Group Discussion of Responses to Proposals for Budgetary Growth
Committee on Enhancing Diversity in Biomedical Research
Report on Bioengineering Conference and Initiatives
Report for the Working Group on Research Tools
Report on Bioethics Programs at the NIH
Contents
Executive Summary
Opening Remarks
Group Discussion of Responses to Proposals for Budgetary Growth Discussion
Committee on Enhancing Diversity in Biomedical Research Discussion
Report on Bioengineering Conference and Initiatives Discussion
Report from the Working Group on Research Tools Discussion
Bioethics Programs at the NIH Discussion
Summary and Conclusions
Table of Acronyms
Appendices
Agenda
Advisory Committee to the Director
Presenters
Related Reports and Articles
Executive Summary
The 76th meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on June 4, 1998. NIH Director, Dr. Harold Varmus, summarized several personnel issues and described recent research developments, including new obesity guidelines, promising anti-cancer drugs and treatments, and restrictions imposed on needle exchange programs to reduce the spread of the human immunodeficiency virus (HIV).
Dr. Varmus also reviewed several issues mentioned during prior ACD meetings, including changes in the NIH Center for Scientific Review, several new clinical research training programs, and discontinuation of the R29, or FIRST Awards (First Independent Research Support and Transition Awards) for non-clinical researchers beginning their independent careers; he also noted several topics for forthcoming ACD meetings, including a review of the Human Genome Project, an update of the Intramural Program, and an interim report on the regulatory burden faced by NIH. He also said that pending increases in the NIH budget for fiscal year 1999 may enable NIH to fund 8,300 new research grants, the greatest number in its history. Meanwhile, several efforts are under way to reassess NIH approaches for setting research priorities.
Dr. Marvin Cassman, Director of the National Institute of General Medical Sciences (NIGMS), Dr. Eric Lander of the Massachusetts Institute of Technology and the Whitehead Institute, Dr. Larry Smarr, Director of the National Center for Supercomputing Applications at the University of Illinois, and Dr. Marc Kirschner, Chair of the Department of Cell Biology at Harvard Medical School, outlined proposals for accommodating substantial new growth in the NIH budget. They and other members of ACD noted that increased resources may enable NIH not only to expand the number of R01 grants, but also to consider broader research initiatives beyond the scale of individual investigations.
Initiatives being considered include the development of tools for diagnosing genetic diseases, a cell circuitry project to measure a wide range of cell activities as they occur, cancer studies, expanded neuroscience research, studies of diseases common in developing countries, new efforts in bioengineering, concerted development of analytical research tools, engineering and transplantation of stem cells, integrated biomedical studies, and high throughput screening efforts by cross-disciplinary teams. NIH also should be more directly involved in the development of advanced computer systems needed for analyzing rapidly accumulating biomedical research findings. Moreover, training programs will need to be broadened and adapted to accommodate some of these new research efforts.
Dr. Harold Slavkin, Director of the National Institute of Dental Research, summarized the interim findings and recommendations of a committee seeking means to enhance the diversity of the biomedical research community and encourage participation from the entire pool of available talent, particularly members of underrepresented minorities. The committee recommends that NIH: develop a trans-NIH plan for recruiting and retaining outstanding, ethnically diverse scientists in all fields; establish an intramural academy for students from underrepresented minorities and sponsor a similar extramural academy; encourage wider use of budget supplement programs to stimulate minority group members to pursue biomedical research careers; encourage closer collaborations with educational institutions that enroll predominately minority populations; and help to coordinate similar programs sponsored by other federal research and education agencies.
Dr. Wendy Baldwin, Director of the Office of Extramural Research, reviewed recent efforts to expand NIH bioengineering programs, noting that NIH formed the Bioengineering Consortium (BECON) in February 1997 and that NIH funded $417 million of broadly based bioengineering research during FY 1996. Bioengineering initiatives will likely involve several if not all the institutes as well as a collaborative research and training program with NSF. The challenge of analyzing large volumes of new data being generated arose as a major theme of the 1998 BECON symposium, with some participants urging that NIH develop a systems approach to meeting this challenge.
Ms. Rebecca Eisenberg of the University of Michigan Law School summarized the findings and recommendations of the Working Group on Research Tools (WGRT), whose members have been reviewing concerns over intellectual property-related issues. Of central concern is whether access to research data and to the use of valuable biological materials and tools is being unduly restricted, thereby interfering with scientific progress by NIH-funded investigators. Despite wide agreement that restrictions on such access present a serious problem, there is little agreement about who might be responsible for this growing problem or how it can be addressed or solved.
Recognizing that NIH options for dealing with this problem are limited, WGRT members nonetheless recommended to the ACD that NIH: promote free dissemination of research tools and, whenever possible, without special agreements; promote the wide use of standard agreements; develop and disseminate guidelines for NIH grantees to follow when developing licenses and material transfer agreements; review its own policies regarding research tools and explore options for asserting existing authorities; and promote the establishment of a research tools forum to develop general principles, educate institutions, explore streamlining mechanisms, and provide a mediation resource.
Dr. Lana Skirboll said that NIH has established a trans-NIH Bioethics Committee that meets regularly to address a broad range of issues in regard to bioethics at NIH and includes representatives from every NIH institute, center, and major office. Dr. Ezekiel Emanuel described the new Clinical Bioethics Department and its program, which he directs, within the NIH Clinical Research Center (CRC). The new program involves many collaborators and has three principal functions: education programs, providing services to CRC staff members, and sponsoring and conducting research projects.
Dr. Baldwin described several bioethics programs within the Office of Extramural Research, which includes the Office for Protection from Research Risks (OPRR) that oversees institutional review boards (IRBs) outside NIH. In addition, she outlined two bioethics initiatives: one to look broadly at informed consent issues, and the other to establish intensive bioethics training for individuals as well as short-term institutional training programs in bioethics. She also described several recent studies of IRBs.
Dr. Steven Hyman summarized the deliberations of a trans-NIH panel that reviewed the bioethical considerations involved in research in which individuals with questionable capacity to consent are asked to serve as subjects. The panel members recommended the following for studies of such subjects: IRBs include at least one member with the knowledge and willingness to represent such subjects; IRBs call for added or eased safeguards for such individuals when risk-benefit ratios warrant; when appropriate, family members or other surrogates make decisions on behalf of such individuals, reflecting their preferences expressed at earlier times; better approaches be developed for providing information to potential research subjects; and one standard should govern all studies involving such subjects.
Opening Remarks
Dr. Harold Varmus, Director of the National Institutes of Health (NIH), began the 76th meeting of the Advisory Committee to the Director (ACD) by reviewing several personnel changes at NIH. First, he announced the appointment of Dr. Gerald Fischbach, who is chairman of neurosciences at Harvard University, to Director of the National Institute of Neurological Disorders and Stroke. Dr. Varmus also noted that Dr. Neal Nathanson, a virologist and Dean for Research at the University of Pennsylvania, is the new Director of the NIH Office of AIDS Research; Dr. James Battey became the Director of the National Institute of Deafness and Communication Disorders in February; and Dr. Al Graeff has been appointed Director of the NIH Center for Information Technology. Dr. Varmus also said that several searches for NIH positions are nearing completion and includes directors for the Fogarty International Center, the Vaccine Research Center, and the Intramural Office of Education.
