The 79th meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on December 2, 1999. NIH Director, Dr. Harold Varmus, who reminded ACD members that this meeting was his last as director, welcomed several new committee members and reviewed a number of personnel changes at NIH. Dr. Varmus noted that NIH Deputy Director, Dr. Ruth Kirschstein will become the acting director in January 2000. Secretary of Health and Human Services (HHS) Donna Shalala began her search to name a new director by asking Dr. Bruce Alberts, head of the National Academy of Sciences, to identify suitable candidates.
Dr. Varmus said that the NIH budget continues to grow. Late in November, President Clinton signed the FY 2000 appropriations bill for NIH that provides an increase of 15 percent, raising the NIH budget to $17.9 billion, about $7 billion more than when Dr. Varmus came to NIH. However, several details remain to be resolved, including a directive that the Department of HHS reduce its overall budget by 0.38 percent and that NIH delay obligating $3 billion until the final days of FY 2000. The FY 2000 NIH budget also reflects 15 initiatives that address various aspects of health disparities, involving minority populations in the United States and abroad; moreover, NIH is taking administrative steps to expand research activities in this area.
Dr. Varmus summarized a series of developments affecting gene therapy research following the death of an 18-year-old who was enrolled in a Phase-I clinical trial at the University of Pennsylvania. Despite that death, gene therapy shows promise, and a sensible approach and long-term outlook are needed. Several ACD members recently agreed to form a working group to review gene therapy safety issues and provide recommendations about whether the NIH Recombinant DNA Advisory Committee is doing what it should. ACD member Dr. Christine Cassel will served as co-chair of this subcommittee, which also will include another ACD member, Dr. Victor Dzau.
In another development, Federal officials recently released guidelines defining research misconduct as either falsifications, fabrications, and plagiarism. The guidelines also describe how to manage investigations into incidents of alleged misconduct and uncouple them from the levying of punishments.
Dr. Varmus reviewed several developments concerning matters that were considered at previous meetings, including: i) NIH recently negotiated an agreement to have most costs of animal research facilities reassigned to the indirect cost pool; ii) Dr. Richard Klausner of the National Cancer Institute will chair a trans-NIH working group to coordinate bioinformatics activities; iii) the Office of Technology Transfer (OTT) recently posted technology transfer guidelines on the Internet and will report to ACD in 2000 as to whether a forum for dealing with these issues should be established; iv) the recently formed Council of Public Representatives (COPR) met for a second time and continues to expand its activities; v) the Office for Protection from Research Risks is organizationally being moved from NIH into the Department of Health and Human Services (DHHS); vi) NIH decided not to establish a graduate degree-granting program; and vii) the Clinical Trials Database that was mandated under the FDA Revitalization Act will soon be tested.
Dr. Francis Collins, Director of the National Human Genome Research Institute (NHGRI), said that full-scale sequencing of human DNA began in February 1999, the first billionth basepair milestone was reached in the fall, and that the sequencing of human chromosome 22 was also recently completed. Other developments include: i) a consortium of researchers, who are assembling a collection of single nucleotide polymorphisms (SNPs) for the human genome, agreed to cooperate with a similar NIH effort involving SNPs; ii) the Mammalian Gene Collection was established to assemble a complete collection of human and mouse full-length copy DNAs (cDNAs); and iii) in October 1999, a consortium of ten research groups agreed to sequence the genome of the C57 black 6 laboratory mouse strain.
Dr. David Lipman, Director of the National Center for Biotechnology Information, said that E-biomed/PubMed Central will be available in limited form in January 2000, that it will distribute information by means of two distinct pathways, and that electronic publishing is changing the publishing industry in ways that may lead to exponential growth of PubMed Central. The concept of PubMed Central will continue to change and develop, and it could become a vehicle for publishing information that does not fit into the model for a scientific article.
Dr. Eric Lander summarized the report from a workshop on June 28, 1999, whose focus was the Burden of Illness. The workshop was held in response to recommendations in a report from the Institute of Medicine that NIH reexamine how it uses burden of illness metrics when setting research priorities. In terms of policy, workshop participants concluded that NIH continue to maintain a balance to cover the full spectrum of research related to human health but also to improve measures of disease burden and invest in models of response. Importantly, priority setting entails assessing probability of success, or opportunity, which requires making judgments.
Dr. Ting-Kai Li summarized the status of the Government Performance and Results Act review under way at NIH. NIH has developed a list of 46 goals for three core programs; 35 of those goals fall under the category of research, while the remainder come under the career or facilities development categories. Although most goals are quantitative, several broad goals are qualitative, and thus require independent assessment. The review board members carrying out that assessment concluded that NIH-supported research not only met but exceeded the goals set forth for it for FY 1999. The final report was being drafted in December, with submission to DHHS scheduled for January 2000. It then is slated to go to the Office of Management and Budget and the White House in February, and to Congress in March.
Dr. Shirley Tilghman described efforts of a working group to develop guidelines for the ethical research use of human pluripotent stem cells. Dr. Lana Skirboll, Associate Director for Science Policy, summarized the draft guidelines for stem cell research that were published in the Federal Register in December 1999. She said that Federally-sponsored research on stem cells cannot begin until after final guidelines are revised and published following the public comment period.
Dr. Elvera Ehrenfeld, Director of the NIH Center for Scientific Review, summarized the recent recommendations of the Panel on Scientific Boundaries for Review for reorganizing the system for scientific reviews. During the first phase, the panel calls for grouping study sections into clusters, called integrated review groups (IRGs), that work in scientifically related areas. Although plans call for redesigning study sections within IRGs, the process will not begin until sometime during 2000. Other efforts are under way to change some of the cultural norms of study sections and to make the system more flexible.
Mr. Steven Ficca, Associate Director for Research Services, introduced several colleagues who described three major construction projects under way at NIH. Dr. Gerald Fischbach, Director of the National Institute of Neurological Disorders and Stroke, and Dr. Steven Hyman, Director of the National Institute of Mental Health, then described plans to form a new, integrated neuroscience research center within the Intramural Program at NIH.
Shifting to extramural construction issues, Dr. David Kaufman, President of the Federation of American Societies for Experimental Biology, said that a Federation panel concluded that the rapid expansion of biomedical research anticipated for the next decade will require a change in existing facility construction support mechanisms. Ms. Susan Quantius, Associate Director for Budget, said that Federal law restricts NIH spending for extramural construction but pending legislation may authorize expanded programs in this area. Dr. Wendy Baldwin, Deputy Director for Extramural Research, said that NIH also provides for extramural construction through cost recovery under indirect costs. Dr. Varmus said that NIH should convene a group to develop a long-term plan for construction spending and to report their findings during the budget planning retreat in June 2000.
In his concluding remarks, Dr. Varmus pointed to several areas of concern that come amid a period of budgetary health and expansion of NIH research programs. Those concerns include how NIH will sustain budget growth and develop medical advances that remain affordable enough to meet public health needs.
OPENING REMARKS
Dr. Harold Varmus, Director of the National Institutes of Health (NIH), began the 79th meeting of the Advisory Committee to the Director (ACD) by reminding members that it would be his thirteenth and final meeting as director. He welcomed several new members of the committee, including Mr. Phillip Williams and Dr. Donald Wilson, who were present, and Dr. Thomas Cech, who was unable to attend.
Dr. Varmus reviewed several personnel changes at NIH, noting that Dr. Steven Strauss was named director of the National Center for Complementary and Alternative Medicine; Dr. Allen Spiegel, who was scientific director, is replacing Dr. Phillip Gorden as director of the National Institute of Diabetes, Digestive, and Kidney Diseases; and Ms. Susan Quantius, who served as a staff member of appropriations subcommittees for both the House of Representatives and the Senate and also worked for the American Association for Universities, was named associate director for budget at NIH. Over the next six months, two individuals will be departing NIH: Dr. Harold Slavkin, who serves as Director of the National Institute of Dental and Craniofacial Research (NIDCR), will be the Dean of the Dental School at the University of Southern California, while Dr. Norman Anderson, who serves as Director of the NIH Office for Behavioral and Social Science Research, will be a professor at the Harvard School of Public Health.
