Designing a successful clinical trial requires strategic thinking regarding all aspects of the study. Beyond enrollment criteria and endpoints, these include establishing a collaborative leadership team and enrolling diverse patient sites. To that end, many physician scientists are adding another crucial consideration into their trial design: patient demographics.
Elisabeth Fall
Maureen Kohi, MD, FSIR
That’s the genesis behind the ELEGANCE trial, led by Maureen P. Kohi, MD, FSIR, and sponsored by Boston Scientific. The ELEGANCE registry will look at outcomes in patients with peripheral arterial disease (PAD) who have undergone intervention for lesions in the peripheral vasculature using Boston Scientific drug-eluting devices—while pledging to enroll at least 40% women and 40% underrepresented minorities into the registry.
The problem with PAD data
PAD is an extremely common and fast-growing disease worldwide. In the United States, it is estimated that 4–10% of adults aged 40 or over are affected by PAD, and the incidence increases with age.1 Current data estimates that over 200 million people worldwide are impacted by PAD.2
“Since 1990, there has been a significant increase in the absolute numbers of PAD worldwide,” said Dr. Kohi. “This translates into approximately 75,000 annual deaths, half a million years lived with disability and over a million years of life lost.”
According to Dr. Kohi, there has been a longstanding belief that PAD is a “man’s disease.” “This myth is simply not true,” she said. “Recent data demonstrates that women have a higher incidence and prevalence of PAD compared to men. Interestingly, women in their mid-80s are more likely to die of PAD compared to similar-aged men.”
Emerging data indicates that women may have different outcomes following PAD intervention, Dr. Kohi said. “A recent publication demonstrated that, compared to men, women had a higher risk of periprocedural complications such as moderate or severe access site bleeding, above-knee amputation and in-hospital mortality following peripheral vascular interventions.”
Dr. Kohi also states that there are racial and ethnic disparities in PAD. “Several studies have demonstrated that Black Americans are disproportionately affected by PAD and are less likely to be diagnosed and treated compared to non-Hispanic white patients.”
However, these realities are not reflected in much of the research being conducted, Dr. Kohi says. Despite comprising half of the U.S. population, women typically make up about 25% of participants in medical device trials, and Black Americans comprise only 5–7% of clinical study participants.7
It’s a glaring discrepancy, according to Dr. Kohi. “When you look at clinical trials in PAD, you find that about 70–80% of the population of patients in the clinical trial are white men.”
This poses a problem when trying to analyze data to see the impact by demographics—even subgroup analyses are fruitless when the sample size is so small.
There has long been a call for PAD studies to reflect these demographics, Dr. Kohi says. The American Heart Association has called for the inclusion of more women in PAD trials, and the National Institutes of Health released guidelines for making clinical trials inclusive of women and minorities.8,9
But this isn’t happening, for a multitude of reasons. Trials are expensive, and investigators are often very focused on recruitment and completion.
“We have to make sure that the populations we study are representative of the disease and reflective of our patients,” she said. “We should not conduct PAD trials with only 20% women.”
The ELEGANCE Registry—or the Drug-Eluting Registry: Real World Treatment of Lesions in the Peripheral Vasculature—aims to collect real-world data which includes populations previously not accurately represented in peripheral vascular disease trials.10
An observational trial, ELEGANCE is an open registry that aims to enroll up to 5,000 subjects at 100 global sites.
“What sets this trial apart from all the other PAD trials to date is the promise that we’re going to enroll at least 40% women and at least 40% underrepresented minorities,” said Dr. Kohi. “That’s never been done before.”
How to curate a diverse patient demographic
Trickle-down leadership
The first step, according to Dr. Kohi, was creating a diverse steering committee with more than 50% of leadership positions occupied by women and underrepresented minorities.
Diverse leadership has trickle-down implications: 41% of the sites participating have diverse principal investigators who are committed to the recruitment of diverse patients.
“The goal is to create the ability for our underrepresented and diverse patients to connect with physicians with whom they can identify and relate,” Dr. Kohi said.
Yolanda Bryce, MD
Yolanda Bryce, MD, who hopes to become a site principal investigator (PI) for the ELEGANCE trial once recruitment opens again, agrees. “There have been studies that demonstrate women have a better chance at recruiting patients. And also for patients from underrepresented minorities, if they see another minority as a PI, there is a higher chance of them joining studies.”
Connecting with patients
Patient connection is key to the recruitment process, Drs. Bryce and Kohi said.
“At each site, we have informational pamphlets about ELEGANCE which our investigators can use to better educate patients about the trial and help breakdown any mistrust they may have about participating in a clinical trial,” Dr. Kohi said.
In addition, we provide specialty training to the research coordinators to ensure they have the tools to successfully recruit diverse patients into the trial.
“I wanted to take part in ELEGANCE because a lot of my patients are women or underrepresented minorities,” Dr. Bryce said. “I’ll be using these devices on them either way; the difference is just that, with enrollment, their data can be collected.”
