A Virtual National Laboratory for Reengineering Clinical Translational Science

Summary

Clinical research is burdened by complex pathways, tedious steps, numerous inefficiencies, and a poor track record of trial completion. The CTSA Program’s consortium supports a unified national effort that has become, in effect, a virtual national laboratory designed to identify, implement, evaluate, and continue process improvement across all the steps required to design, approve, initiate, and complete clinical trials. If it is properly supported by academic centers, industry, and funding agencies, the virtual national laboratory could succeed in advancing and maintaining major improvements in clinical trial conduct and efficiency.

Translational research is the process of taking biomedical laboratory findings through preclinical and clinical testing into treatments in the community and ultimately into improved population health. It encompasses all of the research steps required to support the entire continuum from discovery to standard clinical practice and measures of effectiveness. The translational process has become sufficiently complex, slow, and frustrating that it constitutes a major challenge facing science and society in the early 21^st century^1-5. Indeed, impaired translation of biomedical research, threatens the pharmaceutical industry, which underwent a substantial reduction in licensing of new molecular entities over the last two decades⁶. Pharmaceutical products ready for clinical testing have failure rates in excess of 80% and development costs of over $1.2 billion per drug. In addition, years of drawn out processes encumber clinical trials^7-10. Until recently, no concerted effort to streamline performance in biomedical product development in the United States has been undertaken, in marked contrast to the automotive and other industries which reduced their production times by 41% in the decade from 1995 to 2004¹¹.

While there are a number of definable phases in the translational pipeline ¹², one of the most critical involves the management of clinical research itself, especially the rapid incorporation of the best available science and technology on behalf of patients and consumers ¹³. Lack of sufficient institutional commitment to streamline clinical research management has challenged efforts to improve the efficiency of this phase. Additional challenges include lengthy and highly variable protocol and contract processing times, duplicative, multi-site IRB review of identical multi-site clinical protocols, delayed study start-up, and closure of an inordinate number of trials without sufficient accruals to arrive at a meaningful research conclusion. These factors add greatly to the time and cost of developing new translational therapeutics. Recently reported observational studies attest to the severity of the need for change. In oncology, the most studied disease area, for example, the development of NCI-sponsored Phase III protocols required a median of 2.5 years¹⁴ with between 25-38% of such trials failing due to accrual issues ^{15, 16}. Lengthy development time, from initial submission to final approval, correlated with low accrual success¹⁵. These and similar findings in other studies led to a call to reinvigorate the national cancer clinical trials system¹⁷.

Improvement in clinical research efficiency at academic health centers (AHCs) across the United States became a top priority of the recipients of the Clinical and Translational Science Awards (CTSAs). Designed to create an academic home for clinical and translational research, in 2006 the CTSAs set their sights on a number of goals, including making clinical research more efficient. Although each site identified its own set of challenges in process management, the 12 initial awardees focused on protocol approval and contract execution times as short term goals; they proposed studies that would enable individual sites to learn to track project completion times, develop performance metrics, analyze protocol processing data, and implement improvements based on the findings. Utilizing tools proven successful in other industries, a number of CTSAs have developed protocol processing improvement activities and have instituted continuous process improvement across a broad range of clinical research management issues. As additional CTSA sites were added to the Consortium in each subsequent year until 2011, they were invited to join the effort to improve clinical research management as a high priority. As a consequence, the CTSA Consortium was able to mount a large, nationwide effort to improve clinical research management for an annually increasing number of sites as reflected by the data in Table I.

Table I.

CTSA Site Participation in Consortium Process Improvement Strategies In Clinical Research Management

