The past decade has seen an increasing concern with the fact that basic scientific breakthrough discoveries do not result in widespread breakthroughs in patient care.1–3 According to some researchers, an analysis of the rate of translation of promising basic research findings to clinical applications shows the difficulty in converting progress in basic research into new treatment and cures. For instance, a study evaluating 25,290 articles published from 1979 to 1983 in six basic science journals found that 101 original articles clearly stated the implications of their research for human clinical applications and made a promise for a major clinical application of their findings.4 Ten years later, only five of those promises were in licensed clinical use, and only one of them had had a major impact on current medical practice.5 Besides the paucity of translational results, others question the linearity of the bench-to-bedside model and defend the need for strengthened clinical research that can provide bedside-to-bench feedback.6–8
The National Institutes of Health (NIH) has responded to these concerns by establishing a series of initiatives that attempt to address the gap between basic research and clinical applications.9 One of them, the Institutional Clinical and Translational Science Award (CTSA), has as its main goal to streamline and facilitate clinical and translational (C/T) research so as to increase its efficiency and speed.10 The NIH has now provided CTSA grants to 38 institutions: 12 in October 2006, 12 in September 2007,11 and 14 in May 2008.12 A fourth round of funding was announced recently.
The CTSA request for application (RFA) lists specific objectives and key functions, defined by the NIH, which an institutional CTSA needed to address to overcome barriers to speeding C/T research. The purpose of this article is to assess whether these NIH-identified objectives and key functions address the major barriers identified in the literature and whether funded institutions offer solutions that attend to these challenges. We argue that although CTSA centers might have an important role in successfully addressing some of the barriers to C/T research, they might ultimately have difficulties achieving their purported goal of facilitating and increasing the efficiency and speed of C/T research because they lack control over solutions to some key obstacles facing such research.
Background: Literature Search and CTSA Review
To explore these questions, we reviewed the literature to identify noted barriers to C/T research. Search queries using combinations of the following key words were performed on PubMed: barriers, challenges, translational, clinical, research, interdisciplinary, collaboration, innovation. In addition, we reviewed relevant publications referenced by these sources. We focused on publications that were the result of firsthand experience or empirical research and on publications that identified barriers through the use of organized interview and survey methodology.
Further, we examined the CTSA RFA to determine the overlap between NIH-listed objectives and key functions and barriers identified in the literature. Finally, we reviewed the CTSA-awarded applications to evaluate which barriers were addressed in the applications and the types of solutions proposed. We evaluated the first 12 CTSA-awarded applications because major portions of these grant applications were available on the CTSA Consortium Web page,13 whereas only brief summaries, at most, of the subsequently funded applications were publicly available.
The CTSA RFA defines two types of translational research: One is the process of applying basic discoveries to clinical applications, and the second is enhancing the adoption of best practices in the community. This article addresses only the first of these definitions.
Barriers to C/T Research
Table 1 summarizes the barriers we identified in the literature. Most articles identified them as a result of firsthand experience in implementing organized C/T research programs,1,14 empirical research on interdisciplinary research centers or programs,15 evaluation of mentoring opportunities,16 or organized efforts to identify barriers using interviews, workshop discussions, and/or survey results.2,17–18
We have grouped them into three areas: research workforce, research operations, and organizational silos (i.e., related to the departmental structure of most institutions). Table 1 also matches the listed CTSA RFA objectives and key functions to these barriers. The RFA most robustly addresses barriers related to the lack of qualified C/T investigators and sufficient mentoring, issues involving research operations, and the systematic implementation of interdisciplinary centers. The RFA does not directly address barriers around the departmental structure of institutions and academic rewards and career disincentives. Unsurprisingly, barriers and solutions proposed in the successful CTSA applications parallel the emphasis placed in the CTSA RFA.
Barriers and solutions addressed in depth
Barriers to C/T research that were emphasized in the CTSA RFA and most widely mentioned in the literature were a lack of qualified C/T investigators,1,2,17,18 inadequate mentoring for these investigators,2,13 an increasing burden of addressing regulatory issues,1,2,17,18 fragmented infrastructure to support C/T investigators,1,2,17 and a lack of clinical trial participants, especially from minority populations.17 Additionally, the RFA addresses the need for systematic implementation of interdisciplinary centers.15 It defines the primary objective of the program as creating an academic home for C/T science and requests demonstration of institutional support for the program and an organizational structure and plan for governance within the overall institution. All of the published applications proposed extensive solutions to these barriers.
Training and mentoring.