Dr. Varmus also noted several recent appointments elsewhere within the Federal Government and in other organizations affecting NIH. Dr. David Satcher has been appointed Surgeon General and Assistant Secretary for Health, with jurisdiction over many sister agencies of NIH within the Public Health Service. Dr. Neal Lane, formerly Director of the National Science Foundation (NSF), was named as the Presidential Science Advisor. Dr. Rita Colwell of the University of Maryland replaces Dr. Lane as NSF Director. Gro Brundtland, the former Prime Minister of Norway, who is now the Director of the World Health Organization, has expressed interest in cooperating with NIH in several areas, including an expanded malaria research program.
Dr. Varmus described several recent biomedical research events and related developments that are attracting wider public attention. For example, the National Heart, Lung, and Blood Institute is issuing revised obesity guidelines that are stimulating widespread public discussions. In addition, officials at the Food and Drug Administration (FDA) approved the first large-scale AIDS vaccine efficacy trial to be conducted in the private sector.
Meanwhile, the results of a clinical trial testing the anti-cancer drug, tamoxifen, among women with a high risk for developing breast cancer showed a 45 percent reduction in numbers of cancers reported during a four-year period. Senator Arlen Specter (R-PA) convened hearings to discuss cancer research, including recent disclosures about angiogenesis inhibitors. In addition, during recent American Society for Oncology meetings, tests involving antibodies against cell surface proteins and new uses of the anti-cancer drug, taxol, suggested dramatic progress may be forthcoming.
The Administration decided that Federal funds would not be used for needle exchange programs. In addition, the House of Representatives has passed bills forbidding use of Federal funds for such purposes. Dr. Varmus said that the National Institute for Allergy and Infectious Diseases (NIAID) and the National Institute on Drug Abuse (NIDA) will assemble technical information and will coordinated efforts to provide such information as well as other appropriate assistance to those running local- and state-funded needle exchange programs.
In response to recent announcements from the private sector about human genome-related initiatives, Dr. Varmus promised a full review of the Federally funded Human Genome Project during the next meeting of the ACD. He noted that the project was also the subject of recent discussions during a five-year planning meeting, held at Arlie House in Virginia, as well as during an annual scientific review, held at Cold Spring Harbor Laboratory in New York.
Dr. Varmus reviewed several topics that were discussed during the 75th meeting of the ACD held in December 1997. One of these topics dealt with the establishment of a panel, which is chaired by Dr. Francisco Ayala, to reorganize study sections as it reconsiders scientific boundaries and how they apply to proposals that come before CSR for review. Under the direction of Dr. Ellie Ehrenfeld, CSR has established 21 new study sections in neuroscience and eight new study sections in AIDS. Dr. Ehrenfeld is leading a behavioral research review and, next year, will integrate those study sections with others within CSR. She has also established two new panels emphasizing clinical research.
Dr. Varmus further noted that three clinical research training programs have been put in place: a program providing fellowships for mentored training, another program providing fellowships for early- and mid-career clinical investigators, and a third program to support didactic programs at institutions that sponsor a substantial number of clinical investigator trainees. The latter program will support didactic programs at 20 institutions, while the other programs will support at least 80 new and another 80 early and mid-career trainees.
In response to a report prepared by Dr. Stephen Strauss and others, Dr. Michael Gottesman, Director of the NIH Intramural Program (IP), is enhancing clinical research and training programs within the IP, with an emphasis on recruiting clinical investigators. Dr. Varmus said that a clinical research training program for medical students within the IP has proved a successful experiment, with two of nine students from the first year staying at NIH for an additional year and 15 additional students recruited for next year.
Following an announcement that NIH would discontinue issuing FIRST Awards, applications for such grants have declined steadily while applications for R01 support have been increasing. Dr. Varmus said that NIH remains committed to funding as many research project grants from new investigators this year as it did last year.
Dr. Varmus also summarized several recent administrative matters. For instance, Mr. Tony Itteilag is overseeing the implementation of many of the 90 recommendations for administrative changes outlined in the Anderson report. Dr. Varmus also reminded members of the ACD that a working group will be formed to assist and advise NIH on complying with the Government Performance and Results Act.
Dr. Varmus outlined several issues that possibly will be on the agenda for the next ACD meeting in December 1998: (1) an overview of the NIH IP, including revised guidelines for conducting research, recruitment efforts, and the results of a comprehensive review that began following as assessment of the IP by a subcommittee of ACD, which was chaired by Paul Marks and Gail Cassell; (2) an overview of the activities of the National Foundation for Biomedical Research, which is working with the clinical research fellows program on genetics education efforts and also on finding support for a guest house for relatives of adult patients at the NIH Clinical Center; (3) an interim report on the regulatory burden that NIH faces (this report is being prepared in response to a request from Representatives George Miller (D-CA) and John Porter (R-IL); (4) NIH annual leadership retreat issues which will include genetic polymorphisms and the relationship of gene variations to disease, particularly as they may relate to race and ethnicity differences; and (5) efforts to assemble a clinical trials database as well as on-going discussions with the broader community on clinical trials-related issues such as the training of clinical pharmacologists, the use of surrogate markers for clinical endpoints, and improvements in trial design.
Dr. Varmus reminded ACD members that NIH, which is operating under authority of the Public Health Service Act, is due for Congressional reauthorization. Although Senator Bill Frist (R-TN), who chairs the Senate Subcommittee on Public Health and Safety, has held three hearings on reauthorization, while Representative Bilirakis (R-FL), who chairs the House of Representatives Commerce Subcommittee on Health and the Environment, has held two such hearings, a reauthorization bill is not expected to be completed this session. Similarly, although several bills forbidding human cloning and restricting disclosure of medical record information or pertaining to genetic discrimination have been introduced by members of Congress, none is expected to be enacted this session.
The President's budget request for fiscal year 1999 propose an increase of 8.4 percent to a level of $14.8 billion for the NIH, with much of the increase coming from anticipated tobacco bill revenues. This increase would enable NIH to: fund 8,300 new research grants; to increase stipends for graduate students and postdoctoral researchers; to initiate specific projects; and to address other matters, such as clinical trials and infrastructural needs.
Although the Senate had passed its appropriations bill with a $1.5 billion increase for NIH, the House had not. As several versions of a tobacco bill are pending, there are considerable uncertainties about the impact of such legislation on NIH. For instance, although the bill introduced by Senator John McCain (R-NM) would provide NIH with about $2.5 billion annually, that money might not become part of the overall commitment base for NIH, and some of it may be earmarked for specific uses.
Dr. Varmus said that, despite such concerns, the prospects are good for continuing increases, and they build on three years of steady NIH budget growth, making it essential for NIH to develop thoughtful plans for using those increased resources. For example, when Senator Specter requested NIH to provide a "professional judgment" budget assessment, the average figure across the institutes came to 20 percent for an idealized growth rate. As part of these assessment efforts, Representative David Obey (R-WI) posed a series of 31 detailed questions for NIH to address, explaining how it would spend such funds. Similar issues continue to come up during Congressional hearings that focus on NIH priority setting procedures and from health and patient interest advocacy groups. A group of institute directors recently met with Representative Obey to address such issues.
An Institute of Medicine report advising NIH on priority setting is expected to be completed soon, and several independent groups such as the American Association of Medical Colleges and the Federation of American Societies for Experimental Biology have been providing advice on these matters. Areas in which NIH is being asked to invest more resources include bioengineering, computer-based activities and bioinformatics, training and recruitment, and genomics research.
