1
Introduction

The United States currently enjoys a remarkably productive system of biomedical research. The basis of this highly successful enterprise is the partnership of academia, government, and industry in making discoveries leading to better understanding and improved ways of preventing and treating disease and promoting health. Congress has set national biomedical research priorities and provided generous research funding. A key part of the system is the National Institutes of Health (NIH), the largest single source of support for biomedical research in the nation and the world. Industry also invests heavily in biomedical research, but NIH provides the bulk of the support for basic and clinical research that is still far from commercial payoff but is essential for the development of new treatments several years in the future. To take advantage of the rich talent of American scientists, NIH carries out its mission of advancing science and its applications primarily by supporting extramural research, that is, research conducted by investigators in universities, academic health centers, and independent research institutes. In addition to producing extraordinary scientific and medical advances, the policy of supporting research in academia insures a continuing supply of well-trained researchers, because graduate students and postdoctoral fellows are able to learn by participating in cutting-edge research.

NIH uses a variety of ways to identify and support high-quality research. The main approach is to invite extramural investigators to submit their best ideas for research projects, have the proposals reviewed and rated by an appropriate peer review group, and give grants for the projects con-



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NIH Extramural Center Programs: Criteria for Initiation and Evaluation 1 Introduction The United States currently enjoys a remarkably productive system of biomedical research. The basis of this highly successful enterprise is the partnership of academia, government, and industry in making discoveries leading to better understanding and improved ways of preventing and treating disease and promoting health. Congress has set national biomedical research priorities and provided generous research funding. A key part of the system is the National Institutes of Health (NIH), the largest single source of support for biomedical research in the nation and the world. Industry also invests heavily in biomedical research, but NIH provides the bulk of the support for basic and clinical research that is still far from commercial payoff but is essential for the development of new treatments several years in the future. To take advantage of the rich talent of American scientists, NIH carries out its mission of advancing science and its applications primarily by supporting extramural research, that is, research conducted by investigators in universities, academic health centers, and independent research institutes. In addition to producing extraordinary scientific and medical advances, the policy of supporting research in academia insures a continuing supply of well-trained researchers, because graduate students and postdoctoral fellows are able to learn by participating in cutting-edge research. NIH uses a variety of ways to identify and support high-quality research. The main approach is to invite extramural investigators to submit their best ideas for research projects, have the proposals reviewed and rated by an appropriate peer review group, and give grants for the projects con-

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation sidered the most promising by the peer reviewers. The research model historically has been a single investigator working with one or two collaborators and several postdoctoral fellows, graduate students, and technicians on a specific project of three to five years duration, after which the investigator must apply for a renewal of the grant or a new award by proposing follow-up studies or a new project. These individual investigator-initiated grants are the mainstay of NIH’s extramural research program, accounting for nearly two-thirds of the research grants awarded by NIH in fiscal year (FY) 2002 and the majority of the funding for the grants.1 Another research model is the multi-investigator research center. In academia, centers have evolved as a structure to facilitate collaborations by multiple investigators on a research problem of common interest. NIH has supported research centers for many years as a means of encouraging interdisciplinary basic, clinical, and population-based research on scientific problems not being adequately addressed by individual investigator grants alone. Over the past decade NIH support for such grants has consistently constituted between 8 and 9 percent of the total NIH budget.2 Box 1-1 provides NIH’s definition of a research center grant. As the definition suggests, center grants are used in a variety of circumstances for a variety of purposes. Chapter 2 explores this variety in more detail, but the committee believes that it is useful to conceive of center grants as members of one of three general types: Center Infrastructure awards, or “core” grants, support administrative and technical services required by a group of investigators whose research is funded by independently obtained research grants. The primary goal is to focus research on a particular set of questions and increase efficiency. Research Center awards fund not only common services but research projects as well. In some cases, they may also support additional activities such as community education, screening and counseling programs, and educating medical and allied health professionals about state-of-the-art diagnostic, prevention, and treatment techniques. 1   In FY2002, NIH awarded 43,500 research grants, of which 63 percent were R01 (individual investigator) research project grants. R01 grants accounted for 53.4 percent of the grant funding ($16.8 billion). Calculated from NIH table “NIH Research Grant Awards by Fiscal Year and Activity, Fiscal Years 2000-2002” (http://grants.nih.gov/grants/award/research/rgbyact0002.htm). 2   NIH also employs a number of types of research grants other than those for centers and individual-investigator research projects, including research project grants for multi-investigator research, cooperative agreements for clinical trials, and research career awards. NIH also gives research training awards, issues research and development contracts, and supports an intramural research program (see section, Background on NIH, below).