To address the lack of qualified C/T investigators, the CTSA RFA emphasizes the need for institutions to develop graduate degree-granting and postgraduate educational and training programs in C/T science. It also strongly encourages institutions to train investigators from diverse disciplines as well as other key research personnel, such as study coordinators and project managers, and to include mentored career development components. Hence, all of the successful CTSA applications included various educational and training programs that target the diverse groups suggested in the RFA. Most institutions planned to offer master of science programs directed at students already enrolled in health professions training, doctoral programs in C/T research, and postdoctoral and junior faculty mentored training programs aimed at physicians. Most also planned to offer programs for study coordinators and project managers. Examples of other types of programs that address training and mentoring are listed in Table 2.
Fragmented infrastructure and regulatory burden.
Two barriers to C/T efforts widely identified by the literature are the existence of a spotty and fragmented infrastructure to support clinical research and the increasingly time-consuming task of complying with governmental regulations in clinical research. In response to these obstacles, the CTSA RFA encourages applicants to propose a comprehensive, integrated, user-focused program. Thus, all successful applicants described approaches that involve building and sustaining infrastructure and regulatory assistance that integrates a variety of functions and supports communication among the different stakeholders. These approaches were variously described, for example, as a “front door,” “one-stop shop,” and “service center.” All of the programs described plans for a Web-based portal as an entry to these services, and all also planned to have various types of supportive faculty and/or personnel to act as guides to access and/or learn how to use resources. Table 2 summarizes several innovative approaches.
Lack of clinical trial participants.
The CTSA RFA emphasizes the need to create resources that promote interactions between clinical researchers and potential research participants, especially recruitment of research participants from the community, which would be expected to address the lack of clinical trial participants, particularly minority subjects. All of the successful institutional applicants described robust efforts to interact with the community, including the creation of community research centers, the development of community research offices or community-based research programs, and/or the establishment of community boards to allow academic researchers to connect with community providers, organizations, leaders, and/or citizens. Whereas all of the applications described efforts to use community outreach as a way to enhance clinical trial participation, 8 of the 12 applications also described other types of efforts to promote clinical trial participation. Examples of both types of programs are summarized in Table 2.
Lack of systematic implementation of interdisciplinary centers.
Establishing an academic home integrated into the institution is central to the CTSA RFA, and so all applicants responded in detail regarding the structure, governance, and integration efforts. The organizational approaches vary greatly by institution. Although seven of the applicants organized the initiatives as institutes and five organized them as centers, the institutional significance and governance of institutes and centers was not consistent across the successful applicants. But, there was an effort to integrate the directors of the C/T effort into the institution's senior leadership to promote awareness of C/T in decision making and resource allocation. Four of the institutions chose directors for the C/T effort (i.e., principal investigator [PI] of the CTSA application) who were already in senior leadership roles, including the dean of the medical school and the equivalent to the vice president for research. Four institutions elevated the PIs to higher-level administrative positions, such as the associate dean or vice chancellor for C/T research, or to a position in the dean's office, and the PI of another institution is an assistant dean for clinical research. Of the 12 institutions, two applications organized the C/T effort so that the director reports directly to the president of the institution, and for eight others the director reports to a senior-level position with broad responsibility for the health sciences at the universities, typically at the level of the executive vice president or chancellor or at the provost level. Table 2 describes examples of particularly tight integration efforts.
Barriers and solutions addressed to some extent
Two other barriers also frequently mentioned in the literature are poor communications between basic scientists and clinicians and the high cost and lack of funding for clinical research. The CTSA RFA addresses these issues but not as directly as the previously mentioned barriers. For example, the need for an organized and systematic function within the CTSA infrastructure to promote dialogue and interactions between basic scientists and clinicians is not discussed among the key functions recommended for a CTSA. Regarding funding for research, the RFA states that an applicant can request support for pilot and collaborative clinical research projects and that corporate partners may be included in the proposals.
Most institutions mentioned inadequate communication between basic and clinical investigators as a barrier to C/T research. All planned to provide pilot grant funding to promote interdisciplinary translational studies, but there were no other solutions that provided incentives for basic scientists to participate in translational research. Three applicants described facilitator-based efforts, in which they identified specific, experienced researchers to proactively act as matchmakers who would bring together multidisciplinary teams to address translational research opportunities. A fourth institution had a formal mechanism in place to conduct ongoing discussions by medical investigators with their basic science colleagues to identify potential opportunities for translational research. A fifth institution planned to rely on experienced investigators to match clinical researchers and scholars with the faculty and staff of core resources for consultation and possible collaboration. Three applicants described educational efforts to develop teams of doctoral and medical students to work on collaborative research projects, and a fourth offered trainees a comentorship with a basic researcher and a more medically oriented C/T researcher. Five applicants, including two with facilitator or education-based programs, planned to rely on Web-based technologies to develop virtual communities in which investigators can find collaborators. Half of the programs, including four mentioned previously that offer additional elements to improve communication, emphasized the need to increase opportunities for investigators to interact generally, such as through campus-wide invitations to meetings, seminars, and journal clubs targeted to translational research. Table 3 outlines examples of these approaches.
