Clinical research for the next 20 years
Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.
Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.
RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.
“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.
RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.
Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.
“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
Time to be inclusive
Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.
“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.
“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”
In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”
The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.