coronavirus vaccine participants, said: “I was excited to sign up for a Covid vaccine trial here in Philadelphia that was just for the 65 and older crowd… I am a healthy oldster who takes no medication with the exception of Tamoxifen for the breast cancer I had 4 years ago. I passed the online as well as the phone screening and gave permission for my medical records to be reviewed. Subsequent to that, I received an email saying that I did not qualify for the trial.” It’s possible that her breast cancer, even in remission, might have been considered too serious of a comorbidity.
What the FDA Says About Including Older Adults
Recent guidance from the federal Food and Drug Administration (FDA), which regulates vaccines, “strongly encourages” the inclusion of diverse populations in clinical vaccine development. That includes racial and ethnic minorities, older people and those with underlying medical problems, as well as pregnant women.
But the FDA does not require drugmakers and researchers to meet those goals, and will not refuse trial data that doesn’t comply. Nor are pharmaceutical firms required to publicly disclose their demographic goals.
Of course, there is no question that some exclusions are needed to protect the health and safety of older adults — such as severe or unstable comorbidities.
However, based on my expertise as a physician specializing in internal medicine and geriatric medicine and as someone who has conducted clinical trials and studies in older adults for over 30 years, I would say that many of the exclusions were not well-justified. They often appear to be more for convenience of the people and companies running the vaccine trials.
For example, it would be hard to justify as a standing exclusion stable hypertension that is being treated. It’s a condition present in over half of older adults and often well controlled with medications.
Why Some People 65+ Are Being Left Out of the COVID-19 Trials
In the rush to develop a vaccine, older adults may have been excluded because of the concern that they might slow down the enrollment process, since they may require accommodations (like hearing aids, large print forms or mobility assistance).
Moreover, older adults may suffer more side effects to the vaccine compared with young healthy adults, which could slow down the process for FDA approval.
In reality, with the appropriate amount of time and staffing, taking into account accommodations and possible side effects might not delay clinical trials much at all. But if those running the trials didn’t have the expertise or didn’t devote resources to it, then perhaps the vaccine trials might be delayed by months.
It would be fair to exclude people where the clinical trial would be unsafe, such as those with severe or unstable comorbidities like kidney or liver failure. In those types of cases, metabolizing the treatment might be impaired by a vaccine trial.
Other real-world factors may require extra steps, which the developers of the treatments may not be willing to take. But excluding older people who could be in the trials will result in missing the mark for these key treatments and vaccines.
The Downside of Leaving Out Older Adults
The reality is that exclusion of older adults from clinical trials will systematically limit our ability to evaluate the efficacy, dosage and adverse effects of COVID-19 treatments and vaccines in the population at highest risk.
For instance, the inclusion of older adults in vaccine trials will allow for assuring effectiveness in this population.
Antibody responses to vaccines can be decreased in older adults, and improved with increasing dosage, adding enhancers or repeating administration. But these approaches cannot be applied or tested without including older adults in clinical trials. Moreover, assuring safety in older adults cannot happen without their inclusion as well.
My research team’s biggest concern is that without clinical trial testing, older adults will ultimately be denied treatments and vaccines — such as due to safety concerns. As a result, equitable distribution to this population will not be possible. An egregious oversight.
Many, though not all, older adults are willing and able to be enrolled into clinical trials. And enrollment challenges can be readily addressed with advance preparation, appropriate staff training and equipment and involving experts in aging research.
What Needs to Happen
This will not happen, however, until investigators make inclusion a priority.
Older adults are the major stakeholder group who will benefit from finding effective treatment options for COVID-19, and their enrollment will ultimately benefit themselves, their family and society at large.
Now, more than ever, we must involve the target population in the development and testing of effective treatments. Involvement of geriatricians or those with aging expertise can assist with enrollment and safe management of older adults in clinical trials.
While requiring some extra time and effort, this will be counterbalanced by the immeasurable increase in validity and usefulness of the results, with immediate applicability to the major target population.
However, this will not occur without forethought and intent, and a priority to make COVID-19 clinical trials as relevant and inclusive as possible.
It’s the right thing to do; let’s find the way to get it done.
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