Dr. Varmus said that, when he leaves NIH at the end of 1999 to become the Head of Memorial Sloan-Kettering in New York, Dr. Ruth Kirschstein, who is NIH Deputy Director, will once again become the acting director. Secretary of Health and Human Services (HHS) Donna Shalala began her search for a replacement director by asking Dr. Bruce Alberts, head of the National Academy of Sciences (NAS), to provide her with a list of candidates.
Dr. Varmus also reminded ACD members of the impending departure of Representative John Porter (R-IL) from the Congress, where he has been a champion of NIH programs and an important figure during the recent period of substantial budgetary growth for NIH.
Dr. Varmus said that the NIH budget continues to grow. In fiscal year 1999, it increased by 15 percent, following several years of 6 to 7 percent increases. Late in November, President Clinton signed the FY 2000 appropriations bill for NIH that provides an increase of 15 percent, raising the NIH budget to $17.9 billion, about $7 billion more than when Dr. Varmus came to NIH. During the complex negotiations over the FY 2000 NIH appropriations bill, improvements came at each stage. However, several details remain to be resolved, including a directive that DHHS reduce its overall budget by 0.38 percent and that NIH delay obligating $4 billion until the final days of FY 2000.
Certain categories of the NIH budget received substantial increases and include: extramural construction; the IDeA (Institutional Development Award) Program, which supports investigators in states that traditionally do not receive high levels of NIH funds; and for shared research instruments, according to Dr. Varmus. In addition, Congress recommended that NIH establish an Office of Bioimaging and Bioengineering, an idea that Dr. Varmus welcomed. However, he said that establishing a new Institute of Bioengineering and Bioimaging is not a good idea because it risks isolating such activities, which benefit more by being distributed among the full range of institutes and centers at NIH.
Planning for the FY 2001 budget is well under way, and some consideration is already being given to the FY 2002 budget, according to Dr. Varmus. Although in past years individual institutes tended to work separately on their specific budget plans, the budget process for FY 2001 has been different because it began with a planning retreat, which included institute and center directors as well as five members of ACD and five members of the Council of Public Representatives (COPR). During the retreat, it was recommended that NIH establish working groups on bioinformatics, on training underserved disciplines, and on domestic health disparities.
As a follow-up to the budget planning retreat, Dr. Varmus and other officials at NIH also are identifying initiatives to be considered by officials in DHHS and in the Office of Management and Budget. Those officials are now deliberating over what to recommend for NIH in the FY 2001 budget that the President delivers to Congress in January.
In addition to the budget retreat, NIH convened its sixth leadership forum in September 1999. One outcome was to establish several working groups, whose members will deal with difficult issues, including how to fund trans-NIH projects and how NIH recruits and retains research administrators who oversee study sections. The first working group is to report on how to bring greater uniformity to the funding of trans-NIH projects, while another group will review how other Federal agencies, such as the National Science Foundation (NSF), bring in investigators from universities to serve as research administrators for two to three year periods.
Dr. Varmus said that several distinguished visitors came to the NIH campus during recent months, with one special occasion being the dedication of the Bumpers Vaccine Research Center on June 7, 1999. Among the visitors were President Clinton, HHS Secretary Donna Shalala, Senator Tom Harkin (D-IA), and former Senator Dale Bumpers and his wife Betty. President Clinton recommended that NIH establish such a center in a speech delivered at Morgan State University in 1997.
During the past year, Dr. Varmus has had frequent interactions with scientists from China and other Chinese scientists who now live in the United States. For example, he met with a group of such scientists in Boston, who expressed concerns about the impact on them of current political differences between the U.S. and China. In addition, Dr. Varmus visited the Chinese Academy of Sciences in November while members and guests celebrated its 50th anniversary. There are several signs of its heightened activity and growing sophistication, including its increasing budget and a reorganization of its programs. Moreover, a contingent of Chinese scientists is now one of the 17 official members of the Human Genome Project. Dr. Varmus also has been meeting with heads of medical science agencies from other countries, mainly in Europe. Those meetings have been hosted by Dr. George Radda, head of the Medical Research Council in London, England.
Dr. Varmus said that the National Cancer Institute recently established an ongoing collaboration with investigators from both the Republic of Ireland and Northern Ireland. To commemorate this cooperative program, he and other NIH representatives participated in the All-Ireland Cancer Conference held late in 1999.
Dr. Varmus described a recent exchange he had with writers and producers from ER, a popular television program, that could serve as a vehicle for describing some of the challenges involved in medical research. Past ER episodes often have portrayed researchers in a damaging light, in sharp contrast to how other episodes have dealt with controversial topics involving medical care. Hence, he discussed with the ER representatives several ideas for episodes that might help to remedy this imbalance.
Dr. Varmus said that he and Dr. Eric Lander participated in a millennial evening and lecture arranged by Mrs. Clinton. Dr. Lander's presentation on genomics stimulated interest in genomics and subsequent discussions by President Clinton on the significance of genetic variation in the context of race.
There is a growing concern within the Administration about how to reduce "health disparities" between different population groups, according to Dr. Varmus. For example, the Surgeon General has developed a set of public health goals outlined in the report, "Healthy People 2010." Dr. Varmus pointed out that certain disease burdens, such as from AIDS, cancer, heart disease, diabetes, and liver disease, tend to affect particular ethnic or racial groups disproportionately. Such matters need to be kept in mind if biomedical researchers are to serve public health needs as they develop new approaches to treating or preventing diseases.
Dr. Varmus said that the FY 2000 NIH budget reflects 15 initiatives that address various aspects of health disparities involving minority populations in the United States and abroad. Moreover, during the budget retreat in June 1999, a working group was formed to coordinate activities among the institutes that are intended to address such health disparities. In addition, NIH is supporting a bill proposed by Senator Edward Kennedy (D-MA) and Representative Bennie Thompson (D-MS) that would strengthen the ability of the Office of Research on Minority Health (ORMH) to coordinate such activities at NIH. Regardless of whether this bill is enacted, Dr. Varmus plans to administratively implement several of the features that are called for in the proposed legislation. For instance, NIDCR Director Dr. Harold Slavkin, Dr. Kenneth Olden, who is Director of the National Institute of Environmental Health Sciences, and ORMH Director Dr. John Ruffin, will co-chair a working group that is to define health disparities research, formulate a strategic plan and budget for research that addresses those disparities, and to report annually, through ORMH, accomplishments in these areas.
Dr. Varmus summarized recent developments affecting gene therapy research following the death of an 18-year-old man who was enrolled in a Phase-I clinical trial at the University of Pennsylvania that was testing a modified adenovirus vector carrying a gene for ornithine transcarbamylase. He said that, despite the death, gene therapy shows promise, and a sensible approach and long-term outlook for such research are needed.
After news accounts indicated that adverse events in other gene therapy trials were not reported to NIH, Dr. Varmus received letters from Senator Bill Frist (R-TN) and Representative Henry Waxman (D-CA). NIH developed plans for a workshop and meeting, under auspices of the Recombinant DNA Advisory Committee (RAC), to review adenovirus vectors in general, the specific incident at the University of Pennsylvania, and related issues having to do with patient confidentiality and adverse event reporting requirements.
These events have generated broad discussions regarding gene therapy on topics such as the oversight role of officials at NIH and the Food and Drug Administration (FDA) as well as the responsibilities of scientists involved in such research, according to Dr. Varmus. NIH has been deeply involved in gene therapy research and, until several years ago, members of RAC reviewed each clinical trial proposal. Dr. Varmus said that NIH is in a difficult situation, particularly as it is not a regulatory agency, a responsibility that belongs to FDA for clinical trials but is also shared by institutional biosafety committees and institutional review boards. Nonetheless, NIH plays an ongoing role in promoting public discussions of novel developments in gene therapy.
