Efforts of the Clinical and Translational Science Awards (CTSA) Program

Barbara Alving, Director, National Center for Research Resources (NCRR) within NIH, described the CTSA program and its role in improving clinical trials in the United States. Launched in 2006 and directed by NCRR, the program makes grants to institutions that provide an academic home for clinical and translational science throughout the United States, working to accelerate the translation of laboratory discoveries into new treatments for patients. The five strategic goals of the CTSA consortium of institutions are:

1. to build national clinical and translational research capacity;
2. to provide training and career development for clinical and translational scientists;
3. to enhance consortium-wide collaborations;
4. to improve the health of communities and the nation; and
5. to advance T1 translational research to move basic laboratory discoveries and knowledge into clinical testing.¹

Currently, 46 academic institutions make up the CTSA consortium, covering 26 states (Figure 8-1). Alving noted that CTSAs are deployed so that their reach is effectively nationwide. In the western United States, the University of Washington works with a number of sites in Idaho, Montana, and Wyoming that do not have medical schools. The IDeA-eligible² states are funded to create Centers of Biomedical Research Excellence.

FIGURE 8-1

CTSAs include 46 institutions in 26 states. When the program is fully implemented in 2011, it will include approximately 60 institutions. NOTE: IDeA = Institutional Development Award.

CTSA institutions are also engaged in public–private partnerships. For instance, the University of Rochester has created an Intellectual Property Portal³ to aggregate and market technologies from CTSA institutions and NIH. Fifteen CTSA institutions are currently contributing information on their technologies to the site. Alving mentioned another Web-based tool, the CTSA Pharmaceutical Assets Portal,⁴ which links those with an interest in pharmaceutical products to investigators nationwide, as well as at NIH, who want to study the products.

Alving listed the six areas in which the CTSA program is focusing significant effort to facilitate improvements in the clinical trial process:

• developing data-driven approaches to process improvement;
• reviewing steps involved in the initiation of clinical trials;
• naming “Champions of Change” at academic health centers—individuals with the authority to effect changes;
• educating academic health centers about uniform templates for clinical trial agreements (CTAs) (see below);
• developing tools for enrollment of clinical trial participants; and
• developing Web-based tools for management of clinical trial data.

Alving noted that currently, the performance of CTSA institutions with respect to the length of time it takes for clinical trial contracts to be initiated is similar to that of non-CTSA academic institutions: both experience significant delays from the point at which a clinical trial protocol reaches an Institutional Review Board (IRB) office to the point at which initial ethical review is complete. While CTSA institutions vary greatly in terms of the time frames involved, Alving hopes that as a consortium, they can develop best practices to effect widespread improvement in these time frames across both CTSA and non-CTSA institutions.

As a broad-based network of academic institutions dedicated to clinical and translational research, the CTSA consortium represents a number of key academic stakeholders engaged in clinical trials. Alving pointed out that while CTSA institutions enjoy the benefits of close collaboration with each other, some CTSA initiatives are available to all institutions, CTSA and non-CTSA alike.

Alving stated that it takes anywhere from 4 to 7 months to negotiate a CTA between an academic institution and industry. She noted that, regardless of the disease of focus in a clinical trial, a contracts office is responsible for negotiating the contract, and providing templates (disease-specific as well as general) for that office to choose from can facilitate the negotiation process. To streamline the lengthy negotiation process, the IOM Drug Forum commissioned the development of templates for both CTAs and material transfer agreements (MTAs).⁵ The templates, which are intended for widespread use, incorporate language considered acceptable to key stakeholders. Where companies and universities tend to have significant differences, the templates annotated the standard language to highlight and provide context for those differing positions. Alving described CTSA program efforts to disseminate the CTA and MTA templates to the CTSA consortium and to educate academic health centers on how they can be used effectively. The National Cancer Institute (NCI) also has created template agreements to facilitate contract negotiations. The NCI templates—Standard Terms of Agreement for Research Trial (START) Clauses—are based on the results of a survey of all NCI cancer centers.

