How Can the National Clinical and Translational Science Awards Program Transform itself?
Anantha Shekhar, director of the Indiana Clinical and Translational Sciences Institute, provides a fresh perspective.
The call for disruptive innovation to address translational gaps in biomedical R&D spurred the birth of both the U.S. National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) and the Clinical and Translational Science Awards (CTSA), which established translational science homes at more than 60 U.S. academic medical centers (1). Both initiatives are bold experiments that must rapidly deliver focused results. In July 2013, NIH unveiled a report sponsored by the Institute of Medicine (IOM) that outlined recommendations to refine the goals of the CTSA program so that the network of institutions can realize its full potential (2). Although the IOM recommendations were excellent and balanced, many unstated challenges and opportunities remain. Therefore, in the spirit of Osler, I present some additional thoughts about the CTSA network’s future path.
TIME FOR TRANSFORMATION
Overall, the IOM committee was positive about the CTSA program and concluded that it has, indeed, contributed to the advancement of clinical and translational research. The report offered seven recommendations of areas in which the program’s effectiveness can be enhanced, and all seven are recognized by anyone familiar with the CTSA program as much-needed improvements. Yet within each of these recommendations, one could easily make incremental changes and then declare that they have responded to the IOM review.
To make a real impact, transformational changes must be defined. This need is particularly pressing in the context of the newly formed NCATS, whose mission—“to catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics, therapeutics, and interventions across a wide range of human diseases and conditions”—differs greatly from that of the National Center for Research Resources (NCRR), the NIH center that previously housed the CTSA program. NCRR’s mandate was to “provide laboratory scientists and clinical researchers with tools and training to understand, detect, treat, and prevent a wide range of diseases.”
So, how can the CTSA program simultaneously transform itself and the current dysfunctional models for translating discoveries into therapies? And from a quantifiable point of view, what will be its short-term versus long-term deliverables? In many ways, joining the CTSA program with NCATS, which has singular strengths in therapeutic innovation (3), provides more focused translational goals for the CTSA network than did the diffuse focus of the past several years. But for the CTSA program to make concrete contributions, the blueprint for changing the translational research landscape must be well thought through, vetted by a broad group of stakeholders, and carefully implemented. Essential refinements and transformational approaches should be pursued in parallel (table S1).
UNACKNOWLEDGED ELEPHANTS IN THE ROOM
Some key problems that could have been, but were not, addressed by the IOM report remain as pressing challenges for the CTSA program and NCATS in general. There are no easily implementable answers to these complex problems, but at the very least, they must be openly articulated to better calibrate expectations and appropriately shape the resources for and deliverables demanded from the CTSA program.
Achievable versus aspirational goals. The IOM report’s expectation that the CTSA institutes (CTSAs) work on “advancing the clinical and translational sciences and human health” is more of a mission statement than a specific set of goals. In addition, other stakeholders are hopeful about what CTSAs can deliver. Disease advocacy groups want the CTSAs to enhance the pace at which new therapies reach their constituents. The pharmaceutical and biotechnology industries want the CTSAs to improve the infrastructure and efficiency of the U.S. academic clinical research enterprise, which will increase the success rates for developing industrial products. Community advocates hope that the CTSAs will provide a national platform for rapid implementation of healthcare best practices. Systems-level advocates want the CTSA network and NCATS to find new ways of doing R&D that will increase both the efficiency and success of translating discoveries into new therapies and diagnostics.
Every one of these goals is important, but each of them is a mission in itself and is stymied by numerous long-standing structural, regulatory, and knowledge problems that will take more than the CTSA network and NCATS to overcome. The network needs a few concrete goals defined by a select group of initial stakeholders and achievable in the next 5 to 10 years. These goals should be aimed at (i) experimenting with new methodologies to accelerate bench-to-clinic and clinic-to-community translation and (ii) providing proof of principle for NCATS’ approach to reducing the human disease burden by targeting even modestly prevalent adult or pediatric disorders that can be impacted in the near term.
Matching scope to resources. The IOM report was mostly silent on the degree of mismatch between the scope of responsibilities and the resources available for NCATS and the CTSAs to accomplish their tasks. Although it is often stated that the CTSAs constitute the single largest NIH program ($461 million in 2013), the total resources dedicated to meeting their broad mission are less than 2% of the full NIH budget. This amount is further slashed by an estimated $100 million per year that the CTSAs spend on locally subsidizing ongoing research projects of NIH’s categorical institutes and centers (ICs) through the legacy General Clinical Research Center. If one compares the CTSA and NCATS budget against the rest of the NIH budget plus pharmaceutical- and biotechnology-company research budgets, then the total CTSA network funding turns out to be less that 0.5% of the total R&D investment in the U.S. translational medicine research space. In short, the available resources are woefully mismatched to the IOM-ascribed task of transforming recalcitrant translational mechanisms.