Dr. Varmus reminded ACD members that several years ago NIH convened a panel, jointly chaired by Dr. Stuart Orkin of Harvard Medical School and Dr. Arno Motulsky of the University of Washington, to review NIH-supported science underpinning gene therapy. The panel's report, which was highly critical about then-current achievements but also encouraging about the long-term prospects for gene therapy, proved highly influential. Also in 1995, another NIH-appointed group reviewed how RAC was operating and recommended a series of changes that led it away from reviewing every gene therapy clinical trial proposal. Dr. Varmus said that, since then, RAC has turned its attentions to other important activities that include sponsoring public meetings to discuss novel approaches to gene therapy; broader public conferences to consider profound issues such as gene therapy in utero, gene therapy in germline cells, and possible use of lentivirus vectors such as HIV; and reviewing the distribution of clinical trials into specific disease categories.
Shortly before the ACD meeting, NIH sent letters to grantees doing clinical research in gene therapy, reminding them of their responsibilities to report adverse events during such trials but also to maintain patient confidentiality. Dr. Varmus said that he asked several ACD members to form a working group to review gene therapy safety issues and provide recommendations about whether RAC is doing what it should. Dr. Christine Cassel agreed to be a co-chair of this subcommittee, which also will include Dr. Victor Dzau.
Dr. Varmus turned his attention to another topic, research integrity, and noted that the university community now manages accusations of violations of integrity in a more enlightened manner than in the recent past. The White House Office of Science and Technology Policy and DHHS recently released guidelines defining research misconduct and how to manage investigations into incidents of alleged misconduct. The definition is restricted to falsifications, fabrications, and plagiarism. Meanwhile, the investigatory process is streamlined, and is uncoupled from the levying of punishments. During a public meeting convened by the National Academy of Sciences, these new guidelines were widely praised.
Dr. Varmus then summarized several other developments and provided follow-ups to discussions at past ACD meetings. For example, he, Dr. Wendy Baldwin, Deputy Director for Extramural Research, and other NIH officials, recently negotiated an agreement to have most costs of animal research facilities reassigned to the indirect cost pool, rather than to direct per diem costs. This change will have little overall effect on NIH budgets.
As a follow-up to the report from Dr. Larry Smarr and Dr. David Botstein on bioinformatics presented during the June 1999 ACD meeting, a trans-NIH working group was established to coordinate bioinformatics activities. It is chaired by Dr. Richard Klausner of the National Cancer Institute (NCI), and Dr. Francis Collins, Director of the National Human Genome Research Institute, and Dr. Marvin Cassman, Director of the National Institute of General Medical Sciences, serve as co-chairs.
As a follow-up to the report on research tools presented by Ms. Rebecca Eisenberg during the December 1998 ACD meeting, the Office of Technology Transfer (OTT) developed guidelines that were posted recently on the Internet. Comments received have generally been favorable, and final guidelines will be issued soon. They will include a model "simple letter of agreement" specifying how investigators in the NIH Intramural Program are to share research materials. Dr. Varmus said that he hoped this approach will be followed more widely by researchers in the extramural community to overcome what is now an impediment to research. OTT will oversee implementation of these guidelines, and will report back to ACD by the end of 2000 as to whether a standing "Research Tools Forum" should be established.
The Council of Public Representatives (COPR) convened for a second time in October 1999. Its members have been involved in budget discussions, evaluation of the NIH Government Performance and Results Plan, reviews of institute directors, and discussions of patient privacy issues and development of a clinical trials database. A newsletter provides council members and the wider group of COPR Associates with information about continuing activities. Dr. Varmus has asked members to work with health advocacy groups to develop prizes and other incentives to stimulate interest in specific areas of biomedical research.
During the June 1999 ACD meeting, Ms. Rene Landers and Ms. Nancy Dubler presented a report on the Office for Protection from Research Risks (OPRR). HHS Secretary Shalala has accepted its recommendations and is moving that office into DHHS. The director of that office will be a member of the Senior Executive Service, and an advisory council will be established. However, the animal welfare component of OPRR will remain at NIH.
Following lively discussions during several previous ACD meetings, Dr. Varmus, Dr. Michael Gottesman, who is Deputy Director for Intramural research, and several other NIH officials decided not to pursue establishing a graduate degree-granting program at NIH. Instead, current activities involving graduate students at NIH will be enhanced, including more courses in areas such as clinical research and bioinformatics. Other activities include constructing a graduate student center as part of the Clinical Center and training students from local medical schools that do not have M.D.-Ph.D. programs.
Dr. Varmus said that NIH is searching for a new director of the Office of Medical Applications of Research. This individual will implement recommendations outlined during the June 1999 ACD meeting with respect to the conduct of consensus conferences.
Dr. Varmus also described several matters affecting clinical trials. For example, NCI has awarded grants to study cancer biomarkers for use in clinical trials. Other workshops are being held to develop biomarkers in other clinical research areas. In another development, the Clinical Trials Database that was mandated under the FDA Revitalization Act is now ready for testing. This effort is being coordinated by Dr. Alexa McCray of the National Library of Medicine, who will report on this subject at the June 2000 ACD meeting.
GENOME UPDATE
Dr. Varmus introduced Dr. Francis Collins, Director of the National Human Genome Research Institute (NHGRI), and noted several significant announcements for the genome project during the week. They included reaching the first billionth basepair milestone and also completing the sequencing of human chromosome 22.
Dr. Collins reminded ACD members that he presented a revised five-year plan for the Human Genome Project to them in December 1998 and, in June 1999, presented an accelerated timetable calling for a working draft of the human genome sequence by the spring of 2000, and a highly accurate sequence by 2003 or sooner. He said that, following several successful pilot projects, full-scale sequencing began in February 1999. Costs have come down, new technologies are now being used, and the organizational structure has coalesced into an efficient, international operation.
Investigators at the 16 major international centers, including the five largest — four in the United States plus the Sanger Centre in the United Kingdom (UK) — confer regularly to coordinate their efforts. Representatives met in September 1999 in the UK to describe their sequencing capacities and accept assignments; they plan to meet again in January 2000 to assess progress and reallocate assignments, if necessary.
The sequencing strategy for the human genome is based on shotgun sequencing of mapped bacterial artificial chromosomes (BACs). The BACs have been mapped into bins using restriction enzyme digests to identify overlapping clones. The clones in the bins are then ordered into contigs using specialized computer programs. Dr. Collins said that some 7,000 contigs have been generated in this way, and the process is working remarkably well. As of November 26, 1999, there was highly accurate sequence information for nearly 0.5 billion human base pairs, or 14.7 percent of the genome, and a rough draft for another 700 megabases. Together that represents 36.5 percent of the genome, a figure that includes the one billionth base pair milestone, a guanine residue on chromosome 2. This achievement was celebrated at NAS.
Dr. Collins said that the sequencing of chromosome 22, the second smallest of the human chromosomes, was also recently completed, except for 11 gaps of no more than 150 kilobases in an expanse of 36 megabases. He considers this achievement a special moment in history. Much of the work was completed at the Sanger Centre, but investigators at the University of Oklahoma, Washington University, and at Keio University in Japan also contributed. The chromosome contains many long repeats, a feature that is probably responsible for the frequent rearrangements that occur within this chromosome and which give rise to conditions such as DiGeorge, velocardiofacial, and cat-eye syndromes. The chromosome appears to encode at least 545 genes, and perhaps an additional 200 to 300, according to computer analysis. The distribution of G-C versus A-T rich regions does not correlate with the chromosome's G-banding pattern.