Group Discussion of Responses to Proposals for Budgetary Growth
Dr. Marvin Cassman, Director of the National Institute of General Medical Sciences (NIGMS), said that, during recent years, chronic shortages of resources have restricted what individual NIH-supported investigators could accomplish. Hence, many of them are poised to quickly and productively expand their individual research efforts without first having to train many new investigators to expand overall research efforts. For instance, having additional resources to replace out-moded scientific equipment or to refurbish badly neglected facilities would quickly boost research productivity across a wide spectrum of biomedical research disciplines.
In addition, new resources will also facilitate cross-disciplinary collaborations that are difficult to initiate or sustain when resources are perceived as scarce. New resources also enable individual investigators to expand beyond the limits imposed by observing strict marginal increases of budgets based on a low inflationary index. Furthermore, overall expanded resources lead to a higher percentage of grants being funded, overcoming the problem that many deserving ideas were being rejected simply because resources have been too scarce to undertake those projects deemed somewhat less likely to succeed.
Dr. Eric Lander of the Massachusetts Institute of Technology and the Whitehead Institute summarized an informal, brainstorming session about how NIH programs might expand if the budget were to double within five years, amounting to an actual increase of about 70 percent. The session was held by an ad hoc group of about 40 leading researchers, who met in February 1998.
Dr. Lander said that, although the members of the ad hoc group discussed expanding the number of R01 grants awarded by NIH, they also considered broader research initiatives that require efforts that go beyond the scale of individual research investigations. For example, to develop the tools for diagnosing genetic diseases or genetic predispositions to common diseases as well as the epidemiologic infrastructure to put such information into context will require efforts well beyond the scope of individual laboratories.
The prime example of such initiatives is the Human Genome Project, which most members of the ad hoc group agreed should be broadened and expanded, according to Dr. Lander. For instance, many scientists believe that NIH should begin planning to support new complex genomic analysis projects at the equivalent rate of completing the DNA sequence of one mammalian species per year. Such information would help to address important questions about genetic regulation and evolution. Moreover, undertaking such an initiative will entail greatly expanding the infrastructure needed for generating this volume of data and analyzing it.
Dr. Lander refers to another major initiative for NIH to consider as the "Cell Circuitry Project." This initiative calls for measuring a wide range of cell activities as they occur, including the activity of signal kinases and the dynamics of gene expression. Model cells for such projects include hepatocytes and retinal pigment epithelial cells from mammalian sources and intact procaryotes, such as Mycoplasma genitalium, which contains a relatively small number of genes and whose genomic sequence has been determined. At the least, such undertakings will require consortia of investigators, some of whom may focus on developing new tools to address some of the challenges entailed in such comprehensive investigations.
Dr. Lander said that cancer and neuroscience research represent other areas poised for major progress that are ready for major initiatives. He also pointed to studies of the diseases of developing countries, research in bioengineering, the development of analytical research tools, and the engineering and transplantation of stem cells, as other major areas for possible initiatives. Provision also should be made for individual laboratories to purchase new equipment and for establishing regional or national centers with specialized analytical equipment, such as advanced light sources or to conduct drug screening programs with specialized reagents that might not be undertaken in the private sector.
Some consideration also should be given to even more basic infrastructural needs, such as laboratory renovations and construction, according to Dr. Lander. He said that NIH should consider matching funds and loan programs. Moreover, additional support is needed for widely used facilities, such as animal housing units, as well as for computing and bioinformatics programs.
While the ad hoc group members identified research areas for initiatives, they also considered measures to be taken to encourage bright young scientists to remain on scientific career tracks. Dr. Lander said that because the early period of independence marks a critical stage of career development for such investigators, NIH should consider alternative funding mechanisms for this cohort, perhaps modeled on grants issued by the Markey Foundation and the Wellcome Trust. In such cases, young investigators are provided support for three to four years, based more on their promise as researchers than on the strength of their particular research proposals.
Other funding mechanisms for NIH to consider include small but venturesome grants for individuals trying out new projects as well as grants that are more diversified in their size and purpose. Dr. Lander said that the ad hoc group members also recommended that the number, level of support, and types of training grants be improved. Students working on their doctoral degrees would benefit from more deliberate exposure to medical topics during their training, and guidance on how to collaborate with scientists in other disciplines. Improvement is needed in attracting and tracking trainees from minority groups.
Dr. Larry Smarr, Director of the National Center for Supercomputing Applications at the University of Illinois and a member of the President's Advisory Committee for High-Performance Computing and Communications, said that NIH has not been as active as other Federal research agencies in developing plans for the 21st century for computing and related advances. Although barriers among other Federal agencies are dissolving as they consider the "national technology grid," biomedical researchers who are supported by NIH seem less involved in this process and poorly organized.
Dr. Smarr said that he will help to make NIH a partner in this emerging national program. He also said that a group should be established to conduct a national scientific needs analysis as a step toward designing an electronic information-based system that meets the needs of scientists conducting biomedical research.
Dr. Marc Kirschner, Chair of the Department of Cell Biology at Harvard Medical School, said that, although integrative science in biology, including physiology and pharmacology, has been underfunded during the past decade, biologists in other specialties such as cell biology, genetics, and molecular biology, are poised to contribute to this recently neglected area. Moreover, a variety of transgenic animals will help researchers redirect some of their attention to studying whole systems and integrative biology.
These possibilities make it important for biomedical researchers to conduct high-throughput genetic screening and to build complex libraries of chemical reagents with which to conduct such studies, according to Dr. Kirschner. Moreover, academic researchers will need to invest more of their efforts into bioinformatics, the development of research tools, and other large-scale activities, such as protein and transcript profiling, to participate fully in this process.
Dr. Kirschner said that such large-scale, multi-disciplinary activities will need to be organized at least at the supra-university level, perhaps by establishing several regional integrative science centers. He recommended that such centers focus on different specialties, with some emphasizing transgenic animal studies, others combinatorial chemistry and high-throughput screening, and still others focusing on protein chemistry. He said that the means by which NIH could support these cross-disciplinary centers will require further thought because the respective research activities of these contemplated centers tend to cut across the missions of the individual institutes at NIH.
DISCUSSION
Dr. Varmus invited comments from members of the ACD, noting that, to implement expanding NIH programs and research initiatives, additional management and administrative efforts also will be needed. However, Congress has imposed a strict spending ceiling on the administrative side of NIH activities, making it essential to recommend priorities among the many attractive ideas for new research and research training programs that are being considered.
In response to comments on Federal-wide discussions of advanced computer-based systems made by Dr. Smarr, Dr. Varmus announced that he is establishing a computer needs analysis panel that Dr. Smarr will co-chair. Meanwhile, NIH is deeply involved in Federal-wide discussions over projects based on high-beam molecular crystallographic analysis. These discussions, which are organized under the Office of Science and Technology Policy and the National Science Technology Council, could provide a model for greater involvement of NIH in advanced computer technology planning efforts.
Dr. Philip Needleman cited his own experiences as applicable to the general challenge NIH faces in fostering research in integrative science. After moving to industry from an academic setting, he assembled a large multidisciplinary team to do integrative research. The team's wide-ranging efforts progressed rapidly to large-scale clinical trials evaluating an anti-arthritic drug candidate and to insights about the role of particular enzymes in colon cancer.
From such experiences, Dr. Needleman pointed out that the Human Genome Project will soon increase the number of targets for pharmaceutical investigations by more than ten-fold. Setting priorities and identifying which biomedical problems to pursue will become an ever greater challenge. However, having the NIH support a dedicated research group in the public sector that will identify therapeutic and diagnostic targets from the Human Genome Project and then take candidate products from early development through clinical trials would be a welcome entity — one that could fill needs that the pharmaceutical and biotechnology industries cannot meet, he said. The NIH intramural graduate program might be designed to undertake part of this challenge by establishing its own program in applied biomedical science, according to Dr. Needleman.