High research costs and lack of funding.
The RFA acknowledges the need for funding to support pilot studies and collaborative research, and all institutions have developed funding programs to support such studies. They also offered funding for the development of innovative research methodologies. A few institutions are planning more extensive strategies to address the high research costs and the need for funding, especially of early-stage applied projects. Others partnered with industry or government-funded entities to bring in complementary funding. Table 3 summarizes examples of these types of efforts.
Barriers not well addressed with solutions
Although the CTSA RFA and the successful applications discussed most of the well-accepted impediments to C/T research with intentionality and detail, other barriers identified by the literature were either overlooked or summarily addressed. These barriers relate to the departmental structure of institutions and to academic rewards practices and career disincentives.
Although the RFA recommends that “the program director have authority, perhaps shared with other high-level institutional officials, over requisite space, resources, faculty appointments, protected time, and promotion,”10 no CTSA PI identified by the applications had authority over promotions, and protected time was available for only a few faculty members accepted into special C/T faculty positions and/or C/T training programs. Similarly, whereas the applications described CTSA PIs who had authority over faculty appointments within the C/T entities, only two PIs, who also have senior-level roles in their institutions, had authority over new faculty hiring, and only as members of a committee authorizing or making the recruitments. Indeed, several institutions explicitly stated that the C/T home needs to be responsive to the departments and should not supersede their role in the areas of promotion, tenure, and salary.
Academic rewards and career incentives.
Successful CTSA applications recognized the importance of transforming current standards and practices for tenure and promotion. In general, all applicants suggested the need to acknowledge the relevance of collaborative and multidisciplinary work and to increase the visibility and esteem of C/T research. Five institutions had already changed or were about to change their promotion and tenure guidelines to recognize team-based investigation. The remaining institutions were vague about what exactly those changes will be and how they will be achieved. Similarly, though awardees acknowledged the absence of adequate career incentive opportunities to perform collaborative research, little attention was given, for example, to how to create opportunities for jobs with similar levels of compensation as those available to clinical practitioners. Nor did most of the applicants tackle problems of a lack of protected time for the majority of faculty members wishing to participate in C/T research activities.
As our analysis shows, CTSA applications tackled various barriers to C/T research with different focus and attention. We argue that the variety of solutions, or lack thereof, responds to the degree of control that the new centers have over possible solutions. Figure 1 outlines these degrees of control. Hence, CTSA centers might be successful in addressing some of the barriers to C/T research. However, their lack of control over solutions to some important obstacles facing such research might ultimately limit efforts to facilitate and increase the efficiency and speed of C/T research.
We recognize that a limitation of this conclusion is that these first 12 institutions to receive CTSA funding might not be representative of all institutions that have now been funded. On the other hand, the barriers for which the initial CTSA awardees do not have sufficient authority to develop effective solutions, such as lack of control over departmental decisions, the high cost of C/T research, limited opportunities to provide protected research time to clinical researchers, and difficulties providing incentives for basic researchers to participate in translational research, are issues that are likely to affect any academic institution in the context of developing a CTSA application. Where the awardees have sufficient administrative authority, they will most likely be able to address obstacles in a fairly focused response. These barriers and solutions are clearly and extensively discussed both by the RFA and the CTSA applications. For instance, the education and training of C/T researchers, the creation of mechanisms to address infrastructure fragmentation and regulatory burden, and the development of strategies to increase local community research participants are barriers that a well-designed and administered research center can address. Notice that this latter barrier, as understood in the RFA and the CTSA proposals, is a problem of a lack of proactive identification of, and response to, the needs of their communities as well as of inadequate data management about recruitment of research participants. So understood, solutions to this barrier could reasonably be effected by CTSA centers.
Addressing the economic aspects of C/T research might, however, prove more difficult for CTSA centers. Solutions to the high research costs and the lack of funding would only be partially under the authority and control of the new centers. Clearly, grants for pilot studies and planning projects would be a needed step. Encouraging and organizing collaborations with industry partners could also contribute to overcoming this barrier. Still, a full solution rests on the actions of parties such as funding agencies and grant-giving foundations, as well as private-industry investment. But whether and how much funding these institutions will offer are decisions over which the CTSA awardees have little or no control.
Similarly, although CTSA centers could have more control over encouraging dialog and collaborations between basic and clinical researchers, for example, through matchmaking and project team building, two important factors remained outside their influence. One is whether researchers would have any genuine interest in talking to and collaborating with each other. The other is the existence of departmental silos and budgets that deter collaborative and multidisciplinary projects. The offering of partial or nonexistent solutions to these barriers in the applications we reviewed was consistent with the limited scope of the CTSA awardees' authority over these problems. However, because of their relevance, inadequate attention to these barriers is likely to hinder the goals of identifying meaningful basic research that can provide a translational opportunity and of speeding significant C/T research. For example, only Rockefeller University, which emphasized its lack of academic departments as a strength, described how its structure of laboratories facilitates interdisciplinary and C/T research.