Alving also described the following programs supporting CTSA institutions and other clinical research programs:

• Research Electronic Data Capture (RedCap)⁶ gives research teams an easy way to collect, disseminate, and protect the privacy of study data. It comprises two secure Web-based applications and provides software and support to partners (CTSA institutions, General Clinical Research Centers, Research Centers in Minority Institutions, and other institutions) at no charge in exchange for participation in the consortium. Alving reported that 3,000 researchers currently use RedCap across 56 institutions and 22 countries.
• CTSApedia⁷ will be a comprehensive online resource for those seeking courses in clinical and translational research. This resource will be available to both CTSA and non-CTSA institutions.
• Researchmatch.org, launched in October 2009, is a Web-based patient recruitment registry connecting willing clinical trial volunteers with researchers. It currently supports the CTSA consortium of institutions.⁸

Clinical Trials Transformation Initiative (CTTI)

CTTI is a public–private partnership founded by FDA’s Office of Critical Path Programs and Duke University. The initiative, which includes stakeholders from government, industry, academia, patient advocacy groups, professional societies, and other organizations, has the goal of identifying practices whose broad adoption will increase the quality and efficiency of clinical trials.⁹ In clinical trials, most of the costs are associated with human time and effort, so unnecessary complexity can be both burdensome and expensive. In the United States, where labor costs are higher than in other parts of the world, unnecessarily complex clinical trial processes can put the United States at a disadvantage.

NIH Roadmap for Medical Research

The NIH Roadmap for Medical Research, issued in 2003, set forth a vision for what the clinical research enterprise in the United States should look like. The Roadmap envisioned that in 10 years there would be a national clinical research system, based on electronic health records, in which all Americans would participate. Data in this system would be open and transparent. Robert Califf said that, although this vision has not yet been fully realized, many of the necessary components are being put in place. He suggested that avoiding additional layers of bureaucracy and focusing only on the core goals of clinical research would help create the system envisioned in the Roadmap. In contrast to the current model of a single coordinating center and a number of research sites conducting a clinical trial (Figure 8-2), existing networks would be linked using electronic health records and patient registries to create a more interconnected exchange of clinical research information (Figure 8-3).

FIGURE 8-2

Typical NIH clinical trial network with academic health center sites surrounding the hub of a data coordinating center. SOURCE: Califf, 2009. Reprinted with permission from Robert Califf 2010.

FIGURE 8-3

A vision of an integrated clinical research system linking existing networks (patients, physicians, and scientists) to form communities of research and conduct clinical trials more effectively. SOURCE: Califf, 2009. Reprinted with permission from Robert (more...)

International Examples

The United Kingdom, Canada, Germany, and Australia are engaging in a similar dialogue on strategies to improve their clinical research infrastructure. According to Paul Hébert, the dialogue on the type of infrastructure needed to carry out clinical trials varies depending on the trial designs one wishes to use and the outcomes one seeks. In the United Kingdom, for example, large, pragmatic trials that have broad eligibility criteria and include a sizable number of patients are frequently used to test the effectiveness of drugs or medical interventions. Data collection in such trials is usually minimal (two to three pages), compared with other trial designs that involve the collection of multiple binders of data.

Hébert explained that in the United Kingdom, national clinical research networks exist on six major themes, and each includes 7 to 10 local clinical investigator networks. The local networks serve primarily as recruiting centers for large, national trials. To support this system, the British government initiated a realignment of research funding so that it is coordinated centrally and provided nationally.

In a discussion of patient registries, Christopher Cannon echoed the sentiment that the goal of clinical research—the outcomes sought—should shape the way a research infrastructure is built. Although the confounding that characterizes registries (why an individual received one therapy versus another) makes it impossible to use these data to compare different therapies, Cannon suggested that patient registries could provide the data collection infrastructure for a system of large, pragmatic trials. For instance, as health information technology advances, the passive collection of data becomes easier. A simple randomization of therapies in a broad population (e.g., the Medicare population), with data being collected inexpensively, could provide the infrastructure necessary to conduct more large, simple trials in the United States, similar to those popular in the United Kingdom.