A consortium of pharmaceutical companies (the SNP consortium), which are assembling a collection of single nucleotide polymorphisms (SNPs) for the human genome, is cooperating with the NIH effort to identify SNPs, according to Dr. Collins. Members of the consortium recently deposited their first set of SNPs into the special database for this purpose that is being managed by the National Center for Biotechnology Information (NCBI).
Dr. Collins said that another program, called the Mammalian Gene Collection, recently was established to assemble a complete collection of human and mouse full-length cDNA clones and sequences. This effort, which involves investigators in the Intramural Program at NIH and in the extramural community, now has an advisory committee that was scheduled to meet in December 1999 for the first time, chaired by Dr. Barbara Wold. Plans call for the program to assemble 20,000 sequenced clones per year into a full collection, whose components researchers may order and use.
Dr. Collins said that plans to develop a mouse genomics and genetics project date to a meeting on that topic in March 1998, following which a trans-NIH working group was established. At a follow-up meeting in October 1998, a strategy for sequencing was formulated. More recently, in October 1999, a consortium of ten research groups agreed to sequence the genome of the C57BL6/J laboratory mouse strain. The approach will depend on a BAC scaffold but will add a whole-genome shotgun component, which provides for early broad coverage of the genome. Dr. Eric Green is leading a group whose members will decide how to balance these two approaches. Data will be released promptly, according to the Bermuda rules calling for 24-hour release into public databases of all data that has been assembled into one-kilobase contigs. The investigators who do the mouse genome sequencing analysis will set aside some of their capacity to respond to requests for special attention to specific sequencing tasks from others who are studying mouse genetics. A special peer review panel will evaluate such requests, which will be submitted electronically. Dr. Collins pointed out that this component of the program must be considered experimental and will be a challenge to manage.
DISCUSSION
In response to a question from Mr. Phillip Williams about the patenting of genomic research findings, Dr. Collins said that he welcomed the investment by biotechnology and pharmaceutical companies in genomic research and also their involvement in partnerships, as in the SNP Consortium. He said that the proprietary claims of companies in areas that appear to describe fundamental properties, such as the genome sequence itself or variations in human genes, are more problematic. He recommended that as much genomic information as possible be kept in the public domain. Although the goals of the publicly and privately sponsored sequencing efforts are significantly different, Dr. Collins said the possibility of collaboration is being considered.
Dr. Philip Needleman asked whether there will be appropriate follow-up research efforts once human genomic sequencing itself is completed. Dr. Collins said that considerable thought is going into this question. Some efforts will be devoted to sequencing genomes of other species, including the mouse, Xenopus, the zebra fish, the chicken, and the rat. Improvements in technology that lower unit costs will help to make these additional efforts more affordable. Other technical developments, such as microarray and sophisticated computational analysis, are changing how genomic information can be used. The Institute plans to establish Centers of Excellence in Genomic Science, some of which will emphasize computational analysis, others population genetics. In response to Dr. Needleman, Dr. Varmus said that genomic information is affecting programs within all the categorical institutes at NIH. Moreover, this information has a wide impact on many related research programs, affecting protein structure, gene expression, analysis of signaling pathways, and others.
Dr. Victor Dzau said that genomics information poses considerable challenges for those who are responsible for educating personnel, including medical students, who deliver health care. He said that questions were raised during a recent meeting at Harvard Medical School about planning the curriculum for 2010 and the difficulty of finding enough qualified teachers to educate medical students about the genome.
Dr. Collins said that the National Coalition for Health Professional Education in Genetics, which includes 120-member organizations and was formed jointly with the American Medical Association and the American Nurses Association, is addressing some of these challenges. It plans to generate electronically-based educational materials with help from the Robert Wood Johnson Foundation. Another group, called Genetic Resources on the Web (GROW), includes 25 groups whose members are trying to assemble validated information about genetics and genomics that will be useful for health care providers. Dr. Varmus pointed out that the Foundation for the NIH, which operates independently, has been involved in some resource-raising activities to support genomics information outreach programs.
PUBMED CENTRAL
Dr. Varmus introduced Dr. David Lipman, Director of the National Center for Biotechnology Information (NCBI), which coordinates GenBank and other components of the genome project. He also is involved in NIH efforts to make the scientific literature accessible through the Internet. This NIH program, now called PubMed Central, is expected to become available in limited form in January 2000, with the Proceedings of the National Academy of Sciences (PNAS) (perhaps including issues going back to 1990) and Molecular Biology of the Cell (MBC), the first two publications that will be accessible through the system.
Dr. Lipman said that PubMed Central refers to a repository for primary research results in the life sciences that NIH is now developing. Plans call for NIH to be responsible for information retrieval and navigation, while existing journals, new publications, and their editorial boards will be responsible for obtaining manuscripts, reviewing them, and depositing them with NIH.
So far, about one dozen scientific societies and journals have agreed to participate in PubMed Central, and they are sending, or soon will be sending, materials for NIH to archive and redistribute, according to Dr. Lipman. Details about formatting and time tables for re-publishing are still being negotiated. Meanwhile, four professionals at NIH are dedicated to developing the software and other systems needed to handle these materials, including high-resolution graphics. He said that pilot runs with materials from PNAS and MBC have proved instructive, indicating that there may be unanticipated gaps in materials and other technical challenges to overcome when making transfers from conventionally published journals to the electronically-distributed PubMed Central.
Dr. Lipman said that information would be distributed by PubMed Central according to two distinct pathways. In one, a query would retrieve an abstract from PubMed, which would then link to a full text article in PubMed Central. In the other, an individual would go directly to the PubMed Central home page or look at the contents pages of journals that are maintained within the system. Plans call for incorporating some uniformity of format while maintaining some of the features that are specific to individual publications. Examples of uniformity will be a fixed width of text, an uncluttered look without figures embedded in the text but present as thumbnails along the border near where they are first mentioned. The electronic version will contain linkages to different segments of each paper and to other articles, books, or other resources.
DISCUSSION
Dr. Larry Smarr said that, by applying artificial intelligence techniques to materials within this system, it may become possible to identify emerging trends or to analyze biomedical information in ways that would not otherwise be possible. In response, Dr. Lipman said that issues such as copyright restrictions on the use of articles and other information within the system will need to be taken into account. He noted that a charter for establishing an advisory board to deal with such issues is almost completed. Dr. Varmus said that PubMed Central will provide opportunities for entrepreneurs to develop guides, highlighted databases, or secondary commentaries.
Ms. Rebecca Eisenberg said that, although valuable for those who use the scientific literature, PubMed Central appears to clash with the business model for traditional publishing. In response to her question about opposition to the plan, Dr. Lipman said that scientific societies and commercial publishers are struggling with these issues. However, he also noted that the Current Science Group, which is published commercially, plans to participate, and another commercial publisher may also join provided that its materials can be published after some delay, which is being negotiated.
Dr. Lipman also pointed out that electronic technologies are changing the publishing industry in many ways and that these fundamental changes may lead to exponential growth of PubMed Central. He further noted that a large fraction of income for many journals comes from library subscriptions, whose subscribing patterns will only change slowly with the advent of PubMed Central. It could lead to a decline in those institutional subscriptions, which may, in turn, force changes on publishers.
Dr. Varmus said that people will continue to acquire information in a variety of ways, and that PubMed Central will not entirely substitute for the reading that people do of news and commentary in current scientific publications. He also pointed out that such spot reading is very different from the literature searches that scientists do when they need to find recently published or older items that they may have missed when casually browsing. In addition, scientists in countries such as China may benefit from access to much more of the scientific literature than they now can obtain. Indeed, many journals there and elsewhere have very limited distribution by traditional means, but might be more widely disseminated if they were available electronically. Moreover, PubMed Central might also publish items, such as incidental commentaries or technical letters, that would not qualify for publication under ordinary circumstances but might provide valuable insights as part of on-going specialized discussions.
