JACC: U.S. trial enrollment small, forced to go offshore
Enrollment in U.S. clinical trials is waning, forcing many to “offshore” clinical research to international participants, according to study results published Aug. 9 in the Journal of the American College of Cardiology. Researchers urged that future research must assess why underenrollment in U.S. trials is so prevalent and an accompanying editorial questioned whether U.S. clinical research has become so “expensive” and “inefficient” that it is no longer a viable competitive enterprise.

“RCTs [randomized controlled trials] provide the evidence base for major societal guidelines and profoundly influence patient care in the U.S.,” wrote Esther S.H. Kim, MD, MPH, of the Cleveland Clinic in Cleveland, and colleagues. “Increased international involvement in clinical trials has been observed, but the rate of international enrollment in NIH [National Institutes of Health]-sponsored cardiovascular RCTs has not been described.

“Subject to intense competition and peer review, NIH-supported cardiovascular [CV] RCTs represent the pinnacle of clinical research and seek to answer critical mechanistic and strategic questions pertinent to the practice of clinical cardiology in the United States,” the authors wrote.

Because NIH-sponsored CV RCTs have not been well-researched, Kim et al searched Phase III or Phase IV CV RCTs funded by the National Heart, Lung and Blood Institute with outcomes of MI, stroke or death between 1997 and 2009. Twenty-four studies met inclusion criteria and 19 trials that enrolled a total of 151,682 patients had international enrollment. Eleven of these trials evaluated coronary artery disease (CAD), three assessed congestive heart failure, six evaluated electrophysiologic disease, one hypertension and three were primary prevention trials.

The researchers reported that the 11 CAD trials had nearly 50 percent international enrollment. Additionally, it was noted that high-risk trials evaluating acute interventions had higher rates of international enrollment. Fifteen percent of the enrollees in NHLBI-sponsored CV RCTs were from outside the U.S.

Due to the fact that these trials need adequate sample sizes, and the fact that U.S. enrollment is often insufficient, international participation has become more prevalent. For example, the recent STICH (Surgical Treatment for Ischemic Heart Failure) trial recruited 80 percent of its subjects from outside the U.S.

“Even in cardiovascular medicine, which has one of the most substantial evidence bases among specialties, only a relatively paltry 15 percent of guideline recommendations are supported by findings from definitive randomized trials,” wrote Robert M. Califf, MD, and Robert A. Harrington, MD, both of Duke University School of Medicine in Durham, N.C., in an editorial. “The widening gap between our need for high-quality evidence and our capacity to produce it is increasingly manifest.”

While international enrollment can be beneficial because it gives an overview of the global CV disease burden, international participation can also be viewed negatively, Kim et al wrote. “The ethical and transparency concerns regarding the conduct of clinical trials in developing countries have been recently highlighted.”

However, Califf and Harrington were not surprised by these trends and said, “When we consider that clinical research offers cardiovascular specialists the chance to lose money, make their practices less efficient, incur risks from regulatory infractions, and contend with reputational problems arising from involvement with industry, we should not be surprised at these trends.”

In fact, of almost 5,000 acute care hospitals in the U.S., Califf and Harrington estimated that only about 5 percent participate in clinical trials. Additionally, Califf and Harrington noted that NIH funding often fails to reimburse costs.

“The NHLBI has an opportunity to lead the way toward a future in which the U.S. clinical research system, instead of becoming an obstacle to be circumvented, participates fully in global efforts to produce relevant, high-quality evidence to guide cardiovascular clinical practice.”

Califf and Harrington suggested several measures to revamp the current NHLBI-sponsored trial process:
  • Separate payment for the proper recruitment, consent and enrollment of research participants and for the collection of high-quality research data from funding for research design and analysis;
  • Ensure that institutions are rewarded separately for these two functions in terms of recognition and academic acclaim as well as funding;
  • Develop networked coordinating centers devoted to the improvement of research across multiple sites, along with the design and analysis of multicenter trials;
  • Participate vigorously with other NIH institutes to solve general administrative issues through the National Center to Advance Translational Science; and
  • Incorporate clinical research within the learning health system, so that evidence generation becomes integral to the culture of clinical practice.

In sum, the authors wrote, “The decreased U.S. participation in NHLBI CV trials is cause for concern.” Kim et al urged academia and medical institutions to recruit U.S. patients into NIH-sponsored trials.