It’s Time to Revamp How Clinical Trials Are Done, Say Cardiology Societies

Despite good intentions, decades-old guidelines on the conduct of clinical trials have become “overinterpreted” to the point of making such research extremely cumbersome and costly: major cardiology societies have come together to advocate for change.

In a “joint opinion,” the European Society of Cardiology, the American Heart Association, the American College of Cardiology, and the World Heart Federation “call for action at a global scale to reinvent randomized clinical trials to be fit for purpose in the 21st century.”

These groups are well suited to make this call because “cardiology has got a really fabulous history of excellent mega trials that have really transformed care,” Louise Bowman, MBBS, MD (Nuffield Department of Population Health, University of Oxford, England), lead author of the paper, told TCTMD. “We’ve kind of led the way, and so I think the cardiology societies feel that they’re in a really strong position to advocate for this. But the intention would be that it goes across all clinical specialties, not just cardiology.”

The viewpoint was co-published in the four flagship journals of the bodies involved in document: the European Heart Journal, Circulation, the Journal of the American College of Cardiology, and Global Heart.

‘Mission Creep’

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) first issued its Good Clinical Practice guidelines in 1996, with the goals of ensuring the safety of trial participants and the reliability of the results.

But in the years since, the process for running clinical trials has become bogged down, “perhaps mostly because of the inappropriate overinterpretation of those guidelines that has built up over the years and resulted in guidelines that are actually quite stifling when the original intention was absolutely very noble,” Bowman said. “I think we’ve had sort of mission creep, if you like, and they have become increasingly burdensome to the point that actually it’s almost unfeasible to run very large trials in a sensible way at times.”

All stakeholders responsible for trials—including investigators, industry sponsors, regulators, and contract research organizations (CROs)—have played a role in this shift in focus toward study-related activities that may not necessarily contribute toward the key aims of ensuring trials are safe and provide clinically useful information.

In addition, according to the joint opinion, past successes in driving down rates of cardiovascular events overall have in turn made it more difficult to assess the impact of new or existing interventions, with larger or longer trials needed to detect significant effects.

“As the size of trials increases, the cost rises, and there may be a temptation to limit the duration of follow-up, in order both to control costs and, from an industry perspective, to get new agents to market faster,” Bowman et al write.

Pandemic Era Shows What’s Possible

The timing of work on this joint opinion was “very good,” Bowman said, “because it then coincided with COVID and a practical demonstration of how, in the case of some of the COVID-19 trials, it was really possible to do excellent, streamlined, highly effective trials that absolutely changed practice very rapidly and most definitely have saved a large number of lives as a result of their findings.” Many of these trials leaned on digital solutions, like mobile app-based data collection, remote monitoring, and virtual trial visits, as well as big, real-world data sources, to make trials more efficient.

“And so I think the societies felt that this was a really opportune moment to highlight that message and also to stress the approaches that are being taken to try to rationalize the guidelines around clinical trials and to demonstrate their support of that activity,” Bowman said.

In the document, the societies express their support for a recent effort by the Good Clinical Trials Collaborative (GCTC), which built on the work of the Clinical Trials Transformation Initiative funded by the US Food and Drug Administration, to revamp guidelines on conducting clinical trials in the 21st century. In the modern era, running trials differs substantially from how they were conducted in 70s and 80s, Bowman said.

She said a key feature of the GCTC guidance, which was released in May 2022, is “proportionality,” or focusing on aspects that matter most in a given trial or situation and not mandating excessive data collection, with the level of detail required adjusted for each individual trial. The guidelines say good RCTs should provide solid answers to relevant questions, respect the rights and well-being of participants, be collaborative and transparent, be feasible within their context, and use effective and efficient quality management.

“The old guidelines still made it very, very hard to undertake low-risk trials with a sensible approach, and I think these new guidelines are very keen to allow more flexibility and to make sure that people really focus on the things that matter, really make sure that everything that’s being done in designing and running a trial is with the end game of getting a reliable result and keeping participants safe, not necessarily ticking a lot of boxes and gathering a lot of paperwork that doesn’t actually meet those goals,” Bowman said.

Role of the Cardiovascular Community

The cardiology societies together “are committed to ensuring that high-quality trials continue to provide randomized evidence that improves the clinical care of all patients across different race and gender identities, socioeconomic strata, and geographies,” according to the joint opinion. They recommend using routinely collected data in electronic health records to ease trial recruitment and follow-up while cautioning against the use of observational analyses to replace RCTs.

“With this document, our societies wish to engage in the development and widespread adoption of consensus guidance for clinical trials, supporting a more-effective regulatory environment and allowing researchers to conduct the trials that are needed to improve patient care much more efficiently,” Bowman et al write.

Without changes in how trials are done, they warn, there may be detrimental impacts on patient outcomes if key clinical questions remain unanswered, either because trials are not performed in a robust way or because they’re not undertaken in the first place.

“There’s been a lot work going into developing new guidance that we hope will start to pave the way to making trials easier and reducing the cost and complexity of trials so that they’re not prohibitive,” Bowman said.