Industry partnerships
According to Dr. Kohi, ELEGANCE is an excellent example of partnership between industry and physicians.
“This is the only PAD clinical trial of its size that is female-led,” Dr. Kohi said. “Having industry support our study and prioritize a diverse steering committee shows that they’re very serious and passionate about diversity and inclusion and know how impactful this is for physicians and patients.”
That passion is shared by all involved in the trial, Dr. Kohi says. It’s driven the commitment on the physician side to recruit as many URM and women as possible, because everyone involved understands the impact of the data.
Recreating the model
While ELEGANCE may be unique in its enrollment pledge, Drs. Kohi and Bryce are hopeful that many trials going forward will include similar goals.
Dr. Bryce has already begun implementing demographic end goals on her own research. She is currently working on a PAD screening trial, which will be beginning soon and will aim to sample Black patients so they represent 25% of the study population. Though her trial and the ELEGANCE registry are the first studies she’s been involved in with these kind of enrollment goals, she believes they’re unlikely to be the last.
“The NIH has begun mandating that for grant funding, you have to provide percentages of the different demographics you’re hoping to enroll,” Dr. Bryce said. “The world is moving that way anyway, because it doesn’t make sense to fund a large trial if the results aren’t generalizable. And in order to move forward as physicians and scientists, we have to make sure that our studies will evoke results that help a big portion of our patients. Not just a fraction.”
It’s a simple model that should be easily replicated, Dr. Kohi says, but physicians may have to be more dedicated to ensuring studies become more diverse from the top-down.
“We may have to become more draconian,” she said. “When we, as PIs, are approached by industry and asked to be involved in trials, we should ask to see the makeup of the steering committee and the suggested PIs and sites. And if the leadership, the PIs and the sites are not diverse, we should not participate in the study.”
ELEGANCE outcomes
In advocating for more diverse trials, physician researchers may be able to point to the success of the ELEGANCE registry, which has successfully completed its enrollment goal: As of July 2022, 46 sites and 579 patients were enrolled, of which 41.6% are women and 40.6% are underrepresented minorities.10
“When we first started, people would ask ‘Well, what if you fail?’” Dr. Kohi said. “Failure was never an option. There was never a doubt in my mind that we wouldn’t succeed and so far we have surpassed our goal. Now all we need to do is to continue and show the rest of the scientific community that such a trial design is possible and should be the new norm.”
References
- Aday AW, Matsushita K. Epidemiology of peripheral artery disease and polyvascular disease. Circ Res. 2021; 128:1818–1832. doi: 10.1161/CIRCRESAHA.121.318535.
- Lin J, Chen Y, Jiang N, Li Z and Xu S. Burden of peripheral artery disease and its attributable risk factors in 204 countries and territories from 1990 to 2019. Front. Cardiovasc. Med. 2022;9:868370. doi: 10.3389/fcvm.2022.868370.
- Altin SE, Gitto M, Secemsky EA, Rao SV, Hess CN. Sex-based differences in periprocedural complications following lower extremity peripheral vascular intervention. Circ Cardiovasc Interv. 2022;15(8):e011768. doi: 10.1161/CIRCINTERVENTIONS.121.011768.
- Hackler EL, Hamburg NM, White Solaru KT. Racial and ethnic disparities in peripheral artery disease. Circ Res. 2021 Jun 11;128(12):1913-1926. doi: 10.1161/CIRCRESAHA.121.318243.
- Shu J, Santulli G. Update on peripheral artery disease: Epidemiology and evidence-based facts. Atherosclerosis. 2018 Aug;275:379-381. doi: 10.1016/j.atherosclerosis.2018.05.033.
- Virani SS, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation. 2020;141:e139–e596. doi: 10.1161/CIR.0000000000000757.
- Clark LT, Watkins L, Piña IL, Elmer M, Akinboboye O, Gorham M, Jamerson B, McCullough C, Pierre C, Polis AB, Puckrein G, Regnante JM. Increasing diversity in clinical trials: Overcoming critical barriers. Curr Probl Cardiol. 2019 May;44(5):148-172. doi: 10.1016/j.cpcardiol.2018.11.002.
- Hirsch AT, Allison MA, Gomes AS, Corriere MA, Duval S, Ershow AG, Hiatt WR, Karas RH, Lovell MB, McDermott MM, Mendes DM, Nussmeier NA, Treat-Jacobson D; on behalf of the American Heart Association Council on Peripheral Vascular Disease, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology, and Council on Epidemiology and Prevention. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation. 2012. doi/10.1161/CIR.0b013e31824c39ba.
- National Institute on Minority Health and Health Disparities. Resource: Diversity and inclusion in clinical trials. 2022. nimhd.nih.gov/resources/understanding-health-disparities/diversity-and-inclusion-in-clinical-trials.html.
- Boston Scientific. ELEGANCE patient registry focuses on women and people of color to address inequities in the treatment of peripheral arterial disease. May 2021. news.bostonscientific.com/ELEGANCE-Patient-Registry#_edn1.
