Testimony

March 25, 2004

Mr. Chairman, Members of the Subcommittee, I am Dr. Elias Zerhouni, the Director of the National Institutes of Health (NIH). I am delighted to appear before you today to testify about NIH's role in clinical research.

With the support of Congress and the White House, NIH has been the driving force behind perhaps the greatest era of discovery in the history of biomedical research. We are gaining unprecedented knowledge about human biology and medical conditions. The human genome has been sequenced. The scientific community is learning how proteins and molecules function and about the mechanisms of disease. In general, the knowledge gap about human biology is shrinking quickly.

Of course, these discoveries have far less meaning if we cannot translate them into prevention methods and treatments for diseases and disabilities. This translation, commonly known as the "bench to bedside" process, cannot happen without clinical research. Broadly defined, clinical research involves the participation of human subjects in various aspects of research. It is the linchpin of the Nation's biomedical research enterprise. Clinical research ultimately establishes the safety, effectiveness and availability of new diagnostic, preventive and therapeutic approaches.

Approximately one-third - $8.4 billion - of the grants awarded by NIH support clinical research. We have established integrated clinical research networks for HIV/AIDS, heart disease, and cancer, among others, that have significantly enhanced the translation of basic discoveries. At all times, our primary concern must be the safety of the people participating in clinical studies and trials. The Federal Government has a rigorous process for ensuring the well-being of human subjects participating in Federally conducted, supported, or regulated research, ranging from the initial reviews by Institutional Review Boards (IRBs), to ongoing reviews by Data Safety and Monitoring Boards, to the authority to investigate and discipline researchers and institutions that do not abide by Federal requirements.

NIH continues to expand its clinical research program and provide resources for infrastructure and training. We have established new programs to support the professional development of medical students and medical school graduates in the conduct and ethics of clinical research. We are funding young clinical investigators and their mentors; reorganizing study sections to enhance the evaluation of grant applications about clinical research; and providing educational loan repayments for new, including minority, clinical investigators. Longstanding programs for the support of clinical research, including the General Clinical Research Centers located in academic health centers around the country and the NIH Clinical Center, also have developed new training initiatives designed to advance translational research. These programs and an array of other infrastructural activities and training mechanisms are aimed at ensuring that the "critical mass" of highly skilled personnel and state-of-the-art resources necessary for a vigorous clinical research enterprise are available.

As the Director of the largest biomedical research agency in the world, I believe it is my responsibility to continually review our programs to ensure that they are working well, and further, to be certain we are heading in the right direction. So for all our success in the clinical research area, the question is: have we done all we can do to speed the process of translation of results from bench to bedside? The answer is, we can do more and we can do it better.

When I arrived at NIH two years ago, I implemented an initiative across all of our Institutes and Centers to explore the key scientific challenges facing investigators today and to delineate the central roadblocks to scientific progress. With a focus on those activities that would require the efforts of the agency as a whole, and through broad consultations with scientists inside and outside NIH, this extensive planning effort has led to formulation of a "Roadmap" for medical research in the 21st century. One of the key goals of the Roadmap is to re-engineer the clinical research enterprise. The purpose of the re-engineering effort is to overcome obstacles to the conduct and translation of clinical research by transforming its very structure. The NIH Roadmap plan on "Re-engineering the Clinical Research Enterprise" has four main parts: Facilitating Translational Research; Enhancing the Clinical Research Workforce; Integrating Clinical Research Networks; and Coordinating Clinical Research Policies.

Facilitating Translational Research

To improve human health, scientific discoveries must be translated into practical applications. Such discoveries typically begin with observations of patients with diseases then move to the "bench" with basic research–where scientists study the mechanisms and progression of a disease at the molecular or cellular level–then progress again toward the study of these phenomena in patients at their "bedsides.".

Scientists have become increasingly aware that this bedside-to-bench-to-bedside approach to translational research requires a variety of non-traditional expertise and intense two-way collaborations with clinicians. Not only do basic scientists complement the expertise of clinicians in making novel observations, clinical researchers also make unique observations about the nature and progression of disease that can, in turn, stimulate basic investigations. Thus, translational research is a key junction in the process, where new knowledge is both tested and gained, producing new observations and hypotheses that keep the system productive and rich with discovery. However, I believe that by strengthening the infrastructure, this critical process and component of the clinical research enterprise can be accelerated.

Key to building a strong infrastructure will be the ability to increase the interactions between basic and clinical scientists, and cross-training of basic and clinical scientists in each other's disciplines, thus easing the movement of powerful new tools from the laboratory into the clinic. In one approach aimed at accomplishing this interaction, NIH intends to develop regional translational research centers. These centers would provide sophisticated advice and resources to better enable scientists to master the many steps involved in bringing a new product from the bench to clinical use. Such steps involve laboratory studies to understand the mechanisms of action of a therapeutic agent, preclinical studies in animals to evaluate how the agent is absorbed by the body and distributed to target tissues, and assessing its effectiveness as well as tendency to cause unanticipated side effects.