CTSA Site Participation in Consortium Process Improvement Strategies
Identified Challenges	Strategic Intervention Team	Intervention	Participation (No. of Sites / Total Sites at time of intervention (%))
Lack of institutional commitment to efficient clinical research management	Appoint Champions of Change	Implement Process Improvement as guided by Consortium wide studies, data, analysis, and recommendations	51/55 CTSA sites (93%)
Lengthy Protocol processing	Protocol Review Committee	Two Consortium wide studies of Protocol processing times	50/55 CTSA sites (91%)
Lengthy Contract negotiation	Contract Review Committee	Two Consortium wide studies of Contract negotiation times	42/46 CTSA sites (91%)
Multi-site IRB review of identical multi-site clinical protocols	Reliance IRB Agreements Groups	Regional agreements member CTSA site (No. of institutions) that signed agreement:  Harvard (10), University of Wisconsin,  Medical College of Wisconsin (Milwaukee)(5),  The University of Texas (15), The University of  California(4), Case Western (4) University of  Rochester(16) University of Colorado(5),  several other sites(2-3)	>20/60
Delayed study start-up, inadequate enrollment of study participants	Recruitment Group	Recruitment model demonstrations Rockefeller Washington U Ohio State University UCSF Virginia Commonwealth University	N/A
	Web-Based Recruitment	ResearchMatch	54/55 CTSA sites (98%)
Delayed completion of studies	Feasibility Group	Pending
	Research Participant Survey	A quality and research experience assessment	13/38 sites (34%)

However, implementation of local improvements will do little to change our national performance of biomedical translation, which requires synchronous completion of clinical trials to move products through the pipeline. Understanding this, the National Center for Research Resources (NCRR) and Yale Center for Clinical Investigation instituted a series of national information sharing meetings. The fourth annual such meeting, completed in June 2011, provided a forum for the current 60 CTSA sites to note the progress in confronting the challenges the CTSA Consortium had previously identified as high priority. As noted in Table I, 91% of the active sites participated in a voluntary process analysis study for protocol approval and contract execution times, and 93% appointed Champions of Change to direct and implement process improvements. Additionally, participants in reliance IRB agreements reported hundreds of single site IRB reviews of multi-site protocols; model recruitment programs with prospective recruitment planning and dedicated staff exceeded expectations in registering participants. Also, by mid-2011, a web-based, nationwide recruitment program, ResearchMatch, which was developed through the CTSAs with NCRR funding, facilitated registration of participants in over 250 studies.

While these are all worthwhile initiatives, it is time to pool these efforts to create a community of practice so that individual institutional efforts can be evaluated using national performance data and the execution of multi-institutional efforts can be fostered. At this juncture, the taskforces are staffed and positioned to use the accumulating data; an advisory group has identified barriers to process completion as reflected in its analysis of process streams. Informed of achievable goals and motivated by the visibility of the data, the CTSA sites have organized a Process Excellence Group to test methodologies and teach each other how to significantly streamline approaches to the often “invisible” barriers to clinical research ¹⁸. Thus, much like the basic sciences who can share experiences to develop national level laboratory results, the CTSAs are combining their efforts to create a virtual national laboratory for clinical translational research. This structure allows for the sharing of successful programs, positive changes, and lessons learned along the way.

What more is needed? The organization that must do the work has formed. Participants at the ground level accept the central concepts of process mapping, project tracking, analysis, implementation of change, and systematic re-evaluation. It remains for national leadership, government, academic, and the private sector to support the fledgling virtual national laboratory of CTSAs as it begins the task of building on these initial efforts into process improvement. What the Consortium has learned is that there are no easy fixes, no simple solutions, no universal remedies for the inefficiencies in US health care research which now includes over 9,700 active, interventional studies and trials in Phases I – III supported by NIH and industry¹⁹. The key process engineering methodologies have been piloted and refined, but, as with all change, not every process refinement will succeed. Indeed, even if process changes do succeed, downstream effects may at times impede overall completion times. With leadership and industrial support, adequate allocation of resources, and a CTSA Consortium committed to facilitating the clinical and translational science process, the virtual national laboratory is positioned to provide an environment where each proposed improvement can be systematically tested, so that the successful ones may be retained and the failures rejected quickly. The expectation is that this incremental evolution will move progressively toward making clinical research more efficient. The initial results suggest that significant improvements in clinical translation are being translated into reality.

It is time to make these changes as there is an ever increasing need for more complex clinical trials that combine ever more “omic” information, coupled with a decreasing level of resources available to complete such studies, an increasing level of international competition, and an increasing number of patients who need better answers sooner. Improving time and quality are of the essence in clinical research if America is to remain world-class and not fall into the difficulties that faced many other U.S. industries that were “too-big-too-fail” ^{20, 21} To implement the necessary changes will require a sustained, prolonged, consistent effort more similar to a marathon than a sprint. Such a sustained effort is underway both locally and in the virtual national laboratory of the CTSAs.