NIH Seeks to Re-Engineer Clinical Research System

National Institutes of Health director Elias Zerhouni recently unveiled a plan for transforming the nation’s medical research capabilities. The “NIH Roadmap for Medical Research” aims to recast the nation’s “entire system of clinical research” by moving away from the single-investigator research model and towards increased use of integrated networks that can quickly study large groups of well-characterized subjects. The process will involve harmonizing clinical research regulatory requirements, training more research professionals, and developing a clinical research informatics network (details available at nihroadmap.nih.gov).

Although these initiatives most directly affect NIH’s grant programs and internal operations, private sector entities would be affected in many ways. Formation of integrated networks of well-trained investigators could provide a valuable resource for sponsors and contract research organizations. More uniform regulatory standards would affect trial conduct overall. And the development of new research tools and methods for analyzing clinical data stand to enhance the design of research protocols and evaluation of study results.

Encouraging innovators

The NIH Roadmap aims to encourage more high-risk studies and to establish a structure for trans-institute and collaborative research. The initiative begins at a time when the doubling of NIH’s budget to $27 billion is complete, and Congress is anxious to see more biomedical breakthroughs emerge from its sizeable investment in the nation’s research enterprise. Zerhouni has devoted his first year as director to mapping out this new vision for NIH, which will begin by spending $130 million in the coming year and $2 billion over five years. Most of the money will come from individual NIH institutes, a perilous strategy given the traditional independence of these organizations.

Initial projects involve building a “better toolbox” that capitalizes on new discoveries from the human genome project and advances in molecular and cell biology. The plan supports development of instrumenta-tion, reagents, proteomics technologies, and other applications for understanding cell networks.

Harmony and integration

A key component of the Roadmap is to “re-engineer” the U.S. clinical research system in order to better translate basic scientific discoveries into needed treatments for many serious diseases. This overhaul aims to:

Harmonize clinical research regulatory requirements. NIH will work with FDA, the Office of Human Research Protections, institutional review boards and other organizations to standardize rules for conducting clinical trials. One model is NIH’s effort to establish a more efficient system for reporting adverse events in clinical trials for gene therapy studies. The aim is to develop better processes and standardize requirements for ensuring the protection and privacy of human study participants, for addressing conflicts of interest, and for standardizing electronic data submission.

Integrate clinical research networks. NIH aims to identify and expand networks of skilled investigators that can test the “vast number of therapies, diagnostics and treatments” in larger numbers of patients more quickly than in the past. To avoid duplication of effort and gain more standardized data that can be shared across studies, NIH will conduct an inventory of the many existing research networks and identify their “best practices.”

A National Electronic Clinical Trials and Research Network (NECTAR) will be established to facilitate data and resource sharing. The system will make it easier for individual physicians to participate in national clinical studies and allow rapid dissemination of research results to subject advocates and the public.

Enhance training for clinical researchers. NIH plans to establish an internal training program to produce more skilled clinical researchers able to work in interdisciplinary projects. Training will cover a broad range of disease areas, professions (nursing, pharmacy) and research activities (biostatistics, clinical pharmacology, epidemiology). To involve more community physicians in clinical research, NIH will explore ways to train NIH clinical research associates, possibly by establishing regional centers to train researchers in “real-world” settings.

Provide services and resources to help move basic discoveries into clinical applications. The aim is to reduce bench-to-bedside bottlenecks by encouraging interaction among basic scientists and clinical researchers. One proposal is to establish Regional Translational Research Centers to conduct laboratory studies examining a therapy’s mechanism of action and animal studies to determine absorption and side effects of an agent.

NIH also is exploring means to supply clinical researchers with access to manufacturing capacity able to produce test therapies that meet regulatory standards. Alternatively, NIH offices could contract with pharmaceutical companies to supply test materials. A model for this program is the National Cancer Institute’s Rapid Access to Innovation Development program, which offers clinical supplies and other research services to investigators who may lack such support.