Once a potential new drug is developed, sufficient amounts of the drug have to be produced according to rigorous standards for testing first in animals and then in people. The clinical research re-engineering plan also envisions translational research core facilities to provide clinical researchers access to sophisticated manufacturing capacity, along with expert advice to ensure that drug-development regulations are observed. Some of these core facilities will be modeled on, or may evolve through expansion of, existing programs such as the National Cancer Institute's Rapid Access to Innovation Development program, which currently provides support for these types of resources to members of the cancer research community. Their availability to the broader research community should expedite discoveries for other disease research as well.

This re-engineering initiative will also support translational research by developing new technologies to improve the assessment of clinical outcomes. Many of the most debilitating, chronic illnesses gradually erode the quality of life because of the associated fatigue, pain and emotional challenges. Currently, these critical symptoms cannot be measured objectively in the same way as, for example, blood sugar levels or blood cell counts. More sensitive, well-validated tools need to be developed to improve measurements of these types of symptoms. Technologies, such as a computerized adaptive health assessment, could revolutionize how symptoms and treatment outcomes are assessed. Scientists will be better equipped to understand how patients perceive changes in their health status resulting from new interventions, thereby directing research to therapies that would be most highly valued by patients.

Enhancing the Nation's Clinical Research Workforce

The second component of the re-engineering plan is aimed at enhancing the Nation's clinical research workforce. To fulfill the promise of 21st century medicine and to make further progress in controlling major human diseases, the Nation must cultivate and properly train a cadre of clinical researchers skilled in translating the findings from clinical trials and other clinical research studies to applications on the front lines of care.

Clinicians must be trained to work in multidisciplinary, team-oriented environments. Specific training in disciplines important to the conduct of clinical studies (e.g., epidemiology, behavioral medicine, and patient-oriented research) is needed, and the expert skills of engineers, mathematicians, physicists, and computer science experts also must be incorporated. This component of the re-engineering plan will enhance and empower the clinical research workforce through two programs–the Multidisciplinary Clinical Research Career Development Program and the National Clinical Research Associates Program.

The Multidisciplinary Clinical Research Career Development Program will be an NIH-wide effort to train doctoral-level candidates in clinical research settings that are multidisciplinary and collaborative. The emphasis will be on new strategies and curricula with training opportunities that span a variety of disease areas; a broad range of clinical disciplines, including medicine, nursing, dentistry, pharmacy and other allied health professions; and a variety of research areas, including biostatistics, behavioral medicine, clinical pharmacology and epidemiology. The new program will be coordinated with and complement other NIH training programs that support scholars who wish to become clinical researchers. NIH plans additional programs to help smooth out the early career development pathway spanning from college to professional school, thus promoting the early identification and training of students who will become the future leaders in clinical research. By exposing students to clinical research early in their careers, it is hoped that this program will also enhance the integration of clinical research into both basic science and clinical medicine.

The clinical research workforce also must be broad enough to support the testing of ideas in large scale studies at the community level, as well as the translation of proven concepts into medical practice at the community level. The National Clinical Research Associates program will help increase the number of clinical investigators and diversify the settings in which clinical research is conducted. Through partnerships with academic investigators, the Associates will form a corps of community-based physicians trained to carry out clinical studies in their own health care settings. Together they will form a robust and versatile infrastructure of researchers well-trained in the responsible conduct of clinical research and positioned to bring research opportunities to patients while rapidly disseminating the best science-based practices.

Several projects will be required to realize the vision of the Associates. These include a study that will examine the challenges involving community practitioners in clinical research. Building on the results of this study, recommendations on ways to reduce barriers to building a model workforce for conducting clinical research are expected to evolve. Other efforts will focus on the establishment of national core competencies and best practices needed to conduct high-quality clinical research and to translate research into clinical practice. These efforts will apply to researchers working in both community and academic settings. Competencies would include relevant board certification; knowledge of clinical research design and implementation, and conflict-of-interest policies; and documentation of training in protecting participants in clinical trials. To train the Associates, the NIH plans to create several nationally recognized regional Centers of Excellence in Clinical Research Training that will be based on the results of the feasibility and pilot studies. These centers will use an integrated approach to conduct training in "real-world" settings.

Integrating Clinical Research Networks

Another component of the re-engineering plan, Integrating Clinical Research Networks, is designed to promote synergy among diverse clinical research activities through the development of linkages among research institutions, medical centers, and existing research networks. Because of the vast number of therapies, diagnostics, and preventive approaches that must be .evaluated through clinical trials, many clinical research networks operate simultaneously, but independently of each other.

Over time, this initiative aims to link research centers and existing networks in order to develop a National Electronic Clinical Trials and Research Network (NECTAR). This network will create a revolutionary new clinical research infrastructure model, which will result in greatly enhanced communication, computational capacities, access to resources, and research and analytical tools. Such a system will ultimately offer economies of scale by allowing complex research programs to benefit from a common infrastructure, rather than recreating infrastructure resources time and time again at multiple sites. Networking will provide for broad access to data and allow investigators to learn from, utilize and build upon existing data. Integration of data will encourage the formulation and study of new research questions and the cross-fertilization of major fields of inquiry in the process.