In response to Dr. Needleman, Dr. Kirschner said that, despite similarities with some features of the pharmaceutical industry, the integrative science programs envisioned for NIH go beyond what industry typically attempts to do. Dr. Lander added that there are important differences both in scale and style between the programs envisioned for NIH and the applied science being done in industry. Nonetheless, there are valuable opportunities for synergy between industry-based and NIH-supported academic researchers, according to Dr. Lander.
Ms. Rebecca Eisenberg said that NIH faces a special challenge when public and private sector funding for particular research projects overlaps. Despite traditional justifications for publicly funding research that the private sector does not undertake, expanded patenting efforts and capturing of publicly funded research findings by companies within the private sector further complicate the picture, she noted. NIH may be faced with a need to develop broader justifications for funding certain kinds of research embodied in some of these recommended initiatives. For instance, NIH officials may want to point out that a broadly accessible research infrastructure leads to scientific achievements and public health benefits that otherwise are not possible.
Dr. Shirley Tilghman said that the multidisciplinary research centers described by Dr. Needleman are contrary to the culture of universities, which tend to favor individual rather than team efforts and to resist making changes that might move the academic culture in that direction. Moreover, faculty researchers typically train young investigators to fit into this tradition-bound culture. She also said that research centers at universities frequently support mediocre researchers and projects that would not be funded if reviewed as R01 proposals.
In response, Dr. Lander suggested that NIH should consider alternatives to centers. Dr. Needleman added that individual members of industrial research teams need to be experts in specialty areas; however, being too narrow in training and outlook can be an impediment to scientific progress. Dr. Kirschner said that some kinds of research simply are beyond the scope of what individual investigators can accomplish. Whether such efforts are organized into centers at specific sites or as virtual centers or other entities will depend on the types of research problems being studied. He also said that deciding whether new incentives will be needed to encourage researchers to participate in such teams will require careful thought. In any case, such research teams should not be viewed as replacing individual investigators.
Dr. Smarr pointed out that, for more than a decade, NSF has sponsored a number of specialized science, technology, and engineering centers that emphasize team- rather than individual-based research efforts. A new NSF program, known as the "Knowledge and Distributed Intelligence Initiative," calls for "distributed" team efforts and has attracted more than 600 proposals from researchers across many different disciplines. Another NSF program, "Partnerships for Advanced Computational Infrastructure," involves large teams whose members may be located virtually anywhere in the country, according to Dr. Smarr.
Dr. Susan Horwitz recommended that courses be developed to familiarize Ph.D.s with medically important subjects and to make them more adept at communicating with M.D.s. Not only should Ph.D.s be trained more broadly, they also should be supported more generously during this prolonged process. Dr. Varmus noted that the graduate program being planned for the NIH intramural program will emphasize training in clinically oriented sciences. Dr. Elaine Fuchs agreed with Dr. Horwitz that young investigators need to be more broadly trained, with an increased emphasis on medical subjects and bioinformatics. She also said that postdoctoral fellows need support for longer periods, perhaps four or more years, instead of the standard three years.
Dr. Jane Menken returned to the theme of diseases in developing countries and the challenge of adapting medical technology developed in countries such as the United States to meet local needs in developing countries. She also said that understanding local social and behavioral factors is essential when studying diseases in such settings. She recommended increased funding for such research and enhanced collaborations with investigators in developing countries. In response, Dr. Varmus noted that the new director of the Fogarty Center will soon be revising the NIH agenda for international research, which also will be considered during the NIH leadership forum in September. He also said that Dr. Norman Anderson, director of the NIH Office of Behavioral and Social Sciences Research, is beginning a priority-setting review as part of a broader effort to encourage behavioral scientists to apply for NIH grant support.
Dr. Ting-Kai Li asked whether current NIH funding mechanisms could be used to develop some of these new programs; and, if not, how much time would be needed to create new mechanisms. In response, Dr. Varmus said that, although a comprehensive conversion to new mechanisms would be difficult, a change involving as little as one percent of NIH efforts could be done quickly and would accomplish a great deal even within a period of one year.
Mr. Norman Francis acknowledged that changing universities is very difficult. However, collaborations are becoming increasingly important, and priorities will need to be re-set. He also said that the cadre of scientists being trained should be more diverse in its makeup. Dr. Baldomero Olivera noted that NIH exerts a great deal of influence over universities, even those that are reluctant to make changes. He also said that NIH might invest more in the training of undergraduate students because, for example, students with scientific training at the premedical level often return to careers in medical research. Dr. Ezra Davidson, Jr., said that the biology of pregnancy, particularly complicated pregnancies, should be included among the priority research areas that Dr. Lander described.
Committee on Enhancing Diversity in Biomedical Research
Dr. Harold Slavkin, Director of the National Institute of Dental Research, summarized the interim findings and recommendations of an NIH committee seeking means to enhance the diversity of the biomedical research community. The guiding principle for the committee, which includes a dozen representatives from the NIH senior staff, is to build a biomedical research community based on the entire pool of available talent, including members of under-represented minorities.
Committee members consulted with other NIH representatives, as well as individuals from an array of other organizations, including: the American Association for the Advancement of Science; the American Association of Medical Colleges (AAMC); the Howard Hughes Medical Institute; NSF; and NAS. Committee members also met with Dr. Freeman Hrabowski of the University of Maryland, Baltimore County, and several other teachers at colleges and universities with successful mathematics and science training programs for students from under-represented minorities.
The committee learned that minority group populations account for 23 percent of the total U.S. workforce but only 6 percent of the medical, science, and engineering workforce. In 1993, for instance, African Americans were 3.5 percent of that work force; Hispanics 3 percent; and American Indians, 0.02 percent. Minority group members were awarded 6.4 percent of the Ph.D.s in 1995, compared to 3.8 percent a decade earlier. In 1996–1997, minority group members were awarded 10.6 percent of M.D.s. Although there is recent growth in minority group involvement in some of these specialties, it builds on a very small base, according to Dr. Slavkin.
The committee also reviewed minority participation in faculty positions in medical schools in both clinical and basic science departments. In 1996, 4 percent of faculty at the 125 U.S. medical students belonged to minority groups, but one-fourth of them held positions in 6 of those schools whose students are predominantly from minority groups. Of the 13,300 full-time faculty members in medical school basic science departments, only 192 individuals, or 1.4 percent, are from under-represented minorities.
Some trends toward greater participation of minority group members are seen in medical school and biological science department enrollments. For example, in the past decade, enrollment of minority students in medical schools has doubled, now accounting for 11.8 percent of the nearly 17,000 students enrolled in 1996–1997. Most of these students decide to pursue medical careers while still in high school, and about 40 percent of them (compared to 10 percent from the majority population) indicate that they plan to practice medicine in deprived communities. Other studies indicated that the number of M.D.s applying for NIH grants recently declined by about 30 percent.
Some 93 percent of minority group medical students require scholarships, compared to 81 percent of majority group students. For such population groups, loan requirements play an important role when individuals are choosing between career paths in medicine and research. Based on AAMC data, the current pool of non-Asian minority group members consists of 2,000 medical residents and 500 to 1,000 individuals who are trained in other health-related professions, such as dentistry, nursing, and pharmacy. The size of the available talent pool is not likely to increase markedly over the next decade, according to Dr. Slavkin, who cited the National Assessment of Education Progress indicating that only about 13 percent of all students graduating from U.S. high schools are prepared to pursue basic science and mathematics course work at college.
