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 care decisions. the widely touted tripartite mission of clinical care, The NHLBI has an opportunity to lead the way toward research, and education, clinical investigators and study a future in which the U.S. clinical research system, instead coordinators usually work without support from their of becoming an obstacle to be circumvented, participates hospital units and clinics; in fact, the relationship is often fully in global efforts to produce relevant, high-quality adversarial, because the clinical care enterprise regards evidence to guide cardiovascular clinical practice. We sug- research as impeding efficiency and thus threatening its gest the following measures: profitability. Several critical misconceptions underlie this systemic 1. Separate payment for the proper recruitment, consent, failure. Previously, the large profits produced by cardio- and enrollment of research participants and for the vascular practices meant that the NIH could count on collection of high-quality research data from funding for significant cost sharing for clinical research; conse- research design and analysis. These activities entail quently, NIH funding often fails to adequately reimburse different skills, and rewarding the latter while marginal- costs. Presently, however, while the hospital-facility side izing the former (11) will ensure further deterioration of of U.S. cardiovascular medicine is profitable, the physi- our capacity and accelerate the offshoring of vital re- cian–clinical delivery side breaks even at best. And search. because salaries are flat or declining, there are no excess 2. Ensure that institutions are rewarded separately for monies for cost sharing. these 2 functions in terms of recognition and academic Another canard is the idea that a portfolio including acclaim as well as funding. Importantly, NIH funding industry-sponsored research can ameliorate these funding is increasingly segregated into “haves” and “have- JACC Vol. 58, No. 7, 2011 Califf and Harrington 679 August 9, 2011:677–80 The Offshoring of U.S. Clinical Research

nots,” with the former characterized by the enormous health care. But if we do succeed in an essential transfor- basal infrastructures needed to compete in discovery mation of the clinical research system, we can renew a science. If funding is allocated for site-based research, tradition of innovation and leadership while participating in which does not require this infrastructure, the “have- critical global efforts to better understand the prevention nots” should be able to compete effectively for NIH and treatment cardiovascular disease around the world funding within this system, thereby allowing the (12,13). development of a group of committed sites, investiga- tors, and study coordinators while also providing Author Disclosures resources to build systems enabling recruitment, data Dr. Califf has received research grants from Amylin, collection, and quality assurance. J&J-Scios, Merck, Novartis Pharma, and Schering- 3. Develop networked coordinating centers devoted to Plough; consulting fees from Heart.org, Kowa Research the improvement of research across multiple sites, Institute, Nile, Parkview, Orexigen, Sanofi Aventis, along with the design and analysis of multicenter XOMA, and the University of Florida; and has equity in trials. These centers should be required as a condition NITROX LLC. Dr. Harrington has received research of funding to develop and sustain methods of collab- grants from Baxter, Bristol Myers-Squibb, CSL Limited, oration with other coordinating centers and with GlaxoSmithKline, Luitpold, Merck, Novartis, Otsuka, site-based research organizations. This will necessitate Portola, Sanofi-aventis, and The Medicines Company; an investment in technological tools, including those and consulting fees from AstraZeneca, APT Nidus, afforded by social networking, to encourage and foster Baxter, Bristol Myers-Squibb, CSL Behring, Cortex, these collaborations. Eisai, Gilead Sciences, Johnson & Johnson, Lilly, Merck, 4. Participate vigorously with other NIH institutes to Mitsubishi-Tanabe, Novartis, Orexigen, Pfizer, Portola, solve general administrative issues through the Na- Regado Biosciences, Regeneron, Sanofi-aventis, and the- tional Center to Advance Translational Science. The heart.org imperatives to address excessive delays in institutional review board review and contract approval, clarify Reprint requests and correspondence: Dr. Robert M. Califf, billing issues and management of indirect costs, and Duke University School of Medicine, 1117 Davison Building, 200 develop common metrics for quality and efficiency in Trent Drive, Durham, North Carolina 27710. E-mail: research are not disease specific, and common solu- [email protected]. tions customized to suit special needs will likely prove effective. This would entail working with U.S. De- REFERENCES partment of Health and Human Services to develop smoother collaboration among federal organizations 1. Kim ESH, Carrigan TP, Menon V. International participation in cardiovascular randomized controlled trials sponsored by the Na- and agencies, most particularly the Food and Drug tional Heart, Lung, and Blood Institute. J Am Coll Cardiol Administration, which has regulatory oversight of 2011;58:671–6. industry-sponsored clinical research. 2. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines (erra- 5. Incorporate clinical research within the learning tum in JAMA 2009;301:1544). JAMA 2009;301:831–41. health system, so that evidence generation becomes 3. Hung HMJ. MRCT planning: a regulatory view. Paper presented at: integral to the culture of clinical practice. This effort, Asia-Pacific Economic Cooperation Multi-Regional Clinical Trials (APEC MRCT) Workshop; September 13, 2010; Seoul, South Korea. which should be led by the NHLBI, would use Available at: http://www.apec-ahc.org/files/tp201002/Session1_ electronic health records and registries as the primary JamesHung.pdf. Accessed February 21, 2011. substrates for data collection, significantly enhancing 4. Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientific implications of the globalization of clinical research. N Engl efficiency and reducing costs to systems burdened by J Med 2009;360:816–23. redundant data systems and procedures. In addition to 5. Getz K. Number of active investigators in FDA-regulated clinical trials drop. Tufts Center for the Study of Drug Development CSDD reducing reliance on clinical data reentry into research Impact Report 2005;7:1–4. records, it should markedly reduce costly on-site 6. National Cancer Institute. A conversation with Dr. James Doroshow monitoring visits, because data quality can be reviewed about NCI’s Clinical Trials Cooperative Group Program. NCI Cancer Bull 2010;7. Available at: http://www.cancer.gov/ncicancerbulletin/ centrally using statistical outlier detection and process 121410/page4. Accessed February 21, 2011. control. 7. Yusuf S, Wittes J, Bailey K, Furberg C. Digitalis—a new controversy regarding an old drug. The pitfalls of inappropriate methods. Circu- This report by Kim et al. (1) represents a wake-up call. If lation 1986;73:14–8. we fail to heed it, we may see the U.S. clinical research 8. Zerhouni EA. Translational and clinical science—time for a new vision. N Engl J Med 2005;353:1621–3. enterprise go the way of so many other American industries: 9. Reis SE, Berglund L, Bernard GR, et al. Reengineering the national lost to more efficient overseas competitors. Such an outcome clinical and translational research enterprise: the strategic plan of the would be more than an economic disaster. It would also National Clinical and Translational Science Awards Consortium. Acad Med 2010;85:463–9. deprive the American public of relevant, high-quality evi- 10. Califf RM, Berglund L. Principal Investigators of National Institutes dence essential for making appropriate decisions about of Health Clinical and Translational Science Awards. Linking scien- 680 Califf and Harrington JACC Vol. 58, No. 7, 2011 The Offshoring of U.S. Clinical Research August 9, 2011:677–80

tific discovery and better health for the nation: the first three years of 13. DeMets DL, Califf RM. A historical perspective on clinical trials the NIH’s Clinical and Translational Science Awards. Acad Med innovation and leadership: where have the academics gone? JAMA 2010;85:457–62. 2011;305:713–4. 11. Califf RM. Clinical research sites—the underappreciated component of the clinical research system. JAMA 2009;302:2025–7. 12. Califf RM, Armstrong PW, Granger CB, et al. Towards a new order in cardiovascular medicine: re-engineering through global collabora- Key Words: clinical trials y internationality y National Institutes of tion. Eur Heart J 2010;31:911–7. Health.