Low US Participation in NIH-Sponsored CVD Trials Cause for Concern

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Randomized trials investigating cardiovascular therapies sponsored by the National Heart, Lung, and Blood Institute (NHLBI) show high rates of international patient enrollment, raising concerns over low US participation, according to a meta-analysis published in the August 9, 2011, issue of the Journal of the American College of Cardiology. The authors say this trend is particularly worrisome in trials focusing on acute disease and high-risk interventions.

Researchers led by Venu Menon, MD, of the Cleveland Clinic (Cleveland, OH), analyzed all NHLBI-funded phase III or IV cardiovascular randomized, controlled trials with outcomes focusing on MI, stroke, or death published between 1997 and 2009. There were 24 trials meeting the inclusion criteria: 11 CAD trials, 6 electrophysiological disease trials, 3 CHF trials, 3 primary prevention trials, and 1 hypertension trial. Nineteen of the trials (n = 151,682) had at least some OUS enrollment. The median international participation rate was 9.5%, with 15% of all participants in NHLBI-sponsored CV trials from outside the United States.

International participation ranged from 100% for M-HART (Montreal Heart Attack Readjustment Trial) to 0 for 5 trials: ACES (Azithromycin in Coronary Events Study), ENRICHD (Enhancing Recovery in Coronary Heart Disease), FAAT (Fatty Acid Antiarrhythmia Trial), REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure), and WHI (Women’s Health Initiative).

Highest OUS Rates for CAD Trials

Stratified by condition, CAD trials were shown to have the highest median rates of international participation (11 trials, 42.0%). Categorized by acuity and risk, studies involving acute disease (10 trials, 23.0%) and high-risk invasive procedures (9 trials, 9.7%) had the highest OUS participation.

Nine of the 11 CAD trials had international participation, and half of all patients enrolled in these trials were from outside the United States. Overall, Canada was the most common non-US site listed among the trials included in the study.

Revascularization trials with high rates of international participation included BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes; 36.7%), OAT (Occluded Artery Trial; 77.5%), SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock; 42.1%), and STICH (Surgical Treatment for Ischemic Heart Failure; 80.0%).

International Enrollment: Pros and Cons

There are a number of potential benefits with international trial enrollment, the authors note. For instance, by participating in research sponsored by the National Institutes of Health (NIH), smaller countries with less developed infrastructure can participate in rigorously conducted trials, exposing researchers there to best practices and cutting-edge treatments and interventions. International participation may also enable trials to enroll sufficiently large patient populations in a timely manner.

However, “increasingly, [international participation] in clinical trials may also be perceived negatively,” Dr. Menon and colleagues write.

There are both ethical and transparency issues with clinical trial practices in developing countries. In addition, increased international participation in NIH trials may also present problems for the generalizability of results and obscure any treatment effect and interfere with physician adoption when applied to US patients. This is especially true since there is geographic variability in baseline patient characteristics, background medical therapy, and clinical follow-up, all of which influence outcomes.

Still, the United States boasts many fine academic medical institutions, and NIH trials are clinically relevant and represent vital CV health issues.

“Why, then, is an important trial such as STICH able to enroll only 200 patients in a country of 308 million, when Poland, with a population of 38 million, enrolls 288 subjects?” the authors ask. “Similarly, overall US enrollment in OAT is 488 at 83 sites, compared with 450 at 27 sites in Canada.”

‘Nearing a Crisis’

While acknowledging that “patient enrollment in clinical trials in the United States can be a difficult task and that many of the trials in this study opened recruitment outside the United States because of inadequate enrollment at US sites,” the authors recommend that “research into the reasons for the underenrollment of US patients in these critical clinical trials is urgently warranted.”

“Clinical research in the United States is nearing a crisis level,” Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), commented in an e-mail communication with TCTMD. “Enrolling patients in clinical trials in the United States has never been more difficult because of the time and money required, regulatory oversight, punitive environment, lack of personal and academic recognition/satisfaction, and the numerous other pressures the average physician is facing which thrusts clinical research to the background.”

Harlan M. Krumholz, MD, SM, of Yale University School of Medicine (New Haven, CT), took a more global view of the study findings. “The central question for me is how best to think about the generalizability of this research,” he said in an e-mail communication with TCTMD. “There is a need for studies that can be applied in a variety of settings and venues. For the global population we need insight about whether there are reasons to believe that some strategies are more effective in some settings than others.”

Dr. Krumholz added that ideally, large studies should have the capacity to assess if there are effects that are specific to certain health care systems or venues. “Unfortunately, the current studies lack that power—and so questions are raised when there is the possibility that effect varies by country or health care system,” he said, noting that the result is uncertainty. “For example, do studies of an anti-anginal agent that are conducted in Eastern Europe have relevance to patients receiving contemporary care in the United States? It is hard to know.”

US Clinical Research: Outsourced

In an accompanying editorial, Robert M. Califf, MD, and Robert A Harrington, MD, both of Duke University Medical Center (Durham, NC), deliver a stinging indictment of the US clinical research system. “This report is 1 of a number of recent reports that raise the question of whether American clinical research, like many other US industries, has become so expensive and inefficient that it is no longer a viable competitive enterprise within our borders,” they write.

Drs. Califf and Harrington acknowledge that globalization of research can be a strong force for social good, but the reality is that “clinical research creates attractive, high-paying jobs,” and that “through [NIH] funding, American tax revenues are supporting the export of good jobs abroad. . . .  [W]hen research is offshored predominantly because the US enterprise has become incapable of conducting it efficiently, we must focus our attention on fixing our own system.”

“Drs. Califf and Harrington are right on in their comments,” Dr. Stone said. “This environment is stifling innovation, costing the United States jobs and loss of prestige as the world leader in quality medicine, research, and innovation. Physicians and patients are already looking to Europe and elsewhere for cutting-edge therapies, and a cottage industry is developing to supply overseas care to US patients.”

Fixing the System

The editorial suggests implementing several steps so that the US clinical research system will no longer be “an obstacle to be circumvented.” These include:

• Pay for recruitment, consent, and enrollment of research participants as well as collection of high-quality data that is separate from funding for research design and analysis
• Reward institutions separately for these 2 functions in terms of recognition and academic acclaim in addition to funding
• Develop networked coordinating centers devoted to the improvement of research across multiple sites
• Participate with other NIH institutes to solve general administrative issues
• Incorporate clinical research within the health care system so that evidence generation becomes integral to the culture of clinical practice

The current report, Drs. Califf and Harrington conclude, “represents a wake-up call. If we fail to heed it, we may see the US clinical research enterprise go the way of so many other American industries: lost to more efficient overseas competitors.”

“Most importantly, the unparalleled gains we have achieved in reducing the burden of cardiovascular disease in the United States over the last 3 decades will not be continued in the future,” Dr. Stone added. “The solutions to reverse this are complicated and will require a readjustment in priorities with major reform from every facet of our society and political system, from training curricula in medical school to legislation in Congress to a new positive direction from the media and our professional societies.”

Sources:
1. Kim ESH, Carrigan TP, Menon V. International participation in cardiovascular randomized controlled trials sponsored by the National Heart, Lung, and Blood Institute. J Am Coll Cardiol. 2011;58:671-676.

2. Califf RM, Harrington RA. American industry and the US cardiovascular clinical research enterprise. An appropriate analogy? J Am Coll Cardiol. 2011;58:677-680.

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