Here again, we need a realistic approach that drives creation of a few key innovations and moves them into wider practice. This can be achieved through strategically targeted external partnerships that can then act as a fulcrum for broader culture change. One such example of success is NIAID’s efforts to successfully transform HIV infection from a death sentence two decades ago to a manageable chronic illness. But such a focused effort is more difficult to mount when the challenges are defined in a disease-agnostic manner. Thus, new creative approaches are needed. For example, the CTSA network could partner with the U.S. Food and Drug Administration (FDA), identify breakthrough therapeutics for a handful of severe unmet medical needs, and assist with their development by bringing together network resources, appropriate categorical NIH ICs, industry partners, and disease advocacy groups. After a few successful projects, broadly applicable best practices would evolve.
Balancing local versus national missions. Another barrier that pervades the CTSAs is the tension between serving the missions of the national network versus transforming and supporting the local infrastructure for clinical and translational research. The funding formula now being used for the individual CTSA grants is to base it on 3% of the total NIH funding received by each applicant institution during the previous year. Currently, there is no clear delineation as to what percent within the total budget of an individual CTSA award should be dedicated to supporting the national network goals. This lack of specification biases the local institutional forces to exert greater efforts toward shoring up local infrastructure and training needs and assigning mostly in-kind efforts toward the national consortium activities. An approach is needed to define concrete network deliverables and gradually allocate CTSA funds (say, one-third) to supporting the national network milestones.
Nurturing trailblazers. Education and training is a major focus of the CTSA network, which spends an estimated $50 million or so on trainee stipends annually. Typically, CTSAs have an institutional career-development (K award) program that provides 2 or 3 years of career-development support to young investigators. Although several innovative programs are emerging to train a new cadre of investigators skilled in the entrepreneurial, business, pharmacometrics, or biomedical device arenas (4, 5), the majority of K awardees have been young investigators whose metrics of success were obtaining an individual K or R grant from another agency (typically an NIH IC) and who have moved on to become independent investigators with “traditional” academic careers.
Thus, a substantial fraction of the CTSA investment ends up providing an extension of the typical 5-year career-development runway from which to launch junior faculty on traditional research careers, instead of creating pioneers who will forge new paths to address translational research challenges. One solution may be to set aside a portion of the CTSA training funds to supporting faculty “trailblazers” with K or R awards who have established independent research to pursue new paths for translating their discoveries toward product development or implementation.
A house divided. Another key focus for NCATS and the CTSA network is to enhance collaboration across multiple stakeholders. Although there are many stakeholders in the field of translational medicine who are broadly united in their global mission of improving human health through biomedical innovation, there are also myriad conflicting motivations, such as lack of trust (public versus private); misaligned incentives (academic promotion criteria versus impact); unproductive internal competitions (academic institution replicating resources for grants and NIH rankings; categorical ICs creating independent clinical and translational networks); and poor knowledge- and data-sharing practices. The CTSA network and NCATS can begin to forge new models of collaboration, but the network must be strongly nurtured by other parties—NIH ICs, federal agencies, industry, foundations, disease advocacy groups, and progressive academic environments—if it is to be freed from the historical burdens of a house divided.
Legislative constraints. Last, because of their high profile, the CTSAs and NCATS have been under unusual U.S. congressional scrutiny, which may be the final barrier toward creating a truly disruptive national network of innovation. There are continued worries about the amount of local resources that must be sacrificed, and the most recent budget language is even more prescriptive than before as to what NCATS and CTSA programs can do without prior consultation with Congress, NIH ICs, and academic stakeholders. In light of the divided house problem, finding common ground that will satisfy all of these different constituents is likely to be difficult, diminishing the chances for the emergence of network-level innovations that transcend individual interests.
An early example of a national network that sets achievable modest goals, matches them with reasonable resources, helps align academic incentives, and provides centrally coordinated regulatory processes to facilitate translational medicine projects may be emerging in the UK (www.nihr.ac.uk/Pages/default.aspx). However, much more effort will be needed to meet translational mandates in the far more complex U.S. research environment. With patience and thoughtful effort, the challenge is not impossible. Rather than yielding to passive skepticism born of despair, we must approach this mandate with a stern, iconoclastic attitude of mind—and get to work.