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation BOX 1-1 NIH Research Center Grants Research Center grants are awarded to extramural research institutions to provide support for long-term multidisciplinary programs of medical research. They also support the development of research resources, aim to integrate basic research with applied research and transfer activities, and promote research in areas of clinical applications with an emphasis on intervention, including prototype development and refinement of products, techniques, processes, methods, and practices. SOURCE: National Institutes of Health FY2001 Investments. April 2001. (http://www.nih.gov/News/BudgetFY2002/FY2001investments.htm#centers). Research Resource Centers develop and provide specialized resources, services, and tools to researchers across the country. Examples of their products include animal models, microarrays for genomic analyses, and production of islet cells for transplantation in patients with diabetes. The first two types of center programs are especially popular with the public, organizations representing patients, and Congress, because they can bring focus, visibility, and, often, more funding (private and public) to research on a specific disease. A citizen with cancer, for example, is more likely to be aware of the existence of a nearby NIH-funded cancer center than to know that the National Cancer Institute (NCI) is also supporting more than 6,000 individual research projects across the country. Centers for research on AIDS, Alzheimer’s disease, Parkinson’s disease, and many other diseases and conditions play a similar role. Establishing research centers is also seen as an effective and at times necessary way to expedite the translation of basic research advances into clinical practice—for example, better diagnoses and treatments—while providing state-of-the-art care to patients participating in the research. Every year Congress, with the encouragement of patient advocacy groups, urges NIH to establish various new centers for particular diseases and conditions. Usually NIH responds by creating a center program or by taking other initiatives it determines would be more effective in advancing research at that time. Sometimes, however, Congress directs NIH to establish a new center program despite NIH’s view that centers would not be the most effective approach to the research/disease problem being addressed and therefore that funding directed towards establishment and support of the center would be better spent differently. The occasion of several of these congressional mandates in recent years led to this study of the conditions in

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation which the establishment of center programs is appropriate. Clearly, in the view of some, congressional intervention may have a positive effect, and such input should be anticipated and integrated into the process. There is certainly evidence that center programs can be and have been very productive ways to organize research. For example, collaborative research among Alzheimer’s Disease Centers supported by the National Institute on Aging has led to a number of discoveries, including the finding that one form of apolipoprotein E is an inherited risk factor for the development of sporadic Alzheimer’s disease and that familial Alzheimer’s disease is linked to genes on chromosomes 21, 14, and 1 (NIA, 2001). There are a number of other examples of multicenter collaborations among ADCs in which pooling clinical and pathological information from a large number of patients and controls has helped advance understanding of the pathological basis of dementia. These include development of the Alzheimer’s Disease Assessment Scale, Clinical Dementia Rating Scale, and criteria for neuropathological diagnosis of Alzheimer’s disease and identification of Mild Cognitive Impairment as a precursor of dementia. Among the other contributions of centers are those of the Centers for AIDS Research (CFARs) supported by the National Institute of Allergy and Infectious Diseases (NIAID) and other institutes. One example is a collaboration of two CFARs on a bench-to-bedside or translational research project which showed that a peptide designed and synthesized to interfere with the replication of HIV worked in an animal model. Next, the centers demonstrated proof of concept in humans in a Phase I clinical trial (OAR, 1999). The peptide (T-20, or enfuvirtide) was then developed by industry, approved by the Food and Drug Administration (FDA) in the spring of 2003, and is now the cornerstone of salvage therapy for HIV-infected patients in the developed world. The use of plasma HIV RNA (viral load) was developed at a CFAR that had established a specimen repository and hosted basic research projects supported by R01 individual-investigator grants. The first description of viral dynamics of HIV was made at two CFARs working on drug development with several pharmaceutical companies and in which basic research by R01-supported investigators helped lead to the findings. A long-term study conducted in Comprehensive Sickle Cell Centers supported by the National Heart, Lung, and Blood Institute (NHLBI) recently showed that the drug hydroxyurea prolongs the life of sickle cell anemia patients with moderate to severe forms of the disease (a 1995 study had shown that hydroxyurea reduced symptoms and the need for hospitalizations and transfusions by half among such patients and led to its approval by the FDA as the first drug for treatment of sickle cell disease) (Steinberg et al., 2003). A clinical trial at a specialized center of research on osteoporosis supported by the National Institute of Arthritis and Muscu-