In the basic biological sciences, the current pool of students from minority groups is also very small. Thus, in 1995, minority group members received 300 Ph.D.s, accounting for 6.5 percent of the total 4,321 such degrees awarded that year. In 1997, some 90,000 individuals were enrolled as full-time graduate students in U.S. biology and other health professional schools. In that same year, NIH supported 4,000 full-time graduate students, 10,327 research assistantships, and 969 postdoctoral fellows.
Such demographic information indicates some of the outside limits within which career changes for individuals from under-represented minority groups may be contemplated over the near term of about 5 years, according to Dr. Slavkin. In this context, the NIH committee makes 6 recommendations in its interim report:
Develop a trans-NIH plan for recruiting and retaining outstanding, ethnically diverse scientists in all fields;
Create an NIH academy, modeled on several university-based programs, to provide synergy between faculty members and students from under-represented minorities; the academy within the NIH intramural program should include a residential component;
Sponsor a similar academy as a pilot program in an extramural setting;
Build community awareness and thereby encourage wider use of NIH budget supplement programs, which amounted to nearly $46 million in fiscal year 1997, to stimulate minority group members to follow biomedical research careers;
Encourage closer partnerships and collaborations between research-intensive health science centers and educational institutions that enroll predominately minority populations;
Optimize and coordinate similar programs sponsored by other Federal research and education agencies.
Dr. Slavkin referred to the 1966 Coleman report on kindergarten through high school education, which notes that many children have educational deficiencies before they enter the school system. Thus, some of the challenges that NIH faces in encouraging minority group members to pursue careers in biomedical research stem from broader societal problems.
DISCUSSION
Mr. Norman Francis praised the committee's interim report and urged NIH to continue to develop and coordinate programs that encourage minority group members to pursue biomedical research careers. He said that the undergraduate science program at Xavier University of Louisiana begins by recruiting students at the junior high school level, brings them to the university for summer programs, and successfully recruits many of them into basic science major programs at the university. Dr. Ezra Davidson, Jr., said that the King/Drew Medical Center is involving students from minority groups at an even earlier stage, with Saturday sessions for elementary school students.
Funding, consistency, and collaborations with major research institutions are essential ingredients for drawing minority groups students into such educational programs, according to Mr. Francis. Information about the Xavier program is available on the Internet, and efforts are underway to bring this approach into wider use at other colleges and universities throughout the country.
Dr. Jane Menken said that having a critical mass of individuals involved in such activities at particular institutions is important for their success. Dr. Varmus said that schools that develop programs intensively focused on these issues provide the best model for the proposed NIH academy to follow. He also noted that the academy atmosphere that the Xavier model fosters appears to be a crucial component for promoting success among such students.
Dr. Larry Smarr said that the growing electronic infrastructure can provide opportunities for collaborations between research mentors at large research institutions and students at educational institutions that enroll predominately minority populations. For example, individuals at Jackson State University in Mississippi and Syracuse University in New York are collaborating on a software-related project without leaving their respective campuses. Both Dr. Shirley Tilghman and Dr. Susan Horwitz pointed out that direct mentoring of minority students is an important, if not essential, component of the Xavier model.
Dr. Elaine Fuchs suggested that NIH establish special grants to support such educational efforts at institutions where research is the primary activity. In response, Dr. Varmus said that identifying appropriate mechanisms for fulfilling the recommendations outlined by Dr. Slavkin's committee will be the next challenge its members need to address.
Report on Bioengineering Conference and Initiatives
Dr. Wendy Baldwin reviewed recent efforts to expand NIH bioengineering programs, noting that, as one important element of these efforts, NIH formed the Bioengineering Consortium (BECON) in February 1997. This consortium includes representatives from all the Institutes as well as a liaison representative from NSF, meets in open sessions, and quickly posts information about its activities on the Worldwide Web. NIH funded $417 million of broadly based bioengineering research during FY 1996, according to an analysis conducted by BECON members.
As part of the NIH effort to review bioengineering programs and plan for their expansion, BECON convened a symposium in February 1998, during which Sen. Bill Frist (R-TN) delivered the keynote address and more than 650 individuals participated. Panel reports outlining priority research areas for NIH to support will soon be posted on the Worldwide Web, according to Dr. Baldwin. Initiatives will likely involve several, if not all, the Institutes as well as a collaborative research and training program with NSF. Efforts are underway to ensure that bioengineering research proposals receive careful consideration during peer review. However, she said, mechanisms other than R01 grants will be needed to achieve some of the bioengineering goals that these stepped-up assessments have recently identified.
Dr. Baldwin said that the challenge of analyzing large volumes of new data being generated arose as a major theme of the 1998 BECON symposium, with some participants urging that NIH develop a systems approach to meeting this challenge. Bioimaging was identified as another area of special importance.
DISCUSSION
In response to a question from Dr. Marc Kirschner about applying for NIH support under a single umbrella proposal versus several individual grant proposals, Dr. Baldwin said that some thought is being given to establishing core centers for bioengineering. Moreover, there is lingering doubt whether support for basic bioengineering projects through R01 awards is yet adequate.
In response to a recommendation from Dr. Larry Smarr that an organized effort to develop an information infrastructure be considered an essential component of the bioengineering initiative, Dr. Baldwin said that BECON will focus on this and other needs that transcend the capabilities of single institutes.
Report from the Working Group on Research Tools
Ms. Rebecca Eisenberg of the University of Michigan Law School summarized the findings and recommendations of an ACD subcommittee, the Working Group on Research Tools (WGRT), which has been reviewing concerns over intellectual property-related issues. Of central concern is whether access to information in regard to research findings and to the use of valuable biological materials and research tools is being unduly restricted, thereby interfering with scientific progress by NIH-funded investigators. In addition to Ms. Eisenberg, two other WGRT members participated in this discussion, Mr. John Barton of Stanford Law School and Dr. Marilyn Hartig of Bristol-Myers Squibb.
WGRT members focussed on problems researchers may be encountering in gaining access to research tools rather than on the effects of patenting practices, according to Ms. Eisenberg. While gathering information on this topic, many individuals and organizations provided advice and support to WGRT, including the Association of University Technology Managers, the Committee on Government Relations, the American Society for Cell Biology, a group from the Organization for European Cooperative Development (OECD), members of the NIH Office of Technology Transfer (OTT), and representatives from industry such as the Biotechnology Industry Organization. Meanwhile, individual scientists proved more reticent in responding to inquiries from WGRT about their problems in gaining access to research tools.
Despite wide agreement that access to research tools presents a serious problem, there is little agreement about who might be responsible for this problem or how it can be addressed or solved, according to Ms. Eisenberg. Moreover, she said, an individual's perspective greatly influences his or her perceptions of the problem, illustrating this point with several anecdotes describing prototypical situations involving researchers at universities and in industry and their dealings with one another and administrators who specialize in technology transfer issues.
The anecdotes also illuminate important problems associated with current technology practices, according to Ms. Eisenberg. For one, transaction costs can consume the potential gains realized from licensing the use of research tools. For another, a university's efforts to maximize revenues by insisting on exclusive or costly license agreements can be at odds with other goals of the institution, such as disseminating information about research and encouraging development of products that benefit the public.
NIH options for dealing with these problems, particularly as they involve arrangements made among industry representatives and NIH-supported researchers at universities, are limited. Although NIH has considerable authority over agreements involving intellectual property developed by its own researchers, the Bayh-Dole Act severely restricts NIH authority over NIH grantees at universities.