International agencies and governments are also grappling with ways to overcome the barriers to clinical research. Hébert shared the results of a survey of U.S. and European companies indicating that the process of negotiating contracts for clinical research is a major burden in terms of both time and cost. While collaborations can be useful for generating new research, the contract and negotiation process across multiple entities can be extremely difficult. For instance, the development of contracts for a large, multisite, international trial that requires funding from a number of different collaborators requires a significant amount of time and money—Hébert estimated the process can take 2 years.

Hébert also cited current efforts to improve clinical research in Canada. These efforts include investing in the workforce (e.g., biostatisticians, health economists, and epidemiologists), using the flexibility and support functions of 89 large national networks already in existence, and integrating research into clinical practice through the development of 20 to 30 support units across the country.

The health care system largely drives the way in which clinical research is conducted, according to Hébert. The United Kingdom and Canada, for instance, have single-payer systems that facilitate centralized control of the clinical research enterprise. Hébert suggested that the United States can learn from the experiences of other countries but that ultimately, the solution to improving its clinical research enterprise will need to be tailored to the U.S. context and take into account the unique driving forces (i.e., the health care system, political perception and motivation of decision makers) behind any systemic change.

Cardiovascular Disease Breakout Session

Discussion in this breakout session focused largely on strategies and policies that could lead to the creation of a national clinical research network positioned to accelerate research efforts in all disease areas. The group suggested that a national network could be based in the primary care setting but should go beyond physicians to include the full spectrum of the primary care workforce. The group discussed components of such a network that might already be in place today. An example is the 46, soon to be 60, CTSA institutions that encompass much of academic medicine in the United States. In addition, 52 Practice-Based Research Networks (PBRNs) comprise groups of primary care practices throughout the country. Historically, PBRNs have been underfunded, but the fact that physicians have joined these networks without the promise of core funding indicates that there is significant interest among practicing community-based clinicians in developing clinical questions and producing research results that can effectively improve everyday clinical practice.

Patient advocacy and voluntary health organizations would have an important role in driving the effort to build a national research network. Groups with experience in using social networking and other outreach mechanisms could be highly effective in engaging the public and building broad interest in clinical research.

NIH and industry, as the key sponsors of clinical research in the United States, also have an interest in building a national research network that would improve the efficiency of clinical trials, with the overarching goal of answering more of the most important research questions.

Several key barriers to creating a more efficient clinical research enterprise were discussed in the breakout session:

• ethics review—delays and difficulties encountered in obtaining approval for a clinical trial protocol;
• contract negotiations—contentiousness and delays surrounding the contract negotiation process between NIH and clinical trial sites; and
• intellectual property—agreements that include requirements that human subjects research results be kept confidential for 5 years. (It was suggested by discussants that they believed that beyond phase II research, intellectual property should not be a contentious issue in the academic arena.)

Depression Breakout Session

This breakout session formulated a broad vision for future research efforts in depression that included successfully treating the disease in all forms and settings, with a goal of achieving remission for 60 percent of patients. The development of sensitive research tools and measures of depression that would accurately convey the state of the disease could improve the development of informative clinical trials. Similar to a point made in the diabetes session, a 100-year goal for depression could be preventing the onset of the disease.

Creating unified standards for every human measure and the data systems to manage them would help in ensuring that the significant investment each human subject confers in agreeing to participate in a clinical trial results in the highest possible value to the clinical trial enterprise. Involving patients and patient advocates throughout the trial design and implementation process would also help improve clinical trials and the validity of the results they generate. Expanding clinical trial design toolkits and increasing the number of depression studies that examine long-term outcomes would also be useful.

The group also discussed the idea of including research in the routine delivery of care so as to remove the current divide between the clinical research enterprise and clinical practice. Integrating these two worlds would require new models to better align research and health care delivery as well as culture change at all levels (e.g., patients, providers, educators, and legislators). To facilitate culture change, large outcome studies that answer important questions could be used to engage stakeholders and gain public trust and involvement.