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation loskeletal and Skin Diseases (NIAMS) was one of two recent studies showing that combining two effective treatments for osteoporosis does not improve bone mineral density more than using either treatment alone, a finding that should reduce medical costs by discouraging the use of the more expensive combination therapy (Finkelstein et al., 2003). Despite successes like these, establishing research centers may not always be the best research strategy. To be cost effective, the advantages of research centers must outweigh the initial investment in infrastructure, extra costs of managing the program, additional costs of center administration, and reduced flexibility in the institute’s budget imposed by a relatively large and long-term funding commitment. As a brief introduction to an analysis developed in detail in Chapter 4 of this report, a minimum set of criteria for initiating a center program should include the existence of promising research opportunities that are uniquely suited to the center approach or can be pursued better or faster through center support than individual project grants, enough qualified and interested investigators to form the nucleus of leadership for the centers, and a reasonable expectation that institute’s budget can support a long-term commitment to the center program without compromising the institute’s balanced research portfolio. Chapters 3 and 4 address the process and criteria that would help guide NIH and the Congress, as well as inform advocacy and other interested parties, about the circumstances in which a program of centers would be the most appropriate mechanism of research support. There is also good reason to believe that demand for centers and other organizational forms for conducting coordinated and collaborative research programs by interdisciplinary teams will increase in the future. This demand is arising from two related trends: the growth of large-scale biomedical science typified by the sequencing of the human genome (IOM and NRC, 2003) and the increasing opportunities for translating advances in the understanding of biological systems into better ways of preventing, screening, diagnosing, and treating diseases (Zerhouni, 2003a). For example, the National Institute of General Medical Sciences (NIGMS), which emphasizes basic research and historically has relied on individual investigator grants, has recently begun a number of new initiatives for better basic understanding of complex biological systems that involve the creation of center programs and other organizational arrangements—such as consortia, alliances, and networks—for creating large interdisciplinary and interinstitutional teams and establishing an infrastructure for integrating results through systematic analysis. These initiatives stem from a planning exercise during 1997 and 1998 in which advisory groups expressed the view that, in addition to continuing its long-time support of research elucidating the individual steps in biological processes at the subcellular and molecular level, it was time for NIGMS to begin to develop mechanisms to gain a

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation basic understanding of entire integrated biological systems, a complex effort that would require an integrated effort by many kinds of scientists (NIGMS, 1998). Other institutes have been receiving similar advice and establishing similar initiatives.3 The need for teams to pursue cutting-edge science in systems biology is also a major theme in the NIH Roadmap for Medical Research, a strategic planning exercise conducted by Dr. Elias Zerhouni, the new director of NIH, in the summer of 2002. One of the major conclusions of the exercise was, “Because of the complexity and scope of today’s scientific problems, traditional ‘mentor-apprentice’ models must be replaced by integrated teams of specialists from numerous disciplines that were considered unrelated in the past” (Zerhouni, 2003a).4 Accordingly, “To foster the creation of multidisciplinary teams of experts in biology, behavior, engineering, mathematics, chemistry, physics, informatics, and clinical research, the NIH will initiate new programs that emphasize support for groups of investigators with diverse expertise who are able to bring forth proposals with novel prospects for scientific advances” (NIH, 2003).5 Research universities are also responding to changes in the nature of scientific investigation by creating large interdisciplinary research and educational centers. For example, the Massachusetts Institute of Technology, Harvard University, and the Whitehead Institute for Biomedical Research are establishing a joint research institute as a vehicle for bringing together experts in biology, medicine, chemistry, engineering, and computer science in large-scale projects to determine the molecular causes of disease by sys- 3   See, for example, the minutes and consensus report of a special emphasis panel on integrative research formed by the NHLBI in 1996 (NHLBI, 1996). 4   In addition to “Changing dynamics of the research teams of the future,” other major themes of the Roadmap were: “New pathways to scientific discovery” (including integrative interdisciplinary research focused on understanding how complex biological systems operate) and “Need to re-engineer the national clinical research enterprise for optimal translation of our discoveries into clinical reality.” 5   On September 30, 2003, after this report was drafted, NIH released the first initiatives of the Roadmap. New center programs were a major feature of this effort “to remove some of the biggest roadblocks that are keeping research findings from reaching the public as swiftly as possible” (Zerhouni, 2003b). Requests for Applications (RFAs) have been issued for five new center programs (National Technology Centers for Networks and Pathways, National Centers for Biomedical Computing, Exploratory Centers for Interdisciplinary Research, Development of High Resolution Probes for Cellular Imaging, and Centers for Innovation in Membrane Protein Production) and at least three more center programs are in the planning stage (Nanomedicine Centers, Bioactive Small Molecule Library and Screening Centers, and Regional Translational Research Centers).