However, NIH can set examples, use the Abully pulpit, educate university-based researchers to act with enlightened self-interest, and establish a forum for addressing such problems, according to Ms. Eisenberg and other members of WGRT. She summarized a series of recommendations from WGRT:
NIH should promote free dissemination of research tools without special agreements whenever possible.
NIH should promote the use of standard agreements, with a suitably modified version of the Uniform Biological Materials Transfer Agreement serving as a model.
NIH should develop and disseminate guidelines for NIH grantees to follow when developing licenses and material transfer agreements; those proposed guidelines, analogous in intent to a document that NIH prepared in the 1980s (in response to the Sandoz-Scripps agreement) addressing sponsored research agreements, could help to establish reasonable standards for universities to follow when transferring research tools.
NIH should review its own policies regarding dissemination of research tools developed under its intramural and extramural programs and should explore options for asserting its existing authorities, including under the exceptional circumstances clause specified by the Bayh-Dole Act.
NIH should promote the establishment of a research tools forum for the biomedical research and development community; it could develop general principles, educate institutions, explore streamlining mechanisms, and provide a mediation resource.
Mr. Barton said that patents represent a large proportion of the problem involving restricted access to biomedical research tools. For instance, some industry report problems with patent "stacking," meaning they sometimes need to negotiate clearances for as many as 10 patents to gain access to research tools and materials, and this process involves a high added cost. Because the scope of such problems extend well beyond NIH authority to deal with them, Mr. Barton recommended that the National Academy of Sciences be asked to conduct a comprehensive study and develop appropriate recommendations for fine-tuning the use of patents in the biomedical area.
Dr. Hartig said that, despite the shared deep concern over these issues among the members of the WGRT, they did not come forth with a resolution for the problems at hand because they are such different stakeholders with disparate perspectives. However, members of the group agreed that NIH should set the highest moral standards for appropriate and reasonable uses of research tools and to use moral suasion for meeting those standards. She said that a forum may help toward developing a better common understanding of these difficult issues.
DISCUSSION
Dr. Yank Coble, Jr., asked whether another country has developed an acceptable, less costly model for dealing with material transfer agreements. In response, Ms. Eisenberg said that, although other OECD countries are dealing with similar problems, the members of the WGRT learned of no such model solution.
Dr. Lander said that the underlying concept of the European Community could provide a model for the U.S. biomedical research community to follow in sharing research tools. Specifically, the nations belonging to the European Community give up a degree of autonomy in exchange for the benefits of belonging to this federation of states. Perhaps universities could belong to a roughly analogous federation that obeyed certain rules in dealing with research tools and other matters of intellectual property. He suggested that, although the members of this proposed, research-oriented federation might forfeit some potential profits, they also would benefit by having freer access to research tools.
In response, Ms. Eisenberg said that she has proposed to university technology transfer officers that a research tools patent pool be established. It might be modeled, for instance, on the music copyright collective organized by the American Society of Composers and Producers, which represents an equitable system, centrally setting the terms for using music and collecting royalties for composers.
Whether such a system could be applied to biomedical research for pooled patents is doubtful, however, particularly because of the heterogeneous value of the patents and the diversity of the inventors, according to Ms. Eisenberg. Moreover, representatives of many universities and companies have indicated to her that they would not accept a system that eliminates exclusive licensing arrangements. In general, university-based technology transfer officers reject such arrangements as not workable for intellectual property such as biomedical research tools. However, she added, it may be possible to experiment with such a model system in a limited area — for instance, with distributions of, and sharing of, information about single nucleotide polymorphisms that are developed as part of the Human Genome Project.
In a similar effort to extend the limits of NIH authority for addressing these issues, Dr. Elaine Fuchs suggested that NIH classify all research tools as an exceptional category under the Bayh-Dole Act, thereby making them subject to free exchange under NIH jurisdiction. Ms. Eisenberg said that this approach would likely be viewed as contrary to the intent of the statute, which gives broad rights to grantee institutions to manage the intellectual property developed by their faculty members. Moreover, taking this approach would be politically unacceptable and also very unwieldy, because defining research tools that are subject to these concerns is itself not a straightforward undertaking.
Dr. Marc Kirschner asked whether the difficulties in transferring research materials are uniform or do they vary depending on the parties involved in negotiating such transfers. He also noted that, at least for a great deal of DNA sequence information, there seem to be few, if any, restrictions on the free exchange of information once it is catalogued in electronic formats. He suggested that this same practice could be applied more generally to research materials, which might be routinely sent to a central repository and distribution center to gain freer use.
In response, Ms. Eisenberg said that university technology transfer officers claim that exchanges between two universities tend to go smoothly, whereas exchanges between a university and a company often prove more complicated. Meanwhile, however, many scientists at universities disagree with that assessment and claim that negotiating agreements among universities is becoming increasingly problematic. Dr. Varmus added that, even by placing materials in central repositories, researchers seeking to use them may still encounter obstacles such as being required to enter highly restrictive license agreements.
Dr. Larry Smarr said that research is being conducted increasingly by virtual teams on a multi-institutional basis, making it less possible to restrict access to intellectual property or materials that are being developed by such means. In response, Ms. Eisenberg said that increasingly higher transaction costs for licensing agreements may force a simplification in the system, thereby leading to an easing of current problems. Responding to another question from Dr. Smarr about how a forum could mediate disputes, Ms. Eisenberg said that it would likely work only in "high-value cases" rather than for many, if not most, other situations where problems are now being reported.
Dr. Smarr also asked whether WGRT members had determined how many universities have net income from their technology transfer operations, suggesting that transaction costs may significantly exceed revenues in most cases. Ms. Eisenberg said that, although the general picture is difficult to evaluate, some universities are big winners and, overall, the system is probably modestly profitable. Moreover, she pointed out, it is a mistake to evaluate university technology transfer activities solely in terms of revenues they generate. Thus, by promoting commercial investments in universities to develop technologies that benefit the public, they serve additional valuable functions, according to Ms. Eisenberg.
Dr. Ting-Kai Li said that little or no concern should be wasted on technology transfer arrangements involving relatively unimportant technical developments. Perhaps NIH could urge investigators as a matter of policy to keep unique research resources in the public domain. Ms. Eisenberg said that, although scientists might circumvent restrictions imposed by technology transfer officers by freely sending out materials, various scientists and other representatives who provided information to WGRT suggested that the impetus for those restrictions sometimes comes from technology transfer officers but other times from the scientists themselves.
Dr. Philip Needleman said that the blanket technology transfer agreement between Monsanto and Washington University calls for a limited, 30-day review with right of first refusal for developments with therapeutic potential. He said that a right to exclusive licensing is an essential component of this agreement. However, once a development is protected by patent or pending applications, biological reagents and other research materials are freely supplied to investigators who ask for them because it is in the company's interest for there to be broad progress in areas of research in which it is working. Ms. Eisenberg pointed out that many companies are interested in developments and processes that are upstream from therapeutic products, thus accounting for their intense interest in the commercial potential of research tools themselves.
Dr. Shirley Tilghman said that an unwillingness to share research results and materials predates current heightened interest in commercial exploitation of such information. There is great diversity among segments of the scientific community, with the cultural behavior of some groups dictating that members freely share materials, while others do not. She also said that, although an authority is needed to enforce the sharing of such materials, neither NIH, universities, nor journal publishers can play this role.
Based on the WGRT report, Dr. Varmus directed the NIH Office of Technology Transfer to review NIH policies in this area and develop guidelines for the wider research community. In particular, they are to develop guidelines for when materials and information should be freely disseminated and when the Uniform Biological Materials Transfer Agreements are to be used.