In response to a question from Ms. Eisenberg about costs, Dr. Lipman said that many journals pass page charges to authors that, in turn, are paid for by NIH or other funding agencies. Dr. Varmus noted that authors pay page charges, special charges for photography, for reprints, and also subscription charges for the journals. PubMed Central may bear some of those costs, according to Dr. Lipman, who noted that many of the cost practices in the scientific publishing industry do not make sense. He also said that there should be ways of cutting the publisher's cost for preparing a scientific article, which typically is about $4,000, by publishing it on the Internet. Thus, he concludes that it would be better to pay for these costs up front, make articles available to everyone, find other ways to reduce costs, and better leverage the overall investment that is being made in disseminating information, both traditionally and by the Internet.
Dr. Lander wanted to know more about the possibility of publishing through PubMed Central articles that have not been subject to peer review. Dr. Lipman said that editorial review boards can function as virtual organizations, with individual members linked through the Internet and much of their regular business conducted electronically. For example, Vitek Tracz, the publisher of the Current Science Group, is establishing a journal called Biomed Central with a special tracking system for peer review and also the infrastructure to support independent editorial boards. Community of Science in Baltimore is doing something similar.
In response to a question from Dr. Lander about commercial advertising on PubMed Central, Dr. Lipman said that outright advertising might interfere with the ability of commercial organizations to create specialized portals. However, an alternative to direct advertising might be to provide links through mention of specific commercial products, such as reagents, in the materials and methods sections of articles.
In response to a follow-up question from Dr. Shirley Tilghman about some items that might not be peer-reviewed at all, Dr. Lipman said that an allied site may be established for reporting preliminary and provisional results before they are subject to peer review. However, there would still be review boards that would screen such items for suitability. Dr. Varmus said that this component of the overall proposal may prove to be one of the most important. For instance, it might provide a means for disseminating so-called negative results that are not typically published but may contain valuable information. Such items can be thought of as useful letters that enrich communication among scientists.
Dr. Steven Chu said that physicists often publish singular findings or other commentaries without peer review. Dr. Lipman said that the concept of PubMed Central will continue to change and develop, and that it could become a vehicle for publishing information that does not fit into current standard models for what a scientific article should be. In general, the aim is to improve everyone's access to such information. However, to do this right, it will be essential to work with the people in the scientific community who will be using it.
BURDEN OF ILLNESS WORKSHOP
Dr. Varmus introduced Dr. Eric Lander, Director of the Whitehead Institute at Massachusetts Institute of Technology, to summarize a report from a workshop on June 28, 1999, whose focus was the Burden of Illness. The workshop was held in response to recommendations in a report from the Institute of Medicine (IOM) that NIH reexamine how it uses burden of illness metrics when setting research priorities. The June workshop brought economists and medical scientists together to consider how several such metrics, as well as available epidemiologic data, can help in setting research priorities to meet public health needs.
Dr. Lander, who chaired the June workshop, said that recommendation three in the IOM report explicitly calls on NIH to "strengthen its analysis and use of health data, such as burdens and costs of disease, and of data on the impact of research on the health of the public." He pointed out that this recommendation does not demand that NIH simply fund research efforts in direct proportion to disease burden, which makes no economic sense. The investment in research needs to reflect the disease burden plus the proportional impact that research might have in reducing the burden.
The larger goal is to optimize that investment across a range of diseases, but defining the goal in this way raises many complex questions, according to Dr. Lander. Measures, such as quality adjusted life years (QALYs) and disability adjusted life years (DALYs), can provide a way of assessing the impact of treatments on specific diseases or conditions, but they are more difficult to apply to research that eventually may lead to such treatments. When such measures are applied over many years, they can be helpful for comparing progress and cost-effectiveness in treating one disease against another.
Dr. Lander said that because predicting the long-term health impacts of biomedical research is difficult, developing a complex economic model for that purpose will likely be a very difficult undertaking. In response to a comment from Dr. Philip Needleman about doing research in areas of unmet medical needs, Dr. Lander said that two issues come into play, a measurable variable such as the prevalence of a particular disease and its public health impact, but also the scientific judgment about whether there are ready opportunities whereby research could have an impact on that disease.
Although summary measures are useful for assessing particular improvements in medical treatment, they do not explain how those improvements occurred, according to Dr. Lander. However, models that provide frameworks for synthesizing information can help explain the contributions of research to the improvement of medical treatments. For instance, the stroke policy model can be used to assess the likely impact of specific treatments on patients with this disease. However, there are very few such models, they are of limited applicability, and they require a great deal of work to construct. Nonetheless, the participants at the June workshop recommended that NIH should convene a meeting to further explore the value of these models and take other steps to encourage their development. Their main value seems to be in the context of defined clinical interventions rather than the early stages of basic research.
Dr. Lander said that, in terms of policy, retrospective measurement of disease-specific burden is not a perfect guide to research priority setting. Projection of future disease burden may be more relevant, but is also more difficult to do well. Priority setting entails assessing probability of success, or opportunity, which requires making judgments. Moreover, for any specific disease-oriented proposal or project, there may be spillover benefits for other diseases. In addition, the assessment is further complicated because NIH provides resources to support fundamental research and infrastructure.
The workshop participants concluded that NIH should continue to maintain a balance to cover the full spectrum of research related to human health but also to improve measures of disease burden and invest in models of response, according to Dr. Lander. However, he said, the overall picture of setting research priorities is complicated and requires judgment.
DISCUSSION
In response to a question from Dr. Steven Chu about whether judgment calls could be made more quantitatively, Dr. Lander said that using economic or mathematic models would probably not be useful. However, forcing discussions of why past judgments were made and explaining how priorities were set would be helpful. Dr. Varmus said that it is possible to quantify the likely impact of a particular therapy that is soon to be made available.
Dr. William Brody said that the only appropriate metric to use is burden of illness, rather than other factors that are part of the complex equation displayed by Dr. Lander. He also said that creativity in research becomes possible when there is a critical mass of people working in a particular area. Hence, the fundamental policy issue for NIH is to decide how much to invest in core infrastructure or basic science versus in specific diseases.
Dr. Varmus said that although experience enables NIH to predict in which areas advances are more likely, creativity does not always come in those areas that receive the most funding. He also said that some diseases are more refractory to progress. For example, in general there is a greater likelihood of success in understanding how to control an infectious disease compared to how to control a chronic degenerative disease. Dr. Brody agreed, and pointed to the example of AIDS. Dr. Lander said that such a disease, which is more burdensome, ordinarily receives a proportionately greater amount of research funding to reflect that greater burden.
Ms. Rebecca Eisenberg said that the burden of disease analysis is faulty because it does not distinguish between publicly and privately funded research--and their respective goals. Public investment is particularly needed where a simple burden-of-illness analysis may suggest otherwise. She said that the more likely an investment will lead to a short-term health benefit, the more likely it will be deemed profitable for the private sector to pursue. In the case of the public sector research investment, there may be political support for problems that are perceived as important and worthy of public spending. She also said that the IOM report seems to suggest that NIH take use burden-of-illness information as a way of accounting for political constituencies that support biomedical research.
Dr. Varmus said that the public strongly supports the NIH investment in rare diseases--not only because such investments sometimes pay off with insights that apply to diseases that are not rare, but also because there is broad agreement that even rare diseases are deserving of attention. Also in response to Ms. Eisenberg's comments, Dr. Shirley Tilghman said that publicly-supported researchers are more likely to try to understand a process, even if there is no obvious way in which it may be applied to a particular disease.
Dr. Philip Needleman said that, because of the high costs of drug development, companies in the private sector cannot work on medical problems that affect small populations. In response to a question from Mr. Arthur Ullian, Dr. Needleman said that the average investment of bringing a new drug through development and regulatory review is $365 million--and $500 million when the cost of drugs that fail is factored in. If a patent on a candidate therapeutic agent is lapsing, many companies will not pursue its development. However, such dropped products can be licensed by others in either the public or private sectors.