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation tematically examining genes and proteins. The institute is seen by its sponsors as a “new model” intended to “complement existing research efforts by serving as a catalyst and nucleus for larger collaborative projects that cannot readily be accomplished in the traditional setting of individual academic laboratories—for reasons such as a need for scale, scientific or organizational infrastructure, or multidisciplinary expertise.” Accordingly, the institute will include “both individual research laboratories and larger, team-based programs to produce and employ genomic tools” (MIT, 2003). Similar initiatives include the Institute for Integrative Genomics at Princeton University, Bio-X Program for Bioengineering, Biomedicine and Biosciences at Stanford University, Interdisciplinary Research Institute at the University of Chicago, and Health Sciences Initiative at the University of California at Berkeley. CHARGE TO THE COMMITTEE A Senate amendment to the Muscular Dystrophy Community Assistance, Research and Education Amendments of 20016 specified that the “Secretary of Health and Human Services shall enter into a contract with the Institute of Medicine for the purpose of conducting a study and making recommendations on the impact of, need for, and other issues associated with Centers of Excellence at the National Institutes of Health.” Specifically, the legislation called for the Institute of Medicine (IOM) to consider: The current areas of research incorporating Centers of Excellence (which shall include a description of such areas) and the relationship of this form of funding mechanism to other forms of funding for research grants, including investigator-initiated research, contracts, and other types of research support awards. The distinctive aspects of Centers of Excellence, including the additional knowledge that may be expected to be gained through Centers of Excellence as compared to other forms of grant or contract mechanisms. The costs associated with establishing and maintaining Centers of Excellence, and the record of scholarship and training resulting from such Centers. The research and training contributions of Centers should 6   P.L. 107-84, Muscular Dystrophy Community Assistance, Research, and Education Amendments of 2001, Sec. 7, Study on the Use of Centers of Excellence at the National Institutes of Health.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation be assessed on their own merits and in comparison with other forms of research support. Specific areas of research in which Centers of Excellence may be useful, needed, or underused, as well as areas of research in which Centers of Excellence may not be helpful. Criteria that may be applied in determining when Centers of Excellence are an appropriate and cost-effective research investment and conditions that should be present in order to consider the establishment of Centers of Excellence. Alternative research models that may accomplish results similar to or greater than Centers of Excellence. Although the legislation refers to “centers of excellence,” the term is a general label that is not specific to a particular kind of center supported by NIH. Not all legislatively mandated centers are centers of excellence, and NIH has initiated centers of excellence programs in the absence of congressional or advocacy group interest. NIH also supports several programs that fund entities that function like centers (and use center grants) but are called “programs of excellence.” NIH does not always use the title “centers of excellence,” even though the legislation establishing a center program does. Finally, several programs called centers of excellence that are of interest to advocacy groups and Congress are not supported with center grants. IOM staff thus sought guidance about the scope intended, and Senate staff confirmed that the study was meant to include all NIH-supported research centers, whether or not they are formally called centers of excellence. In September 2002 the NIH Office of Extramural Research contracted with IOM to conduct the study, and at the request of IOM, the National Research Council established the Committee for Assessment of NIH Centers of Excellence Programs. The committee was charged to: … conduct a one-year study of the use of research centers at the National Institutes of Health. The study will focus on the criteria and procedures used in deciding to adopt the use of centers, how they are designed and administered, comparisons with other mechanisms of research support, their impacts and costs, and how they are evaluated as a mechanism (as well as how individual centers are evaluated). The emphasis will be on how NIH uses centers as a program mechanism, compared with other mechanisms, rather than on how individual centers are chosen for awards. The committee will prepare a consensus report with findings and recommendations for improving the use of the center mechanism, given the many factors that must be taken into account in a specific area of re-

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation search, including the state of the science, presence of promising research opportunities, burden of disease, need for interdisciplinary approaches, alternative mechanisms (e.g., research project grants, program project grants, and contracts), and adequacy of the research infrastructure. The report will include recommended criteria and processes for deciding whether research centers should be created. This report contains the results of the committee’s deliberations in responding to this charge, including findings and recommendations. The report is organized around broad topics: current use of extramural centers by NIH, initiation and management of center programs, and evaluation of center programs, but each element of the charge is specifically addressed at an appropriate place in the report. BACKGROUND ON NIH As noted above, supporting extramural research centers within universities, medical centers, hospitals, and other research institutions is one way that NIH carries out its mission, which is “science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability.”7 NIH itself is part of the Department of Health and Human Services, along with other health-related agencies, including the Agency for Healthcare Research and Quality, Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention (CDC), FDA, Health Resources and Services Administration, Indian Health Service, and Substance Abuse and Mental Health Services Administration. NIH is the primary federal agency for support of health research, accounting for more than 80 percent of annual federal expenditures on health research and development (R&D).8 In FY2003, NIH’s budget was $27.3 billion, and the President’s budget request for FY2004 would increase it to $27.8 billion.9 Most of the budget (approximately 83 percent) funds extramural activities, including the research centers that are the subject of this report.10 Other extramural activities include support of individual and small-group research projects, clinical trials networks, research training programs, R&D contracts, research equipment and instrumentation, and research facility construction and renova- 7   http://www.nih.gov/about/. 