This effort will promote and expand clinical research networks that can rapidly conduct high-quality clinical studies that address multiple research questions. An inventory of existing clinical research networks will be undertaken to explore existing infrastructures for informatics and training, in order to pinpoint characteristics that promote or inhibit successful network interactivity and productivity and expand or broaden research scope. Once identified, "Best Practices" can then be widely disseminated, further enhancing the efficiency of clinical research networks.

To function effectively, these clinical research networks will need to harness and help integrate information technology and develop a national informatics network using standardized data, software tools and network infrastructure. NECTAR, which will dovetail with current medical informatics initiatives in the Department of Health and Human Services, will maximize connectivity among existing and newly created clinical research networks and help researchers to generate, use and share data, thereby reducing duplication and unnecessary overlap among trials.

To accomplish this, NECTAR will create common vocabularies, research and business tools, and common platforms and architectures. NECTAR will enable more efficient business practices and processes; enhanced data sharing and analysis; coordinated oversight and improved patient protections; and rapid translation of research into clinical findings and practice. NECTAR ultimately will assist in accelerating the pace of discovery and development, thereby helping clinical researchers better serve their patients.

Coordinating Clinical Research Policies

The last critical component of re-engineering the clinical research enterprise recognizes that other potential impediments to efficient clinical research are the diverse regulations and policies of the multiple federal agencies that fund, conduct and oversee clinical research. For example, researchers face varying requirements that pertain to reporting adverse events to NIH, the Food .and Drug Administration, the Office for Human Research Protections and IRBs, among others. Clinical researchers must understand and fulfill these varying requirements.

NIH is working in concert with regulatory agencies, research communities, and patient advocacy groups to catalyze Federal-wide coordination of policies pertaining to clinical research, to develop better processes, and to standardize requirements for reporting adverse events, human subjects protections, privacy and conflict-of-interest policies, and standards for electronic data submission. Coordinating policies and reporting requirements will help minimize unnecessary burdens that slow research while enhancing patient protections. Thus, the goal of NIH's Clinical Research Policy Coordination Initiative (CRPCI) is to work within the federal system of clinical research oversight to promote the coordination of policies, requirements, and procedures concerning clinical research, and, where appropriate, to help create streamlined approaches. The CRPCI will examine an array of issues and activities on behalf of the NIH and all its Institutes and Centers and work with other Departmental components and Federal agencies to help stimulate the development of coordinated policies, practices and new tools for compliance that take account of the goals and points of view of NIH's varied organizational components and stakeholders. As the most important part of our system of human subjects protections, IRBs will be a primary audience for our efforts. Some representative activities will include:

1. Studying existing requirements for the conduct and oversight of clinical research to assess the extent to which unnecessary or duplicative rules can be addressed without diminishing protections;
2. Exploring the expanded use of central Institutional Review Boards to facilitate and achieve greater efficiency in the review of multicenter clinical trials, such as the National Cancer Institute's Central Institutional Review Board program for adult oncology trials;
3. Developing tools and materials to help ensure and facilitate compliance with existing rules;
4. Promoting the development of coordinated clinical research policies by working with other Federal entities (such as FDA, OHRP, and the Departments of Defense and Veterans Affairs) that fund, conduct, oversee, and establish policy for clinical research;
5. Soliciting input on various policy goals from key communities, such as patients, scientists, institutional leadership, IRB members, and other constituencies with a stake in the conduct of clinical research; and
6. Developing educational and training tools to assist investigators and IRBs in the interpretation of and compliance with human subjects and related research requirements.

While NIH has assumed a leadership role in conceptualizing and implementing this plan to reconfigure the clinical research enterprise, many other stakeholders have broader roles and vital responsibilities in assuring the future of clinical research, including other federal agencies, academic health centers and biomedical research institutions, private foundations, the pharmaceutical and biotechnology industries, the health insurance industry, patient advocacy groups, and the general public. In implementing the re-engineering plan, NIH recognizes that success will depend on continuing close collaborations and consultations with these many partners.

Conclusion

In taking bold steps to re-engineer the clinical research enterprise, NIH hopes to create a new infrastructure to support clinical research that will facilitate the rapid translation of discoveries from the laboratory to the clinic and provide a robust force of clinical investigators to test new diagnostic, therapeutic and preventive strategies in patients far sooner than is possible at present. By enhancing the interoperability of clinical research networks, and by improving the coordination of the important rules and regulations that ensure the safety and ethics of these studies, the system will be more efficient and there will be far fewer impediments to the conduct of clinical research. Clinical research will advance more swiftly, more and better therapies and preventive measures will be developed more quickly, and, ultimately, significant improvements will be made in human health and the quality of life. We look forward to keeping Congress apprized of our continuing progress in Re-engineering the Clinical Research Enterprise.

Last Revised: March 25, 2004

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