In response to a question from Dr. Jane Menken about whether burden of illness could be applied more broadly to examine how a disease differentially affects different groups of people, such as members of different ethnic groups or racial minorities, Dr. Lander said that the participants at the June workshop did not pursue this topic.
Dr. Varmus said that there is a similar issue, which was broached during the workshop, as to how Congress might weigh burden of illness against other societal needs. In response, Dr. Lander said that even there the discussion was more narrowly-focused on whether burden-of-illness metrics can be refined for use in specialized decision making, but that broader policy questions will continue to depend on more qualitative judgments.
Dr. Varmus halted the discussion and said that Dr. Lana Skirboll, who is Associate Director for Science Policy, would bring these issues before ACD for further consideration.
PRELIMINARY REPORT OF THE GPRA REVIEW
Dr. Varmus introduced Dr. Ting-Kai Li of Indiana University School of Medicine to summarize the status of the Government Performance and Results Act (GPRA).
Dr. Li said that GPRA, which was enacted in 1993 to improve government agency accountability and effectiveness, establishes an annual requirement for evaluating performance and GPRA compliance. As part of a plan to meet these requirements, NIH has developed a list of 46 goals for three core programs; 35 of those goals fall under the category of research, while the remainder come under the career or facilities development categories.
Although most goals are quantitative, several broad goals such as adding to the body of biomedical knowledge and developing new approaches to prevention, diagnosis, and treatment of diseases are qualitative, and thus require independent assessment, according to Dr. Li. The review board that was established for this purpose included representatives from ACD and COPR, other members with scientific expertise as well as additional representatives from the health care delivery community and patient groups. Board members reviewed background materials, held a series of teleconferences, and subsequently were assigned specific reviews from a compendium of assessment materials. The group met in October 1999 to produce a preliminary report.
GPRA goals were considered met if the results yielded new findings and were published; they were exceeded if additional criteria were met, such as if a discovery opened a new avenue of research, according to Dr. Li. These evaluations were conducted for a broad range of scientific, medical, and technical developments, including in cancer research, immunology, neurobiology, stem cell research, community health, and the refinement of many imaging techniques. The review board members concluded that the NIH Office of Science Policy (OSP) did an outstanding job of preparing the background documents. The materials reflected the high quality and relevance of NIH-supported research, and thus NIH not only met, but exceeded, the GPRA goals set forth for it for FY 1999. The final report was being drafted in December, with submission to DHHS in January 2000, the Office of Management and Budget and the White House in February, and to Congress in March.
DISCUSSION
Dr. Varmus commended Dr. Li and members of the review board as well as Dr. Lana Skirboll and her colleagues within the OSP for their GPRA compliance efforts. In response to a comment from Dr. Lander, he noted that this evaluation also considered how well NIH met its "means" goals in areas of management, such as dispensing grant money. However, evaluating the program components of overall NIH performance was the more challenging undertaking.
Dr. William Brody said that the evaluation materials were well written and could be used in a broader arena. Dr. Varmus said perhaps the materials could be distributed to science writers for wider dissemination to the general public.
In response to Dr. Lander, who asked for a fuller description of whether this evaluation will satisfy the GPRA requirements, Dr. Varmus said there were many discussions about how to do this review, and that he insisted that it not focus too much on quantitative analysis. For instance, the Genome Project, which does contain quantitative goals and convenient metrics, was viewed as an exceptional program amid many other scientific efforts at NIH that do not fit that mold.
Dr. Skirboll said that this review represents the first time that NIH will report back to DHHS, OMB and the White House, and to Congress on GPRA compliance. Thus, it will be the first time that NIH can expect feedback on how successful this approach is considered to be. There will be presentations to Congress on this comprehensive GPRA review of NIH programs, some within the context of appropriations bill hearings. Those hearings will provide opportunities to highlight some NIH management innovations.
Dr. Varmus said that such presentations will help to explain that recent growth in the NIH budget has not been matched by essential growth in its administrative staff. Demonstrating to Congress that there is little waste in the system but a genuine need for a build-up in management staff will be another useful outcome of the GPRA undertaking.
UPDATE ON STEM CELL RESEARCH
Dr. Varmus summarized the recent history of stem cell research-related issues, starting with a NIH review panel to look at human embryo research that was set up in 1994 and chaired by Dr. Steven Mueller from Johns Hopkins University. Although the panel report delineated certain research areas that were eligible for NIH support, Congress passed amendments to appropriations bills that ban the use of Federal funds for research that might damage or destroy human embryos. In November 1998, researchers from two different laboratories reported the derivation of human pluripotent stem cells--in one case from fetal tissue and in the other from human embryos that were in excess of clinical need at in vitro fertilization clinics in the private sector.
Because Federal funds may be used to support fetal tissue research, research on stem cells derived from that source also may receive Federal support, according to Dr. Varmus. Moreover, the DHHS General Counsel's office concluded that, because stem cells derived from human embryos are not and cannot become human embryos, Federal funding for research on such stem cells also is permissible. Members of the National Bioethics Advisory Commission (NBAC) provided additional support indicating that this position is based on sound ethics.
Dr. Varmus said that before NIH funded such research, he thought that guidelines were needed to ensure compliance with the law and with agreed-on ethical principles. A working group of the ACD was formed for this purpose, and it was co-chaired by Dr. Shirley Tilghman of Princeton University and Dr. Ezra Davidson of Charles R. Drew University of Medicine and Science. The guidelines were posted in the Federal Register in December 1999.
Dr. Tilghman described the process whereby the working group developed guidelines for the ethical research use of human pluripotent stem cells. She said that the working group reviewed the way that the two separate research groups derived stem cell stocks and concluded that the guidelines first need to address those methodologies. According to one method, a fertilized egg developed to the blastocyst stage in vitro and inner mass cells were obtained to produce pluripotent stem cells; the fertilized eggs that were used had been intended for in vitro fertilization use, were prepared without using public funds, and exceeded clinical need. According to the second method, pluripotent cells of the fetal genital ridge were obtained from a fetus from a terminated pregnancy.
Dr. Tilghman said that the working group was asked to develop guidelines to address how, not whether, to use such cells in research; it included scientists, members of the public, ethicists, physicians, and lawyers. Dr. Tilghman and Dr. Davidson prepared a draft document describing a series of issues for the working group members to consider; the group met during a public meeting at which individuals representing a broad range of interests presented their views; and then working group members extensively revised the original draft document to present provisional guidelines for further public review.
Dr. Lana Skirboll, Associate Director for Science Policy, summarized the draft guidelines for human pluripotent stem cell research that were published in the Federal Register in December 1999. She said that Federally-sponsored research on human pluripotent stem cells cannot begin until after these guidelines are revised and a final version is published following the public comment period. She said that the guidelines will not permit researchers to derive human pluripotent stem cells from human embryos using Federal funds, as that is against the law. Researchers may not use stems cells that were derived from human embryos created for that purpose. The guidelines also prohibit using such cells to create a human embryo, combining cells with an animal embryo, or for reproductive cloning of a human. Also, use of human pluripotent stem cells derived using somatic cell nuclear transfer is prohibited by the guidelines.
Dr. Skirboll emphasized that these ethical guidelines are restricted to research uses of human pluripotent stem cells. For the cells derived from frozen embryos, the guidelines specify that only the embryos produced for infertility treatment, not for research purposes, and in excess of clinical need may have been used. Potential donors of such embryos may have been approached only after they have completed their in vitro fertilization procedures, and they may not have been offered any inducements to donate materials. Moreover, the fertility physician may not have been the stem cell researcher and vice versa. All identifiers are to have been removed from donated embryos, donations must have been unrestricted, and protocols are to have been reviewed by institutional review boards (IRB).