8   http://grants.nih.gov/grants/award/research/sourfund.htm. 9   http://www.nih.gov/news/budgetfy2004/fy2004presidentsbudget.pdf. 10   http://www.nih.gov/about/NIHoverview.html.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation tion.11 Currently, NIH is supporting about 46,000 research grants, 2,400 R&D contracts, and 17,000 research training positions at 2,000 extramural institutions.12 The scientific structure of NIH consists of 20 institutes and 7 centers (these centers are part of NIH itself and are not the subject of this report; they are included in the term “institutes” in the remainder of this report to avoid confusion about the term “center”). Most of the NIH institutes are focused on a disease (e.g., NCI), vital organ system (e.g., NHLBI), or population group of special concern (e.g., National Center for Minority Health and Health Disparities). Appropriations are made to the individual institutes after Congress has considered testimony from NIH officials, representatives of the scientific and medical communities, health advocacy groups, and concerned individuals. Most research grants are reviewed and scored for scientific merit by independent peer review groups that are organized by field of research (e.g., immunology) rather than disease (e.g., Parkinson’s). In this way NIH attempts to ensure that the research it supports is both responding to the health needs of the public and pursuing the most promising scientific opportunities. Support of extramural research centers has a long history at NIH. The first center program was the General Clinical Research Center Program of the National Center for Research Resources (NCRR), which began in 1959 after Congress asked NIH to improve the quality of clinical research and help move laboratory research into clinical practice more quickly. In 1960 NHLBI established the first primate research center after Congress appropriated $2 million to establish one or two such centers. In 1961 NCI began funding cancer research centers at universities and other nonprofit research institutions, and NHLBI and other institutes soon followed suit in their respective areas of research. The War on Cancer Act of 1971 mandated the establishment of “comprehensive” cancer centers, which were modeled after several leading extramural research institutions of the time that combined excellence in treatment and public education with research and training of researchers and clinicians.13 The use of centers has grown steadily over time. NIH funded 296 center grants in 1970, 542 in 1980, and 686 in 1990. 11   The intramural research program accounts for another 9 percent of the NIH budget, and the remainder funds the extramural research management and support staff, Office of the Director, National Library of Medicine, and construction and renovation of NIH buildings and facilities. 12   Calculated from NIH table “NIH Competing and Noncompeting Research Grants by Kind and Type, FY2000” (http://grants1.nih.gov/grants/award/research/kndtyp00.txt). 13   M.D. Anderson Hospital and Tumor Institute, Memorial Hospital and Sloan-Kettering Institute complex, and Roswell Park Memorial Institute.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation CENTERS TODAY Today, every NIH institute supports extramural centers (Appendix A). NIH reports funding 1,137 research center grants in FY2002. Although the number of extramural centers funded by NIH has grown steadily during the past 30 years, the percentage of the total NIH budget accounted for by center grants has remained between 8 percent and 9 percent since the mid-1980s. It should be noted, however, that one of the findings of this study is that some center programs use awards that are not formally classified, and therefore not counted, as center awards. This issue is addressed in Chapter 2, where recent quantitative trends in center awards are analyzed. Many of the oldest, largest, and best known center programs fund multidisciplinary laboratory, clinical, and population-based research on a disease or other health problem with the expectation that advances in basic research will not only be facilitated in a center setting but will be translated more quickly into improved treatments there as well. These centers are also commonly expected to contribute by training new researchers and clinicians, demonstrating innovations in care in their localities, and disseminating information to health professionals and the public. Examples include the Cancer Centers, Specialized Centers of Clinically Oriented Research (in heart, lung, and blood diseases), Alzheimer’s Disease Research Centers, Diabetes Research and Training Centers, and Centers for AIDS Research, which are supported by NCI, NHLBI, NIA, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and NIAID, respectively. Congress has long favored the use of centers as a means of focusing attention on a disease it perceives as underfunded, beginning in the 1950s with the establishment of NIH’s own Clinical Center and the extramural General Clinical Research Centers. In many cases, the appropriations committees have urged NIH to establish extramural research centers in reports accompanying appropriations bills, and sometimes they have specified a number of centers or earmarked an amount of funding in report language or (rarely) in the appropriations act. From time to time, the authorizing committees establish a new center program, or codify an existing center program, by including it explicitly in the Public Health Service (PHS) Act, which means not only that NIH has to establish and fund the program but that it must go back to Congress to make major changes in the program. In recent years, the PHS Act has been amended to establish centers on Parkinson’s disease (1998), autism (2000), fragile X syndrome (2000), minority health and health disparities (2000), muscular dystrophy (2001), and rare diseases (2002). Patient advocacy groups were instrumental in persuading Congress to mandate these recent centers, which are similar in purpose to many of the earlier center programs such as the Cancer and Alzheimer’s Disease Cen-