In addition, Dr. Varmus called for convening a forum within six months to review the guidelines that OTT drafts. The forum will help to determine whether such guidelines prove acceptable and whether the forum itself provides a useful way of dealing more generally with these important issues. He said that restrictions on the use of research tools are a serious problem for science, not only in terms of what can be achieved but also in terms of the atmosphere in which researchers do their work.
Bioethics Programs at the NIH
Trans-NIH Bioethics Committee
Dr. Skirboll said that NIH has established a trans-NIH Bioethics Committee (TNBC), which grew out of the Educational, Legal, and Social Implications (ELSI) program that is part of the Human Genome Project. TNBC meets regularly and includes representatives from every NIH institute, center, and major office. It also is involved in specific discussions of bioethics that are taking place in specialized programs or at particular institutes within NIH and elsewhere in the Federal Government.
An important issue that TNBC members are currently addressing arises from provisions in the Health Insurance Portability and Accountability Act (HIPAA) that deal with the privacy of research-related information in clinical records, according to Dr. Skirboll. A TNBC subcommittee is developing provisional recommendations for the Secretary of HHS to consider. These recommendations address two parallel issues: access by researchers to individually identifiable information about patients as well as access by patients to research-derived clinical information about themselves. Meanwhile, another trans-NIH group is considering privacy issues as they relate to human tissue and specimen resources.
Dr. Skirboll said that another TNBC subcommittee is discussing ethical issues that arise when clinical research is conducted in countries other than the United States. The subcommittee plans to confer with researchers and patient groups before drafting a document outlining ethical principles for such research.
The members of TNBC are also considering institutional review boards (IRBs) and informed consent issues, according to Dr. Skirboll. In particular, TNBC plans to develop guidelines for how well IRB members need to understand the science before they make ethical judgments about proposals that come before them as well as specific recommendations for the training and education of IRB members.
When human cloning legislation came before Congress, members of TNBC reviewed a white paper describing the research importance of somatic cell nuclear transfer techniques, which might be affected by some versions of this legislation. TNBC members also kept the institutes informed about the NIH position on these issues. TNBC also provides a forum for reviewing research-related ethical issues that arise in other Federal departments, such as the Department of Energy, which also has an ELSI component in its genome research program. TNBC also is involved in wider discussions of xenotransplantation research.
Dr. Skirboll noted that the NIH Recombinant DNA Advisory Committee (RAC) has convened several gene therapy policy conferences. One of them focussed on the ethical implications of using gene therapy to enhance individuals. Another considered the safety of using lentivirus-based vectors.
Bioethics Activities at the Clinical Center
Dr. Emanuel described the new Clinical Bioethics Department and its program, which he directs, within the NIH Clinical Center (CC). The new program involves many collaborators and has three principal functions: education programs, providing bioethics-related services to CC staff members, and sponsoring and conducting research projects. Major collaborators include the Agency for Health Care Policy and Research as well as the Food and Drug Administration within HHS and researchers at more than nine universities in the United States and Canada.
Dr. Emanuel said that the educational program has several components, including presenting ethics grand rounds with specific case studies, training of CC staff members on ethical issues, sponsorship of NIH staff to attend intensive bioethics training workshops, establishment of a bioethics fellowship program, and development of an intensive course along with appropriate materials with a focus on protecting human subjects that can be taught throughout the country.
The major service component of the new program is a revamped ethics consultation service within CC, according to Dr. Emanuel. Consultations that formerly involved a single ethicist now are routinely conducted by a team of at least three individuals. In addition, the program supplies ethicists to IRBs within NIH, manages a continuing education program in bioethics, and consults with various institutes on an ad hoc basis.
Dr. Emanuel said that the new Clinical Bioethics Department is expanding its program into several research areas, with an early emphasis on two areas: human subjects research and health policy. Projects involving human subject-related issues include bioethics studies of paying research subjects; of cognitively impaired subjects, such as patients with Alzheimer's disease or children; IRB reviews; and protecting particular communities, such as Ashkenazi Jews, who are at greater risk for certain genetically determined disorders, or aboriginal communities.
Other projects involving health policy include a review of best ethical practices in managed care settings and end-of-life practices among oncologists, according to Dr. Emanuel. Some of these studies involve collaborative efforts with some dozen leading for-profit and not-for-profit managed care organizations in the private sector. Another project involves a comprehensive study of the impact of state confidentiality laws on clinical research.
Bioethics Training Program
Dr. Baldwin described several bioethics programs within the Office of Extramural Research. For instance, the Office for Protection from Research Risks (OPRR) negotiates assurances, oversees compliance, and runs education activities involving IRBs outside NIH. OPRR is developing a plan to streamline the assurance process and also is working with the National Cancer Institute to develop informed consent documents for multisite trials.
Dr. Baldwin also outlined two bioethics initiatives, one arising from the Presidential Committee on Human Radiation Experiments. Following this review, OER, along with several institutes, as well as the Department of Energy and the Veterans Administration, developed a Request for Applications from researchers who will look more broadly at informed consent issues. So far, 14 projects have been funded for about one year.
The second activity involves a training program that arises following President Clinton's apology for the Tuskegee syphilis study. One component of this program entails intensive bioethics training for individuals, while the other is a short-term institutional training program. Applications for this program are in the first round of review, according to Dr. Baldwin.
Dr. Baldwin also described a study of IRBs that was scheduled to be released during a Congressional hearing scheduled for the week following the ACD meeting, on June 11, 1998. In addition, Dr. Baldwin summarized some of the findings in a separate study of IRBs that belong to multiple project assurance institutions, meaning those institutions that oversee a relatively large volume of clinical research projects. The study consists of a survey of IRB administrators and other representatives of the institutions, who were asked to report on how well their IRBs are functioning and what their main concerns are. The primary concern that they expressed is a near-universal tension between how human subjects are protected and the administrative burdens of conducting a large volume of reviews.
Among the highlights of this survey are: the great variability of the IRBs and their parent organizations as well as their funding sources; the challenges to be faced for IRBs in reviewing multisite trials; and the relative lack of diversity in the composition of IRBs, whose members are predominantly white and whose chairs are predominantly men. Only about half the research that is formally exempted from IRB review nonetheless is subjected to such reviews, according to Dr. Baldwin. However, those projects eligible for expedited review by less than the full IRB were, in fact, subject to expedited review on a far more irregular basis than might be expected. Although time spent on reviews varies markedly with the overall volume of review that any IRB conducts, about 85 percent of IRBs are said to be run with reasonable efficiency. Similarly, 46 percent of respondents report that IRB workloads are appropriate, and another 47 percent said the workloads are heavy but manageable.
In other activities, the Office of Extramural Research is beginning a series of best practice meetings, according to Dr. Baldwin. One goal is to guide IRBs in using expedited reviews appropriately and more freely than they now do.
Report on Research Involving Individuals with Questionable Capacity to Consent
Dr. Hyman summarized the deliberations of a trans-NIH panel that reviewed the bioethical considerations involved in research in which individuals with questionable capacity to consent are asked to serve as subjects. This panel's deliberations, which overlap with a review being conducted by the National Bioethics Advisory Commission, led to several recommendations:
IRBs should include at least one member with the knowledge and willingness to act as a representative of subjects who might have impaired ability to consent.
When appropriate, and with an emphasis on having transparent review processes, IRBs can call for adding safeguards for particular kinds of individuals or for easing specific safeguards when risk-benefit ratios warrant.