Dr. Skirboll said that other precautions are delineated in the informed consent section, which researchers in the private sector need to follow if researchers who receive Federal funds are to use such stem cells. Donors will have been fully informed as to how such cells may be used; moreover, they may be kept in use for many years, but that the donors will not receive direct benefits from any of those uses. Potential donors are to have been approached only at the point when a decision needs to be made about what to do with excess, stored embryos. Meanwhile, researchers planning to use such cells are required to supply extensive documentation of what they plan to do, and of compliance with informed consent and review procedures stipulated in the guidelines.
Dr. Skirboll also outlined some of the differences in the guidelines as they apply to use of human pluripotent stem cells derived from fetal tissue. The main difference is that NIH funds may be used to derive such cells, and all applicable local and Federal laws and guidelines need to be observed, including Federal rules governing fetal tissue transplantation. The informed consent process, although not required of basic fetal tissue research as such, is modeled on the consent for cells derived from frozen embryos and represents an extra step that researchers need to follow.
Dr. Skirboll said that the draft guidelines recommend establishing a Human Pluripotent Stem Cell Review Group, which would hold public meetings to review non-routine proposals for studying new sources of human stem cells to ensure there is compliance with the guidelines. To begin with, anyone submitting such proposals will be subject to this special review, but only those proposals that are deemed to have scientific merit will go through the entire process. The review group also will compile an annual report summarizing the projects under way; it will also from time to time recommend how to amend the guidelines.
Dr. Skirboll emphasized that, although this compliance procedure is to be governed by guidelines, no NIH funds will be provided for human pluripotent stem cell research until and unless a proposal has been certified as complying with those guidelines.
DISCUSSION
Dr. Varmus said that, although most Federally-sponsored stem cell research likely will involve existing cell lines, investigators will need to document that they are complying with the guidelines. Thus, some reviews will be done at the administrative level, rather than publicly.
In response to questions from Dr. Philip Needleman and Dr. Elaine Fuchs, Dr. Varmus and Dr. Skirboll said that researchers at a second institution who plan to collaborate with someone who has documented compliance with the guidelines will themselves need to demonstrate compliance. In the case of stem cell lines that already are cleared for use, that information will be made public and will not, by itself, require further review. However, the investigators planning to use those lines will need to have their own proposals reviewed.
REPORT FROM THE PANEL ON SCIENTIFIC BOUNDARIES FOR REVIEW
Dr. Varmus said that the Panel on Scientific Boundaries for Review, which is chaired by NAS President Dr. Bruce Alberts, has been dealing with the contentious topic of peer review. He then introduced Dr. Elvera Ehrenfeld, Director of the Center for Scientific Review (CSR), to summarize recent activities of the panel that are aimed at keeping the review process in tune with modern science and balancing expertise against breadth when putting together the members who serve on study sections that review research proposals.
Dr. Ehrenfeld said that, soon after she arrived at NIH in 1997, she began contacting the diverse communities of researchers whose work NIH supports. A common theme among them was that they wanted changes in the organization and more appropriate functioning of study sections, particularly in light of emerging areas of research. There was also concern that then-current study sections could not accommodate interdisciplinary research, that some productive areas were confined to too few study sections, and that other areas had developed a sense of entitlement to continuing research support.
Dr. Ehrenfeld said that the 15-member Panel on Scientific Boundaries for Review was formed in 1998. Its members determined that scientific reviews should be reorganized into clusters of study sections, called integrated review groups (IRGs), that worked in scientifically-related areas. These clusters are being used as fundamental units, with overlap of interests and mobility of members among study sections within an IRG. Although plans call for redesigning study sections within IRGs, that process will not begin until sometime during 2000, according to Dr. Ehrenfeld. The panel members also examined some of the cultural "norms" that determine the behavior of study sections.
Dr. Ehrenfeld said that the panel members completed a Phase I concept report during the middle of 1999. It outlines the goals of the peer review process, proposes a new set of IRGs, describes the cultural "norms", and outlined the procedures for Phase II of the panel's activities, which will entail establishing individual study sections within each group.
The IRGs that are proposed in the Phase I report fall into disease groups and systems that are designed to accommodate how modern science is being applied to many different areas of medicine. The proposed system also accommodates collaborative and complex multidisciplinary approaches to research, and it is designed to review all kinds of research approaches within the context of the biological problem that those proposals address. There are also clusters for basic scientific discovery, instrumentation development, and design-driven research that is not hypothesis-driven. The proposal also allows for reviewing proposals that come from cross-cutting fields.
Dr. Ehrenfeld said that panel members recognized that a critical mass of qualified reviewers is needed to provide an adequate review of proposals. However, although a study section requires expertise, it cannot include experts in every field but also should not focus too narrowly in its expertise. This problem of appropriate balance presents a continuing challenge.
The panel's concept paper was posted for public review in July 1999 and received about 750 comments, mainly from individual scientists but also from scientific societies. The panel met in November 1999 to review the comments, to revise the concept paper, and to consult further with several organizations. The comments are mainly supportive, expressing enthusiasm for the cultural changes that will likely be implemented, according to Dr. Ehrenfeld. For instance, changes that will alter the requirement for preliminary results and will move away from strictly hypothesis-driven research seem to be particularly welcome. In response to some of the comments, three additional IRGs will be created: renal and urological sciences, development and aging, and AIDS and AIDS-related research. The revised report will be presented to the CSR Advisory Committee in January.
Dr. Ehrenfeld noted that some comments indicated a misunderstanding about the panel's Phase I and Phase II plans, with confusion over the absence of any changes to specific study sections, a task that is reserved for the second phase. Hence, the revised report will clarify the IRG concept, and specify how the IRGs differ from study sections themselves. Moreover, the report will explain that the recently reorganized set of neuroscience and behavioral and social science study sections will not be further changed before they operate for a period of time and can be evaluated. Phase II will begin in 2000, with the goal of completing this phase by the following year, and the process will be modeled after recent changes implemented in the neurosciences and behavioral sciences study sections.
Plans call for interim evaluations as one way of allaying recurrent anxieties about these reform measures, according to Dr. Ehrenfeld. IRGs will be reviewed by external groups, and these groups will conduct site visits, attend study sections, and take other steps to monitor and evaluate how well the new system is functioning. In addition, OMB has approved a proposal to conduct surveys of study sections and grant applicants to determine how successful these changes are.
DISCUSSION
Dr. Varmus asked about the challenges and potential problems of trying to introduce gradual changes within CSR when so many of its components are linked. Dr. Ehrenfeld said that, although implementation of changes will be tricky, a starting point with a new IRG consisting of some intact study sections affords an opportunity for trial runs.
Dr. Shirley Tilghman said that the reform approach is thoughtful and following up plans for monitoring IRGs with advisory committees is essential. Dr. Ehrenfeld said that the accelerating pace of change throughout the biomedical field necessitates a mechanism for making adjustments and that external advisors will help in meeting this need. She also said that early experiences in implementing the IRG concept also indicate that a mechanism for making adjustments and corrections is essential.
In response to a question from Dr. Tilghman about changing the sense of entitlement that grew up around some study sections, Dr. Ehrenfeld said that this question is being dealt with in two ways: (1) the general shake-up of the system is a corrective force; and (2) asking reviewers to start anew and then instituting a monitoring system to ensure that the new system functions properly also serves as a corrective force. Dr. Varmus suggested that the apportionment could be examined in the context of the GPRA evaluation.
Dr. Elaine Fuchs asked whether there would be changes in composition of study sections, selection of chairs, and terms of service for reviewers. She also asked about anticipated changes in the review process--for example, whether more attention could be paid to creative grants from young scientists, with less time spent on proposals from established investigators.
In response, Dr. Ehrenfeld said that, because recruiting suitable reviewers is crucial to the success of the system, changing to a more flexible term of service and testing other reforms are important components of the system. Dr. Varmus said that a surprisingly large percentage of NIH-supported scientists have served as reviewers, making it all the more important to develop a flexible scheme to recruit senior investigators for second terms of service and who may move from one study section to another to broaden the outlook of different groups.