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation ters. They are intended to bring together basic and clinical researchers from different disciplines to focus the research on a particular disease and promote translation of the research into better treatments for patients, and they are expected to become regional resources for public information and education, clinical research training, and state-of-the-art care for patients participating in clinical research protocols. As noted above, NIH also funds a number of other types of centers, such as centers to provide research resources (e.g., NCRR’s Regional Primate Centers, Animal Resource Centers, and Biotechnology Resource Centers) or promote institutional capacity building (e.g., NCRR’s Research Centers in Minority Institutions and Centers of Biomedical Research Excellence). There are also centers for multidisciplinary basic research (e.g., NIA’s Nathan Shock Centers of Excellence in Basic Biology of Aging and some of NCI’s Cancer Centers). Some centers were established to accelerate the development of a scientific methodology, data set, or research tool that would benefit a broad range of researchers (e.g., the Human Genome Centers set up by the National Human Genome Research Institute [NHGRI], NHLBI’s Proteomics Centers, and the new Centers of Excellence in Chemical Methodologies and Library Development funded by NIGMS). At the same time, NIH also funds activities called “centers” that are in the nature of service providers, such as data centers for clinical trials networks, but do not conduct research per se. These are usually but not always operated under contract rather than under a grant. Current examples include a Statistical and Clinical Coordinating Center for the Contraceptive Clinical Trials Network supported by the National Institute of Children and Human Development (NICHD) and a Coordinating and Biostatistics Center for the Food and Waterborne Diseases Integrated Research Network supported by NIAID. Chapter 2 examines this variety and suggests a classification scheme to better organize thinking about centers. CONTEXT OF THIS STUDY The immediate impetus for the congressional request for a study of centers of excellence at NIH was a question about the advisability of Congress mandating the establishment of Centers of Excellence for Muscular Dystrophy Research against the advice of NIH. The question was not an isolated one. Patient advocacy groups have pressed Congress to establish a series of center programs in recent years, and similar pressures from other advocacy groups for specific centers will no doubt be proposed in the future.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation Immediate Context NIH was directed to expand research on muscular dystrophy by the Children’s Health Act of 2000, which had a brief section that said little more than that “The Director of NIH shall expand and increase coordination in the activities of the National Institutes of Health with respect to research on muscular dystrophies, including Duchenne muscular dystrophy” (DMD) and that “There are authorized to be appropriated such sums as may be necessary to carry out this section.”14 The bill addressed a number of childhood diseases and mandated five autism and three fragile X syndrome centers, but when it was discussed on the floor, a number of members of the House commented that NIH was not doing enough about muscular dystrophy. NIH responded by holding a workshop in May 2000 on DMD and issuing a new Program Announcement (PA), “Research on Therapeutic and Pathogenic Approaches for the Muscular Dystrophies,” in January 2001 soliciting research proposals from extramural scientists. NIH also sponsored a conference on facioscapulohumeral muscular dystrophy in May 2000 and issued an RFA soliciting exploratory research on the disorder in November 2000. In February 2001, at the urging of muscular dystrophy patient advocacy groups, Representative Roger Wicker introduced H.R. 717, the Duchenne Muscular Dystrophy Childhood Assistance, Research and Education Amendments of 2001. The bill called for expansion of research and related programs concerning DMD and establishment of at least three DMD “centers of excellence” by NIH, establishment of three regional centers of excellence in DMD epidemiology by CDC, and establishment of an interagency muscular dystrophy coordinating committee to prepare a plan and report annually to Congress. Two weeks later, the Senate Appropriations Subcommittee on Labor, Health and Human Services, and Education held hearings on muscular dystrophy. Jerry Lewis, chairman of the Muscular Dystrophy Association (MDA), and Dr. Leon Charash, chair of MDA’s Medical Advisory Committee, testified that, while MDA had funded most of the advances in knowledge to date about muscular dystrophy and the genetic defects causing it, turning that knowledge into effective therapies was going to be so expensive that federal funding would be needed. The president of Parent Project for Muscular Dystrophy Research and its scientific director testified that NIH funding was small and hardly growing and endorsed centers to provide an environment in which a critical mass of researchers could be assembled and promote more rapid translation of research into treatments. 14   P.L 106-301, Children’s Health Act of 2000, Title XXII, Muscular Dystrophy Research.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation In May 2001 Senator Paul Wellstone introduced S. 805, a bill similar to the House bill, except that it broadened the focus of research to include all muscular dystrophies.15 To handle the broader scope, the bill increased the number of mandated centers from three to five. The House Subcommittee on Health held hearings on H.R. 717, dubbed the MD-CARE Act, in June 2001. Subcommittee members and patient advocates testified that NIH was not doing enough and called for a greater effort in developing therapies and clinical trials. Representative Charles Pickering, one of the bill’s sponsors, noted the January 2001 PA setting aside $5 million over five years and said, “This is a positive development but more needs to be done. NIH must reorder its priorities to assure that developments in therapies to treat this disease are translated to clinical trials and to the patients.”16 When the bill was marked up by the House Energy and Commerce Committee several weeks later, Chairman W.J. “Billy” Tauzin released a statement that the legislation authorized Centers of Excellence for Muscular Dystrophy “so that extramural research supported by NIH will bring some focus to this disease.” NIH’s position was that too little was understood about muscular dystrophies to justify the costs of clinically