Again, when appropriate, family members or other surrogates can make decisions about participating as research subjects on behalf of individuals whose ability to consent may be impaired; those decisions should reflect preferences expressed by those individuals at earlier times;
The issue of appreciation, meaning a subject's ability to understand how informed consent information applies to his or her specific situation, deserves further study; in more general terms, better approaches are needed for providing information to potential research subjects.
One standard should govern all studies involving those with questionable capacity to give consent.
Dr. Hyman said that the members of the panel, including patient advocates, agreed that, despite the difficulties involved when individuals with impaired capacities to consent are being asked to serve as research subjects, valuable research involving such individuals should be continued, particularly for the wide range of diseases affecting mental functions for which animal models cannot fully substitute for clinical trials. An additional challenge is to develop ethical guidelines for employing those procedures that might exacerbate a subject's symptoms, according to Dr. Hyman.
DISCUSSION
Dr. Varmus said that the foregoing presentations served to remind members of ACD that NIH faces a wide range of bioethical issues, that there is also a variety of mechanisms for addressing those many issues, and there remains a range of questions to address with additional research in bioethics.
Ms. Eisenberg said that doing research on bioethical problems will help to improve the current IRB system. Dr. Varmus noted that the increased volume of clinical research undertakings expected in the near future will further challenge the current IRB system, as will the increasing number of multisite clinical trials that may require a substantially different approach to reviewing protocols than the current system permits.
In response to comments from Dr. Elaine Fuchs about whether postdoctoral fellows as well as graduate students are mandated to take course work in bioethics, Dr. Baldwin said that NIH training grants specify that graduate students being supported by that mechanism fulfill course requirements in which scientific misconduct is the subject. However, she added, institutions may decide for themselves whether other students and junior researchers may enroll in courses on subjects such as bioethics or scientific misconduct. However, NIH probably cannot mandate such training for researchers who are not receiving NIH funding.
Dr. Emanuel pointed out that, although NIH mandates course work on issues such as scientific misconduct and plagiarism, there is no such mandate for course work on protecting human subjects, which he calls a serious deficiency. Dr. Varmus said that efforts are being made to establish such training through new didactic programs for clinical research, but there are limits to what NIH can reasonably require of other research institutions. Dr. Michael Gottesman said that investigators in the intramural program are required to take a course in human subjects research and that this short course may serve as a model for other institutions.
Summary and Conclusions
The Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) met on June 4, 1998, to consider proposals for research initiatives in response to accelerated budgetary growth, recommendations for expanding diversity within the community of biomedical researchers, bioengineering initiatives, a report on problems the scientific community is facing in gaining access to valuable tools for conducting biomedical research along with recommendations for addressing some of these problems, and several summaries describing the variety of NIH programs in bioethics.
The ACD acknowledged and commented on these programs and reports, and recommended that several of the recommendations outlined in reports that it considered be implemented.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Ruth L. Kirschstein, M.D. Executive Secretary, Advisory Committee to the Director, NIH
Harold Varmus, M.D. Director, NIH
Table of Acronyms
ACD
Advisory Committee to the Director
AIDS
Acquired Immunodeficiency Syndrome
AAMC
American Association of Medical Colleges
BECON
Bioengineering Consortium
COX2
Cyclooxygenase 2
CC
Clinical Center
DHHS
U.S. Department of Health and Human Services
ELSI
Educational, Legal, and Social Implications
FY
Fiscal Year
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
IP
Intramural Program
IRBs
Institutional Review Boards
NAS
National Academy of Sciences
NBAC
National Bioethics Advisory Committee
NCI
National Cancer Institute
NIAID
National Institute for Allergy and Infectious Diseases
Harold Varmus, M.D., Chairman Director, National Institutes of Health The Shannon Building, Room 126 Bethesda, MD 20892
Yank D. Coble, Jr., M.D. Physician Jacksonville, FL 32205
Ezra C. Davidson, Jr., M.D. Professor and Chairman Department of Obstetrics and Gynecology King/Drew Medical Center Los Angeles, CA 90059
Rebecca S. Eisenberg, J.D. Professor of Law University of Michigan Law School Ann Arbor, MI 48109-1215
Norman C. Francis President, Xavier University of Louisiana New Orleans, LA 70125-1098
Elaine V. Fuchs, Ph.D. Amgen Professor of Basic Sciences The University of Chicago Department of Molecular Genetics & Cell Biology Chicago, IL 60637
Jane E. Henney, M.D. Vice President for Health Sciences Health Sciences Center University of New Mexico Albuquerque, NM 87131
Susan B. Horwitz, Ph.D. Professor Department of Molecular Pharmacology Albert Einstein College of Medicine Bronx, NY 10461
Eric R. Kandel, M.D. Professor Division of Neurobiology and Behavior Columbia University New York, NY 10032-2603
Marc W. Kirschner, Ph.D. Professor and Chair, Department of Cell Biology Harvard Medical School Boston, MA 02115
Eric S. Lander, Ph.D. Professor, Department of Biology Massachusetts Institute of Technology Whitehead Institute Cambridge, MA 02139
Ting-Kai Li, M.D. Distinguished Professor of Medicine and Biochemistry Indiana University School of Medicine Indianapolis, IN 46202-5124
Philip Needleman, Ph.D. Senior Vice President Monsanto Company St. Louis, MO 63167
Baldomero M. Olivera, Ph.D. Professor, Department of Biology University of Utah College of Sciences Salt Lake City, UT 84112
Larry L. Smarr, Ph.D. Director, National Center for Supercomputing Applications University of Illinois Champaign, IL 61820
Shirley M. Tilghman, Ph.D. Professor, Department of Molecular Biology Princeton University Princeton, NJ 08544
Executive Secretary Ruth L. Kirschstein, M.D. Deputy Director National Institutes of Health Bethesda, MD 20892
Appendix C – Presenters
Wendy Baldwin, Ph.D. Deputy Director for Extramural Research National Institutes of Health Bethesda, Maryland 20892
Rebecca S. Eisenberg, J.D. Professor of Law University of Michigan Law School Ann Arbor, Michigan 48109-1215
Ezekiel J. Emanuel, M.D., Ph.D. Chief, Clinical Bioethics Department Clinical Center National Institutes of Health Bethesda, Maryland 20892
Steven E. Hyman, M.D. Director National Institute of Mental Health National Institutes of Health Bethesda, Maryland 20892
Lana Skirboll, Ph.D. Associate Director for Science Policy National Institutes of Health Bethesda, Maryland 20892
Harold C. Slavkin, D.D.S. Director National Institutes of Dental Research National Institutes of Health Bethesda, Maryland 20892
Appendix D – Related Reports and Articles*
The NIH Bioengineering Symposium Information
Report of the National Institutes of Health (NIH) Working Group on Research Tools
NIH Interagency Bioethics Training Initiatives Information Sheet
Memo from the Secretary, DHHS, dated June 17, 1997, "Ethics in Human Subjects Research"
NIH Guide announcement, dated November 7, 1997, "Mentored Scientist Development Award in Research Ethics"
NIH Guide announcement, dated November 7, 1997, "Short-term Courses in Research Ethics"
NIH Guide announcement, dated September 27, 1997, "Informed Consent in Research Involving Human Participants"
Expert Panel Report to the National Institutes of Health (NIH)
"Research Involving Individuals with Questionable Capacity to Consent: Ethical Issues and Practical Considerations for Institutional Review Boards (IRBs)"
* Copies of these reports and articles are available upon request. Call (301) 496-0959