Develop technologies to better assess clinical outcomes. The aim is to develop validated tools for measuring improvements in subjects’ quality of life (fatigue, pain) as accurately as methods for measuring blood sugar levels or blood cell counts. Scientists will explore new computer systems that can improve assessment of symptoms and treatment outcomes and help direct research to therapies of highest value to patients.

Challenges ahead

The broader goal of the NIH Roadmap is to shift from single-purpose, isolated clinical trials and towards increased use of a common infrastructure. Expanded partnerships among patient groups, community physicians, and academic researchers will help move clinical studies out of academic centers and into communities. Innovative investigators will gain assistance and technical support to translate new ideas into clinical trials.

Not all these proposals will meet with universal applause. The directors of NIH institutes traditionally have had tight control over programs and resources and may be reluctant to support trans-NIH initiatives, particularly if budgets continue to tighten. Efforts to encourage more public-private partnerships are likely to generate charges that pharmaceutical companies reap too-high profits from taxpayer-supported research, making industry wary of entering into licensing agreements with NIH programs. Efforts to streamline federal rules governing study participant protections and conflicts of interest also are likely to meet resistance in Congress and among patient advocates.

Zerhouni unveiled the Roadmap in September partly to address calls for streamlining NIH’s increasingly fragmented structure and for ensuring that its resources are used most efficiently and most effectively. A panel formed by the Institute of Medicine issued a report in July (2003) offering fairly modest recommendations for dealing with these issues, primarily by halting creation of new NIH institutes or centers and by giving the NIH director more authority and resources to fund trans-NIH initiatives and special projects (“Enhancing the Vitality of the National Institutes of Health,” 29 July 2003, at www.iom.edu).

At a joint Senate-House hearing last month (2 October 2003), former NIH director Harold Varmus supported these proposals and called on Congress to authorize NIH to form “clusters” of institutes and centers to fund large, cross-cutting projects. Zerhouni acknowledged at the hearing that his office lacks funding to implement the Roadmap initiatives and has to rely on individual institute directors to support major collaborative programs.

Call for comparisons

The Congressional hearing provided a prime example of the broad range of pressures on NIH to fund specific disease research programs, such as obesity, or to respond to hot political issues, such as stem cell research. Several legislators questioned NIH grants for sex-related studies, while others urged the agency to do more research on the comparative effectiveness of new drugs.

Senator Hillary Rodham Clinton (Democrat, New York) asked why NIH does not support more studies, such as one showing that older blood pressure therapies may be more effective than newer, more costly medicines. Representative Tom Allen (Democrat, Maine) sought support for his legislative proposal that would give NIH $50 million to conduct studies on the comparative effectiveness, cost-effectiveness, and comparative safety of prescription drugs. The Agency for Healthcare Research and Quality (AHRQ) also would gain $25 million to explore such issues through evidence-based practice centers.

Separately, officials at AHRQ and Medicare offered a proposal to encourage more clinical research on the clinical effectiveness of different products and medical procedures in a recent article in the Journal of the American Medical Association (Sean Tunis, Daniel Streyer, and Carolyn Clancy “Practical Clinical Trials,” Journal of the American Medical Association, Vol. 290, No. 12, 24 September 2003). The article urged public and private entities to collect scientific evidence through “practical clinical trials” (PCTs) to support clinical and health policy choices. Such studies would involve large, diverse study populations and would collect data on a broad range of health outcomes in order to compare alternative interventions.

Because pharmaceutical companies generally do not fund comparative studies for fear that the results could reflect poorly on a new product, the authors suggest that the Institute of Medicine develop a list of topics where such research data would be most useful in filling important “knowledge gaps” about clinical effectiveness.

Zerhouni commented at the October hearing that NIH may support some comparative drug studies that address major public health issues, but is likely to face criticism from heavy investment in areas linked to specific policy issues. He added that Roadmap initiatives to establish standardized data networks may provide information on medicine use and prescribing that could address concerns about whether increased spending on prescription drugs is appropriate and justified.