oriented centers. It argued that expanded funding should be used to support individual-investigator grants to advance the state of the science to the point that more elaborate programs, such as program projects, and eventually centers, would be productive. There were concerns that there might not be five good proposals and that center grants would most likely go to the small cadre of top investigators in the field who were already funded through individual project grants rather than expand the pool of researchers. NIH was also worried about the expectations of patient groups that research centers would also be treatment centers, because NIH’s mission does not include treatment except for the limited number of patients involved in clinical protocols. Advocacy groups for dystrophies that were less studied than DMD were also concerned about a premature emphasis on centers. During the hearing, Representative Wicker thanked the scientists from NIH “who helped us refine the 15   Although Duchenne is the most common, others include myotonic dystrophy, facioscapulohumeral muscular dystrophy, the limb-girdle muscular dystrophies, Emery-Dreifuss muscular dystrophy, and congenital muscular dystrophy. 16   Representative Pickering, at the hearing on the proposed legislation by the House Subcommittee on Health on June 27, 2001. In addition to centers, the bill included language directing the NIH director, in coordination with the directors of National Institute of Neurological Diseases and Stroke (NINDS), NIAMS, NICHD, and other institutes, to “expand and intensify programs of such institutes with respect to research and related activities concerning various forms of MD,” and provisions for an interagency MD Coordinating Committee to develop a research plan and report biennially to Congress on progress, a National MD Epidemiology Program by CDC, and a program of public and professional information and education.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation language to make it more workable.” The bill reported to the floor still required centers of excellence but did not specify a number, and the scope of the bill was broadened to address all muscular dystrophies.17 The Senate Subcommittee on Health heard the same arguments from NIH as the House committee did. NIH said that legislation that did not specify the number of centers was an improvement, but it still did not think that centers were the best use of funds for research on muscular dystrophy. For its part, the subcommittee was concerned about what seemed to be a growing trend among advocacy groups to consider centers a key element of every research program, regardless of differences in the state of knowledge about the disease in question. This concern was probably reinforced by the initial draft of the MD-CARE Act, which appeared to be little more than the earlier bill for autism research, including centers of excellence, in the Children’s Health Act of 2000, but with “muscular dystrophy” substituted for “autism” wherever it appeared. A related problem was the difficulty experienced by NIH in conveying to the subcommittee how it determines if and when centers are appropriate vehicles to support research. The decision to establish a center program is, according to NIH, a complicated judgment. Among other factors, it is based on the specific state of the science involved, including whether there are promising research opportunities and enough qualified investigators to take the lead. This complexity makes it more difficult for Congress to judge the merits of requests for centers from advocacy groups (or other members of Congress). The subcommittee added a section to the bill that required NIH to go to the IOM “for the purpose of conducting a study and making recommendations on the impact of, need for, and other issues associated with Centers of Excellence at the National Institutes of Health.” The amendment was accepted in both houses and the MD-CARE Act was signed into law on December 18, 2001. Broader Context The interactions among Congress, NIH, and the voluntary associations lobbying on behalf of muscular dystrophy patients and their families might 17   Subsequently, the Senate Labor-HHS Appropriations Subcommittee, in its report on the FY2002 appropriations for NIH, “strongly” urged NINDS “to establish no fewer than three centers of excellence for basic and applied research in the muscular dystrophies.” The report also called for “meaningful implementation” of the new centers of excellence in autism research mandated in the Children’s Health Act of 2000. In October 2003 NIH announced the establishment of three cooperative research centers for the muscular dystrophies and plans to establish two more. NIH funded two Autism Research Centers of Excellence in May 2002 and seven more in September 2003.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation never have led to the present study had the MD-CARE bill been an isolated case, but as noted above, it was perceived to be part of a larger trend. In 1997, for example, advocates for more research on Parkinson’s disease lobbied for legislation authorizing a $100 million program consisting of research centers, training grants, a patient information center, and other mechanisms. NIH director Harold Varmus testified against the bill, telling the Senate Committee on Labor and Human Resources that advances were more likely to come from basic research than from Parkinson’s-specific research, and that NIH could not “responsibly fund” the 10 Parkinson’s Disease Research Centers of Excellence called for in the bill (Wadman, 1996).18 The support for the Udall bill was so strong that when the effort to pass a reauthorization bill foundered over disputes about use of fetal tissue, the Parkinson’s program was added to the PHS Act by including it in the Labor-Health and Human Services-Education appropriations act. Bills specifying not less than five “centers of excellence regarding research on autism” and for at least three “centers to conduct research for the purposes of improving the diagnosis and treatment of, and finding the cure for, fragile X” were folded into the Children’s Health Act of 2000.19 NIH argued against the autism centers on the grounds that the field was not advanced enough to warrant centers, and that the Collaborative Programs of Excellence in Autism, a multisite cooperative research network established in 1997 and funded by the program project grant mechanism, was the more appropriate mechanism for pushing research on autism beyond the R01 stage. There was concern that having to fund five centers in short order would mean that those already working in the field, whose best ideas were already funded, would be most likely to compete successfully for center grants, and that the net gain in effectiveness would be less than using the funding to increase the number of individual project grants, which would be more likely to attract new talent into the field. Congress was not convinced, and the five centers were mandated. In the last session of Congress, several bills included research centers, and one was passed into law. The Rare Diseases Act of 2002 authorizes the director of the NIH Office of Rare Diseases to fund “regional centers of excellence for clinical research into, training in, and demonstration of diagnostic, prevention, control, and treatment methods for rare diseases.”20 Each of these cases posed the question: When is it appropriate to estab- 18   The centers, called Morris K. Udall Parkinson’s Disease Research Centers of Excellence after the congressman who died of the disease in 1998, were established in 1998 and 1999. 