Tuesday, August 2, 2011

Are problems in subject enrollment leading to non applicable results?

International Enrollees May Skew U.S. Trial Results

By Chris Kaiser, Cardiology Editor, MedPage Today
Published: August 01, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points  
  • Explain that the increasing enrollment of international participants in U.S.-sponsored cardiovascular clinical trials has several negative ramifications, including the questionable applicability of the results to the U.S. population.
  • Point out that the area of cardiovascular research with the highest rate of non-U.S. participants was for coronary artery disease (CAD).
The increasing enrollment of international participants in U.S.-sponsored cardiovascular clinical trials has several negative ramifications, including the questionable applicability of the results to U.S. populations, researchers warned. Rates of non-U.S. enrollment were highest in coronary artery disease (CAD) trials (about 50%), followed by high-risk trials, and trials testing acute interventions such as for myocardial infarction, reported Esther S.H. Kim, MD, from the Cleveland Clinic, and colleagues.
To quantify the number of non-U.S. participants in clinical trials, Kim and colleagues searched the National Institutes of Health registry for phase III or IV cardiovascular randomized controlled trials funded by the National Heart, Lung and Blood Institute between 1997 and 2009.
Of 24 studies that met the inclusion criteria, 19 trials with more than 151,000 patients had international participation, with a median rate of 9.5% (range 0% to 100%), according to the study published online in the Journal of the American College of Cardiology.
"The wide heterogeneity in the enrollment of international patients in large cardiovascular randomized clinical trials does not appear to be a fleeting trend," researchers wrote.
They pointed to the FREEDOM trial, a "potentially landmark study" examining optimal management of multivessel disease in diabetics, whose recently completed enrollment includes 81% of non-U.S. participants.
Writing in an accompanying editorial, Robert M. Califf, MD, and Robert A. Harrington, MD, from Duke University, said, "This report is one of a number of recent reports that raise the question of whether American clinical research, like many other U.S. industries, has become so expensive and inefficient that it is no longer a viable competitive enterprise within our borders."
The Duke editorialists wasted no words describing the "myriad problems besetting American clinical research," such as patient compliance and rigorous regulatory strictures.
In addition, the clinical environment is often antagonistic toward research, viewing it as an impediment to efficiency and a threat to profits.
The negative attitude toward research is exemplified by the fact that only 5% of the approximately 5,000 acute care hospitals in the U.S participate in clinical trials, and 1% of them "account for the vast majority of participant accrual," Califf and Harrington noted.
CAD Trials
Of the 24 trials included in this study, there were 11 involving CAD; three on congestive heart failure; six for electrophysiologic disease; one for hypertension; and three on primary prevention.
The overall international participation was 15%, with those dealing with CAD constituting the largest share of participants from outside the U.S.
One NIH-sponsored CAD trial consisted of 100% international participation, with three others enrolling more than half non-U.S. participants at 95.5%, 80%, and 77.5%, respectively.
Two more trials enrolled at least 40% of non-U.S. participants while another selected 36.7%. The lowest rates of non-U.S. enrollments came in at 16.3% and 7.2%.
Only two of the entire 11 CAD trials had no international participation.
Applicability of Results
The enrollment of patients outside the U.S. for trials dealing with other cardiovascular diseases was much smaller, ranging from 0.3% (prevention) to 16.3% (electrophysiology). The one hypertension trial had 15.8% outside participation.
Researchers found a trend toward increased international participation in higher risk trials, such as those testing physically invasive interventions, and trials performed during the acute phase of illness.
Kim and colleagues noted that randomized controlled studies often lead to "Class 1 recommendations in the American College of Cardiology and American Heart Association treatment guidelines."
Yet, questions have been raised regarding the applicability of results from patients in Europe, Asia, and South America to those in the U.S.
"Recent U.S. Food and Drug Administration data show that when multiregional clinical trials are conducted, the magnitude of the treatment effect is often smaller for U.S. volunteers compared with participants randomized abroad," Califf and Harrington wrote.
Kim and colleagues pointed to a number of trials where results from international populations differed from those from the U.S., including:
  • The HERO-2 trial, which showed significant variations in 30-day mortality ranging from 6.7% in Western countries to 10.3% in Latin America and 13.7% in Russia and Asia
  • The PURSUIT trial in which North American participants saw the greatest benefit from the antiplatelet drug eptifibatide (Integrilin) compared with those from Latin America and Eastern Europe
  • The PLATO trial, which showed increased rates of clinical outcomes for all efficacy measures with ticagrelor (Brilinta) over clopidogrel (Plavix) in U.S. participants
In the current analysis, Canada was the most commonly listed international site and enrolled patients for 16 of 24 trials. Even this is troubling, researchers said, as it has been shown that Canadian outcomes have varied from those of U.S. citizens.
For example, Kim pointed to Canada's universal healthcare system, which leads to important differences in care. Her group also noted differences in disease prevalence and presentation between Canadians and people in the U.S.
Not a 'Pastime for Hobbyists'
While international participation in NIH-sponsored research could be beneficial for countries that "do not have the robust research infrastructure of the United States," there are troubling "ethical and transparency concerns regarding the conduct of clinical trials in developing countries," Kim and colleagues said.
But for the U.S. to recoup its leadership, clinical research can no longer be a "pastime for hobbyists" and all aspects of research must be adequately funded, Califf and Harrington said. This includes "separate payment for the proper recruitment, consent, and enrollment of research participants and for the collection of high-quality research data."
They also said they want to see funding for coordinated networks that are dedicated to improving research across multiple sites. Funding would be conditional, and dependent on how well these networks sustain collaboration.
Finally, they called for investment in technologies such as electronic health records that would allow for the collection and analysis of data so that "evidence generation becomes integral to the culture of clinical practice."
Kim and colleagues acknowledged that many U.S. trials open enrollment to international participation because of weak U.S. recruitment. They called for research to determine the reasons for under-enrollment of U.S. patients.

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