Cancer Breakout Session

Meeting patients’ expectations of the clinical research enterprise was the focus of this group’s discussion. Patients should expect that their treatment is evidence-based and that their treatment experience will form the basis for an increase in knowledge, which in turn will lead to improvement in their care. In such a learning health care system, physicians, nurses, data managers, payers, patients, and regulators would all contribute to the process by which health care outcomes would inform clinical practice.

Numerous gaps exist between the current health care system and the ultimate goal of a learning health care system. The group discussed, for instance, the need to correct public misconceptions about clinical trials and the overall value of clinical research. For practitioners, the progression through the core curriculum of medical school and eventually continuing medical education includes limited instruction in conducting clinical research. In addition, misaligned incentives exist in a reimbursement system based on the volume of patient visits or procedures completed. Another important gap is the lack of coordination and prioritization of clinical trial research questions. These and other barriers discussed in Chapter 3 characterize the inadequate research infrastructure that exists at every level of the health care system. The group also highlighted significant gaps in the instruments used to analyze issues surrounding end of life and quality of life.

While the above gaps are substantial, the group discussed four areas of oncology that have exhibited best practices in clinical research:

• Pediatric oncology—Based on a relatively small network of practicing pediatric oncologists, this area of medicine has created a culture shift in which oncologists in training have mentors and role models in the field to further the circulation of clinical information. The majority of practitioners are salaried, which removes the traditional focus on performing a high volume of procedures. In addition, the field of pediatric clinical oncology includes significant patient and family involvement, enhancing the flow of information throughout the network and overall public investment into this area of clinical research and practice. Many children with cancer have been enrolled in clinical trials, which have resulted in significant advances in cancer treatment and patient health.
• Gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML)—In these two areas, patients have largely instigated the sharing of information on clinical research and the use of effective treatments for these conditions.
• Multiple myeloma and prostate cancer—The advocacy community has assumed significant responsibilities for financing research and clinical trials in these two areas, thus creating an alternative and more flexible structure than the NIH funding system.
• Breast cancer—Advocacy collaborations between patients and researchers have influenced federal legislation and the allocation of additional funding to clinical research.

The group also discussed how payers would benefit from supporting and financing clinical trials in that they could be the first to demand the most effective, evidence-based treatments. In the case of solid tumor transplantation, for example, payers are already demanding fast screening, whereas the FDA has yet to improve the test for this type of screening. Putting payers on the cutting edge of clinical research could be a powerful approach to advancing clinical practice.

During the discussion, it was noted that, to accelerate clinical research and improve the infrastructure underlying clinical trials, leadership and coordination from the highest levels of government would be necessary. A caution was expressed, however, that the bureaucratization of clinical research should be avoided—care should be taken when considering the creation of new structures and the accompanying regulatory and legal constraints.

Finally, discussion focused on the need to build a sufficient clinical research workforce. An important step in this direction would be to improve the academic culture such that clinical investigation is widely viewed as a legitimate academic pursuit.

Diabetes Breakout Session

This group’s discussion focused primarily on how the clinical research system can meet the needs and expectations of patients. Patients should be empowered and provided access to the clinical research enterprise. Voluntary health organizations such as the American Heart Association (AHA) and the American Diabetes Association (ADA) could be instrumental not only in improving patient awareness of clinical trial opportunities, but perhaps more importantly, in helping individuals understand the role of clinical research in improving health care.

In addition, the clinical research enterprise should be founded on the enthusiasm of providers. To create such a system, clinical investigators and academic leaders should be rewarded, not just financially, for their efforts in clinical research. In addition, trust in the clinical research system needs to be restored and skepticism regarding associations with the pharmaceutical industry needs to be reduced.

The discussion identified the prioritization of clinical research needs as the main challenge to any new clinical research system. A key question is who will decide which areas of disease research will receive resources.

Finally, the group acknowledged that information technology holds great promise for long-term improvement in the way clinical research is conducted. However, revamping the regulatory and ethical foundations of clinical research is essential in the short term.