View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 58, No. 7, 2011 © 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2011.03.048 move research to regions that offer efficiencies and cost EDITORIAL COMMENT savings, or both? When an intervention is evaluated outside the environ- American Industry ment in which it will ultimately be used, the results achieved in practice may differ from those observed in trials. Recent and the U.S. Cardiovascular U.S. Food and Drug Administration data show that when multiregional clinical trials are conducted, the magnitude of Clinical Research Enterprise the treatment effect is often smaller for U.S. volunteers compared with participants randomized abroad (3). The reasons for this are not entirely clear, but genetics, practice An Appropriate Analogy?* patterns (including the use of concomitant medications and procedures), environment, culture (including diet), health Robert M. Califf, MD,†‡ care system structure, and the play of chance all likely Robert A. Harrington, MD‡§ contribute to the phenomenon. Durham, North Carolina We also note that clinical research creates attractive, high-paying jobs. Given the current U.S. economic climate, the realization that through National Institutes of Health (NIH) funding, American tax revenues are supporting the The report by Kim et al. (1) in this issue of the Journal export of good jobs abroad may prove economically and documents the increasingly widespread phenomenon of the politically unattractive. “offshoring” of clinical research—in this case, clinical trials Nevertheless, we strongly believe that the globalization of conducted in foreign countries despite being funded by U.S. clinical research is a powerful social good (4) when it stems taxpayers, administered through grants and contracts from from a universal need for collaborative research that informs the National Heart, Lung, and Blood Institute (NHLBI), each country’s practice and reflects the biology of relevant and intended to inform American practice decisions. This populations. But when research is offshored predominantly report is 1 of a number of recent reports that raise the because the U.S. enterprise has become incapable of con- question of whether American clinical research, like many ducting it efficiently, we must focus our attention on fixing other U.S. industries, has become so expensive and ineffi- our own system. cient that it is no longer a viable competitive enterprise The myriad problems besetting American clinical re- within our borders. search are well documented. The system is slow and often fails to meet recruitment targets. It is more costly than other See page 671 systems and suffers from poor quality, as evidenced by high rates of nonadherence to study protocols and treatments and Clinical research provides the quantitative evidence that trial withdrawal by study participants. Furthermore, there is consumers, patients, health care providers, and payers need no reliable indication that the American system produces to weigh risks and benefits when making decisions about data that are of higher quality or better managed than data medical care. Unfortunately, there is a dearth of high- collected outside of the United States. Unsurprisingly, quality evidence to support such decision making. Even in investigators have become discouraged, and an exodus of cardiovascular medicine, which has one of the most sub- talent has recently ensued (5). stantial evidence bases among specialties, only a relatively When we consider that clinical research offers cardiovas- paltry 15% of guideline recommendations are supported by cular specialists the chance to lose money, make their findings from definitive randomized trials (2). The widening practices less efficient, incur risks from regulatory infrac- gap between our need for high-quality evidence and our tions, and contend with reputational problems arising from capacity to produce it is increasingly manifest. The way to involvement with industry, we should not be surprised at bridge this gap, however, is less obvious: should we attempt these trends. Only the intellectual excitement, challenge, to improve U.S. performance in clinical research conduct, and fun of answering critical questions while participating in advancing knowledge keep the investigator pool at its current level. From our experience leading an academic coordinating center for clinical trials, we note that although *Editorials published in the Journal of the American College of Cardiology reflect the there are approximately 5,000 acute care hospitals in the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. United States, only about 5% consistently participate in From the †Division of Cardiology, Department of Medicine, Duke University trials, and 1% account for the vast majority of participant School of Medicine, Durham, North Carolina; ‡Duke Translational Medicine Institute, Durham, North Carolina; and the §Duke Clinical Research Institute, accrual (L. Berdan, personal communication, February Durham, North Carolina. For full author disclosures, please see the end of this paper. 2011). 678 Califf and Harrington JACC Vol. 58, No. 7, 2011 The Offshoring of U.S. Clinical Research August 9, 2011:677–80 Although the many disincentives for participating in gaps. However, industry understandably funds trials most clinical research are plain, the causes underlying the ineffi- likely to provide a return on investment and thus is likely to ciencies of our most powerful academic medical centers, explore questions that differ from those posed by trials which receive the majority of NIH funding, are more designed to investigate issues relevant to the public health. obscure. While the National Cancer Institute has been Additionally, industry-funded trials, which frequently in- evaluating this problem (6) and the NHLBI has initiated its volve contract research organizations, have largely shifted own effort (Clinical Research United in Successful Enroll- away from academic centers and toward the private setting ment) to address the issue, we believe the current situation to avoid challenges in dealing with the complexities of the is actually a predictable by-product of the evolution of former. modern American medical schools. When the NIH Finally, there is a widely held view among leading emerged as the primary funding engine of global basic academic centers that clinical research should not need biological research in the postwar era, schools of medicine institutional support. Before the modern clinical trials era, focused on building capacity to respond to requirements when clinical research was typically a small-shop enterprise imposed by this funding juggernaut. Concurrently, the or even a hobby for interested clinicians, this view might profitability of industry-funded clinical research gave rise to have been justifiable. However, increasingly sophisticated a common assumption that private industry rather than trial methodologies, along with a regulatory regime requir- government could pay for it. Equally important, the con- ing extensive infrastructure and imposing substantial pen- cepts of unbiased evidence generation and clinical effective- alties for failure to ensure quality in data acquisition, data ness, as well as the daunting need for larger sample sizes to analysis, or protection of research participants, have made reliably detect modest treatment effects, had not yet clinical research a professional activity and no longer a emerged (7). pastime for hobbyists. The result of this history is clear to anyone who makes Recognizing that this problem is endemic across special- rounds in our “best” academic medical centers. Little prior- ties and disease areas, former NIH director Elias Zerhouni ity is afforded to clinical research, and faculty members who wisely created the Clinical and Translational Science do participate in multicenter trials get little academic credit Awards to provide a home for clinical and translational unless they lead those trials. Furthermore, “indirect” fund- researchers within academic health and science systems (8). ing from the NIH is often diverted from infrastructure But despite a commitment of $500 million per year, as well needed for clinical research and allocated to support discov- as considerable effort and significant progress in other areas ery science infrastructure. Consequently, there is a prevail- of translation (9,10), there is as yet no evidence that clinical ing notion among many academic medical centers that research has become more efficient. We hope the decision to participation in multicenter collaborative investigations con- place the Clinical and Translational Science Awards under stitutes second-tier research. the new National Center to Advance Translational Science As with all U.S. health care delivery systems, academic signals an intent to hold academic health and science health and science systems are hard pressed to find systems accountable for prioritizing the conduct of efficient efficiencies, and the clinical enterprise has little tolerance clinical trials that generate the medical evidence American for slowing practice to accommodate prolonged consent providers, patients, and policy makers need to make rational processes or for deferring profitable procedures. Despite health