Clinical Research Sites—The Underappreciated Component of the Clinical Research System

As the culture of medicine moves toward an evidence-based learning health system, high-quality research is needed to guide choices made by patients, physicians, administrators, and policy makers. However, the system responsible for generating that evidence in the United States is in crisis, as demonstrated by erosions of system efficiency,¹ waning interest in clinical research among practitioners, and financial insolvency among participants in the clinical research enterprise.

Recent efforts have aimed at improving research coordination and data analysis through centralized organization and application of technology, while leveraging databases and registries has achieved an exalted status in comparative effectiveness research. Less attention, however, has been paid to issues surrounding prospective research in the patient care setting, and the fundamental unit of clinical research—the clinical research site (CRS)—has been particularly neglected. Despite their vital contributions, CRSs are largely underappreciated in the clinical research enterprise, toiling in obscurity while others reap the rewards of their efforts.

Many professional CRSs relegate care beyond protocol requirements to the health care system, thus avoiding conflicts of commitment unless a research participant becomes ill and requires immediate medical care. An increasing proportion of clinical research will likely occur amid routine patient care settings due to widespread recognition that knowledge obtained in highly controlled “unnatural” environments may not be generalizable. In an era of comparative effectiveness, patients, physicians and other health care professionals, regulators, and payers are interested in real-world effects on meaningful outcomes, supported by robust evidence. Accordingly, clinical research and care will increasingly take place concurrently within the same system.

Recent media attention has focused on prominent cases in which investigators placed a research study above patients' interests (especially in terms of financial return). Even though such concern remains valid, opposing incentives now apply and compensation for study activities at CRSs often fails to cover the actual costs of research. Moreover, many health care systems are not structured for or institutionally committed to supporting research. Faced with choosing between optimizing practice efficiency in the setting of decreasing reimbursements or assuming additional burdens and risk to participate in research, US clinicians, practices, and health care systems are increasingly opting out of the latter.

Research costs vary according to local markets, and high-cost regions are less financially competitive than low-cost regions. This pressure, combined with increases in bureaucracy in high-cost regions and the imperative to enter new markets, has led to increased off shoring of research.²

With global competition, many US sites are losing money in research activities. The number and complexity of protocol-mandated procedures and criteria are expanding, increasing the length of studies, and significantly affecting workloads.³ Meanwhile, compensation per procedure has decreased.

As awareness of the risks of participating in research has increased, rules governing research conduct have correspondingly proliferated.⁴ Research mishaps offer sensational reading but lost is an understanding of the denominator of transactions in the background of such stories; furthermore, such one-sided discussion may inhibit investigators' willingness to question regulations for the purpose of improving them.

Thus, at present, few regulations governing clinical research are critically evaluated, leaving no empirical case for removing ineffective rules. Accordingly, bureaucratic burdens at CRSs have burgeoned, particularly in North America and Western Europe,⁵ increasing costs, hindering patient access to research, and delaying timely answers to critical questions without commensurate evidence that safety is actually improved.

These burdens are compounded by contract-related and institutional review board (IRB)–related delays. A detailed examination of practices at National Cancer Institute–funded Cooperative Groups⁶ reveals astounding inefficiencies, fueled largely by institutional risk aversion. Many question whether US IRBs are focused on protecting patients or on protecting their institutions from risk.⁷ Informed consent documents required by local IRBs are freighted with complex legal language rather than straightforwardly detailing a study's rationale and potential risks and benefits.

In addition, CRSs exacerbate these problems by failing to appropriately prioritize research, wasting resources on relatively low-quality projects. Despite widespread acknowledgment of these issues, streamlined approaches are lacking to ensure that research dollars are applied to science and evaluation rather than bureaucracy.

Given pressing needs for more efficient processes and greater satisfaction for investigators, staff, and participants, the following changes are proposed:

First, CRSs must apply research- and process-improvement methods to IRBs, contracting, regulations, and sponsor behavior (both industry and National Institutes of Health [NIH]) and focus on training and career development for investigators and research coordinators so that all parties are accountable for efficiently producing high-quality research.

Second, institutions that house research sites in academia and in the broader practice community must become more responsive to the needs of site-based research, paying particular attention to systems and policies governing contracting and IRB issues. The fundamental need is to improve efficiency without harming patient protections, increasing institutional legal exposure, or jeopardizing data quality. Furthermore, administrators should be accountable for unjustified delays and obstruction to research activities.

Third, clinical research should be explicitly identified as a key mission of health systems and practices and should be incorporated into the balanced scorecard that drives the behavior of hospital and health care system leadership. If research is treated as an imposition on efficient provision of health care rather than an integral element of modern learning health systems, the current decline of the research enterprise will continue or accelerate.

Fourth, institutions housing CRSs must establish clear processes for reviewing and assigning priority to research projects to avoid wasting resources on poorly designed investigations that add to the total burden of central oversight and impede other research critical to the public health.

Fifth, a significant educational campaign is needed to improve public understanding of clinical research and its importance to the health of individuals, their families, and their communities. A complementary campaign at academic medical centers and schools of medicine should reinforce the value of patient-oriented research to students and trainees in all health care disciplines.

Given the interlocking nature of the current research system, collaborative efforts involving multiple stakeholders are needed. The NIH, through its Clinical and Translational Science Award program (http://www.ctsaweb.org), is taking an interdisciplinary approach in transforming the clinical research enterprise at NIH-funded institutions; these efforts are implemented through collaborative projects that share knowledge and best practices. Within the NIH, the National Cancer Institute is engaged in restructuring initiatives, including study standardization and improvement of operational efficiency, and seeks to reduce study activation time by at least 50%, increase the percentage of studies reaching accrual targets, and improve timely trial completion. Importantly, the US Department of Justice confirmed that the development of standards for clinical research contracts does not violate antitrust laws.⁸ With nearly 1900 US sites participating in National Cancer Institute trials, the potential effects of these streamlining efforts are significant.

The Clinical Trials Transformation Initiative (CTTI) is a public-private partnership that includes government, practice, academia, the medical products and clinical research industries, and patient advocates⁹ that seeks to identify practices that will increase the quality and efficiency of clinical trials. Its efforts are complemented by the Sensible Trials Guidelines group, which focuses on international efforts to streamline clinical trial activity. The concentrated efforts of the United Kingdom directed at “bureaucracy busting” are especially notable.¹⁰

No amount of lofty concern with central oversight and coordination nor efforts to circumvent prospective research in the patient care setting through professional research sites or database analyses can overcome a failure to focus on the essential transaction between patient and investigator at a research site. By comprehensively addressing these issues through practical incentives and improved business procedures, patients, investigators, and study teams can be liberated from laboring at poorly rewarded, pointlessly burdensome tasks. All participants in clinical research must be regarded as the essence of dignity, and institutional and health care system leaders must be accountable for supporting them so that their efforts will inform society about the risks and benefits of health interventions and will serve as the foundation for the modern learning health care system.