19   P.L. 106-310, October 17, 2000. 20   P.L. 107-280, November 6, 2002. On November 3, 2003, NIH announced the establishment of seven Rare Diseases Clinical Research Centers and a Data and Technology Coordinating Center.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation lish a center program as part of NIH’s portfolio of extramural activities addressing a particular problem? This report examines the program planning procedures NIH uses to decide on whether to initiate a new extramural center or other program and recommends ways to clarify and improve the process and criteria for determining whether to establish centers. METHODS OF THE PRESENT IOM STUDY In the autumn of 2002, IOM assembled a committee whose members provided expertise in the fields of basic, clinical, and population research; research administration; grants management; center administration; evaluation of research programs; patient advocacy; health education/research training; biostatistics; and voluntary health association management. Members also have a wide range of experiences participating in centers supported by NIH and other federal agencies. This was accomplished in accordance with the established procedures of the National Academies, including examining possible biases and conflicts of interest and providing an opportunity for public comment. Brief biographies of the committee members are provided in Appendix B. The committee used a wide variety of sources to assemble the data and information necessary to respond to its charge. An initial organizational meeting of the committee in December 2002 provided an opportunity to explore the parameters of the study with the study sponsor, the NIH Office of Extramural Research. The meeting also gave the committee time to discuss a background paper by Michael McGeary on the history and current status of NIH center grant programs, which formed the basis of Chapters 1 and 2 of this report. At a subsequent meeting, in February 2003, the committee learned details of the legislative and NIH origins of a wide variety of center programs. Present and former institute directors provided their views on the pluses and minuses of centers as a means of advancing research, as did the president of a major medical center, dean of a leading school of nursing, president of the National Health Council, president of the Association of Academic Health Centers, president of the Federation of American Societies for Experimental Biology, and representatives from the Association of American Medical Colleges, Association of Professors of Medicine, American Psychological Association, American Society for Nutritional Sciences, Association of Population Centers, and American Autoimmune-Related Diseases Association. The director of program development for the Agency for Healthcare Research and Quality described her agency’s model for evaluating the impact of medical research, and the leader of the health team of the staff of the Senate Committee on Health, Education, Labor, and Pensions explained the committee’s reasons for mandating this study.

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NIH Extramural Center Programs: Criteria for Initiation and Evaluation IOM staff advertised widely for input from scientific and professional societies, voluntary health associations, and other interested groups and individuals, and received written responses from 11 additional groups. In addition, IOM staff conducted telephone interviews with the NIH scientists listed as points of contact for 12 center programs for which RFAs were published in 2002 and 2003. These interviews focused on the circumstances surrounding the origins and decision-making processes underlying these RFAs as well as plans for managing and evaluating the programs when they were implemented. The sponsor’s project officers compiled and provided several custom reports on the number and funding of center programs as additional sources of information. The committee members themselves contributed both personal contacts and specific information from their own files and experience. The NIH website provided much information about specific center programs, institute-specific analyses and evaluations of center programs, and responses to laws and legislative language. Project staff examined all center-related RFAs and PAs published in 2002 and the first two months of 2003 for information on the genesis and purpose of each center program and contacted NIH program staff for clarification and additional information, as necessary. The present report was the result of extensive discussion among the committee members at two-day meetings in April, June, and August 2003, during which the committee discussed and drafted answers to each of the specific questions specified in P.L. 107-84 in its charge to the committee. Revisions were reviewed and modified via e-mail, and committee members signed off on the review draft in August 2003. After review by a panel of independent reviewers and attendant revisions to the manuscript, the report was released in February 2004. ORGANIZATION OF THE REPORT The remainder of this report is organized into chapters that address the major issues: What are centers and what are their unique contributions or added value in achieving NIH’s goals? (Chapter 2); How are center programs initiated and managed? (Chapters 3 and 4); How should centers and center programs be evaluated? (Chapter 5); and closing comments (Chapter 6). Several appendixes provide further information about the committee and NIH Center programs. REFERENCES Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. 2003. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. New England Journal of Medicine 349(13):1216-1226.

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