The problem becomes even more difficult when one attends to barriers such as departmental structures and lack of career incentives. Thus, although a department-based budgeting structure and the different policies and procedures of departments are recognized as barriers to interdisciplinary research, neither the RFA nor the CTSA applicants (excluding Rockefeller University, where it is not relevant) attempted to address the physical and disciplinary separations inherent in a departmental structure.
Having clearly defined departmental boundaries, departmentally based salary, and promotion and tenure policies are widely accepted, and deeply entrenched, aspects of academic medical centers. However, because CTSA centers will have little power over departmental practices and decisions, and given that departmental structures will be unchanged, it is unclear how the new centers can offer suitable academic rewards. Even if new standards and practices for tenure and promotion are developed, questions remain about whether department chairs will embrace the new standards, who will form part of promotion and tenure committees, and how much weight standards will receive.
Similarly, the great discrepancies in compensation between physicians and clinical researchers are part of the accepted market system of health care research and provision in this country. Though CTSA centers recognized this as a serious obstacle to attracting clinical practitioners into C/T research, their lack of control over the matter prevents them from articulating adequate solutions. Additionally, problems related to a lack of protected time for faculty who wish to participate in C/T research activities were understood as an important barrier to C/T research. Nonetheless, because CTSA centers have only partial control over funding issues, their ability to offer successful solutions to this problem will be equally limited.
On the other hand, the recognition that CTSA centers have varying degrees of control over different C/T barriers creates the opportunity for developing different strategies targeted to each level of control. For example, in the area in which the CTSA awardees have most control, there is an opportunity for each to identify best practices and implement them effectively. The middle level of control will require that academic institutions create more incentives and opportunities for basic science departments not closely involved with the CTSA to collaborate with the CTSA centers. Academic institutions may need to work on behalf of the CTSA centers or authorize them to be able to reach out to other sources of funding, such as industry, foundations, or state resources, to address high research costs and lack of funding. For the third level of control, barriers that are deeply entrenched within academic institutions, such as departmental budgeting and policies, or within society, such as differential career incentives for clinicians, may need to be taken up by institutions with broader impact, such as the Institute of Medicine and the Association of American Medical Colleges.
Most agree that the recent decades-long boom in biomedical research discoveries has not had a sufficient effect on the public's health. Understanding the obstacles to C/T research and proposing adequate solutions to them is an essential task.
We have provided an overview of barriers to the new C/T efforts and a summary of the responses that CTSA awardees have given to them. For some of these barriers, the solutions presented are methodic and detailed; for others, the responses are vague or nonexistent. We have argued here that the differences in how the barriers have been approached are consistent with the degree of authority and control that the CTSA centers will have over the problems and the solutions. Hence, for those barriers over which centers have significant control, the solutions seem careful and detailed. However, when such control is limited or nonexistent, the possible answers seem vague or unaddressed. Importantly, though, some of the areas, such as departmental structures and lack of career incentives, over which CTSA awardees have limited or no control, correspond to what are recognized in the literature as significant barriers to C/T research. Hence, this lack of control might limit how effective the CTSAs can be on improving the speed and efficiency of bench-to-bedside research translation.
Certainly, our noting the fact that awardees have recognized particular barriers to C/T research and that they have offered carefully crafted solutions is not an endorsement of the adequacy of such solutions. For instance, it might well be the case that rather than creating degree-granting programs to train C/T investigators, a better way might be to integrate training in C/T research in existing graduate programs. Similarly, it could be that creating separate homes for C/T research would effectively worsen communication and collaboration rather than encourage them. Whether such solutions will be successful in promoting bench-to-bedside C/T research is an issue that requires time and empirical studies.19 However, recognizing those barriers over which CTSA centers have most control offers the opportunity to focus on the solutions being implemented, to study them in depth, and to identify best practices.
Finally, our discussion of bench-to-beside barriers to translational research should not be taken as indicating that they are the only barriers to C/T research.20 Aspects such as a possible growth in regulations promulgated by the NIH or the FDA, the complexities of product development in this country, and the multifaceted intersection between care and research could certainly pose problems to the goal of translating basic science discoveries in more efficient ways. Nonetheless, to the degree that these barriers do interfere with successful C/T research, the lack of or inadequate attention to some of these obstacles might limit the attainment of a more efficient and speedy bench-to-bedside research translation. Therefore, there is a need to recognize the different levels of control over the various barriers and to consider developing strategies to address barriers outside of CTSA awardees' control.