In response to Dr. Fuch's second question, Dr. Ehrenfeld said that plans for funding productive investigators after minimal review of their research proposals is not a matter for CSR but one for the institutes and centers to decide. However, making long-term commitments to senior investigators can cause problems for newer investigators, particularly when budgets are not growing, making it essential to strike a proper balance in research-support strategies.
Ms. Rebecca Eisenberg, who praised the CSR reform efforts, said that some of the changes might help NIH in responding to questions about progress in studying specific diseases. In response, Dr. Varmus said that such responses typically come from each of the institutes, which support both basic and clinical research on specific diseases. Although in the past some proposals do not fall neatly into specific categories, the IRG clusters should help to overcome some of those assignment difficulties.
Dr. Eric Lander asked whether CSR reviewers could rely more on the Internet and other electronic technologies, particularly for dealing with specific technical questions that may arise when dealing with individual proposals. Dr. Ehrenfeld said that she and her colleagues are thinking a great deal about innovative ways to expedite the review process--particularly where it involves the exchange by electronic means of factual clarifications among reviewers, the institutes, and investigators. For instance, CSR is doing a pilot test of a procedure in which there is an electronic preview exchange of opinions before a study section meets; this approach enables reviewers to develop a consensus sooner when they actually convene. Dr. Ehrenfeld said that the tenor of a review often changes during discussion at a study section meeting, making it difficult to rely on reviews submitted by mail.
Dr. Varmus said that another drawback in having extensive interaction between the reviewers and the investigator over a proposal is that the process becomes a tutorial that can turn a weak proposal into an acceptable one that no longer represents the investigator's ideas. He also said that reviews can become skewed when one reviewer dominates the meeting of a study section. Dr. Ehrenfeld said that electronic exchanges may help to overcome the latter problem.
Dr. Lander asked how CSR is evaluating how well some of these experimental changes are working. In response, Dr. Ehrenfeld said that such evaluations are very difficult because it often is impossible to make comparisons between two alternative practices. For instance, it is not possible to review a proposal twice by two different procedures--as such a test, in effect, would make the reviewers experimental subjects. In fact, most "tests" of new review procedures are pilot studies. Dr. Varmus noted that the pilot test of the modular grant concept proved very successful, but this success was judged essentially by acclamation.
Dr. Steven Chu asked how CSR reaches individual reviewers to change their minds about these reforms. In response, Dr. Ehrenfeld said that many small changes, such as explicitly establishing five review criteria, are helping to reeducate reviewers and change some of the culture of study sections. Moreover, the turnover in membership helps, as does efforts by the CSR Advisory Committee to develop guidelines for reviewers and to make the review process more transparent.
CONSTRUCTION ISSUES
Dr. Varmus said that the presentations on construction projects at NIH reflect a need to update committee members on these activities, to discuss general budget increases as well as new funds designated specifically for extramural construction, and to review the need for renovation and construction of research facilities. Some of those extramural construction needs are documented in a report from NSF. In light of NIH budget increases and current planning efforts for FY 2001 and 2002, Dr. Varmus asked ACD members to think about what more NIH might do to support construction and other infrastructure needs.
Update on Campus Construction
Mr. Stephen Ficca, Associate Director for Research Services, said that badly needed construction now under way will help NIH address a deteriorating infrastructure by providing facilities that are safe and will support modern research. In particular, three new research facilities are being built on the Bethesda, Maryland, campus: the Mark O. Hatfield Clinical Research Center, the Louis Stokes Laboratories, and the Dale and Betty Bumpers Vaccine Research Center.
Mr. Ficca reminded ACD members that NIH began in a one-room laboratory on Staten Island, moved to the Bethesda campus which now encompasses 322 acres, opened the Clinical Center in 1952, and by 1992 when Dr. Varmus arrived had 9.4 million gross square feet of research space in service. When the new Clinical Research Center is completed in 2002, research space at NIH will have grown by 35 percent in a decade's time. To address aging and deteriorating structures elsewhere on the campus, NIH has developed a comprehensive Facilities Revitalization Program.
Mr. Ficca said that parts of the revitalization program date to 1991 when the Army Corps of Engineers completed a review of NIH facilities and recommended that the Clinical Center be replaced. The report also recommended building a new consolidated research facility instead of upgrading older buildings within the historic core of the campus. Subsequently, the 1994 report from the committee that reviewed the NIH Intramural Program similarly recommended replacing the research hospital housed in the Warren G. Magnuson Clinical Center.
Mr. Ficca said that the Mark O. Hatfield Clinical Research Center will replace the research hospital in Building 10 and, along with the ACRF, serve as the focus for NIH patient-related research. The Louis Stokes Laboratories, or consolidated laboratory building, replaces three of the oldest laboratories on campus. The new facility will house research in structural biology and part of the intramural program within the NHGRI. The third new building, the Dale and Betty Bumpers Vaccine Research Center, will be a state-of-the-art research and pilot plant facility containing 86,000 square feet. It was designed and construction began soon after President Clinton announced in May 1997 a major new NIH program to develop an AIDS vaccine. All three facilities emphasize program effectiveness, show high functional efficiency, meet stringent energy conservation and low pollution standards, and allow for flexibility and adaptability in use.
Clinical Research Center
Mr. Yong-Duk Chyun, Project Director of the Clinical Center Renewal Project, said the new Mark O. Hatfield Clinical Research Center is a state-of-the-art clinical research facility that will replace all existing NIH hospital beds with 250 inpatient beds plus 100 day-patient stations. It also provides 250,000 square feet of laboratory space. The floor plan puts lab space close to hospital beds, and inpatient care is adjacent to the outpatient clinic in the next building. To maximize flexibility, the patient care units and research labs are built as standard modules, and the nursing wing can be adapted to lab use (or vice versa) as needed. The patient care units and labs are organized around a central atrium, which contains a double-helical stairway. The new building will cost $360 million and is scheduled for completion by the end of 2002.
Louis Stokes Laboratories Building
Mr. Frank Kutlak, an architect and Project Officer in charge of the Louis Stokes Laboratories building, said that the new facility will contain 290,000 square feet to replace several aging facilities on the NIH campus. The construction schedule was divided into two phases, with the first beginning while the documents needed for the second phase were being completed. The project is scheduled for 4.5 years and $93.1 million. A typical floor will contain six "neighborhoods," each containing six or seven open lab modules around the perimeter, with equipment rooms and support function rooms along the core. Each neighborhood contains a stair permitting access to adjacent floors without traveling by means of the central elevators. An interstitial space divides the central part of each floor, allowing ready access to utilities for maintenance, but permitting higher ceilings near the windows and work space area.
Mr. Kutlak said that the new facility contains many energy conservation features, including energy recovery wheels, which provide a 40 percent savings in energy to provide chilled water and steam, and variable air volume systems, which distribute air as needed. These and other measures, which make the building 60 percent efficient, earned the government a $2 million rebate from the local power company. This rebate, construction efficiencies, and market factors permitted the architects to change plans and add a floor to the building after construction was under way. In response to several questions and comments, he noted that furniture design and laboratory spaces can be adapted to meet specific research needs. For instance, some labs were designed to meet specifications by investigators who use NMR analytic technology.
Vaccine Research Center
Ms. Nancy Boyd, Project Officer of the Clinical Center Renewal Project, described the five-floor Dale and Betty Bumpers Vaccine Research Center, which has a budget of $31.5 million and is on a fast-track schedule that calls for occupancy in August 2000. The main floor contains a conference center, administrative offices, and support space, while other floors contain BSL-2 lab space, additional offices, a BSL-3 lab, and a vaccine production suite.
INTRAMURAL NEUROSCIENCE PROGRAM AND NEUROSCIENCE CENTER
Dr. Gerald Fischbach, Director of the National Institute of Neurological Disorders and Stroke (NINDS), reminded ACD members that neuroscience research is becoming increasingly important — providing new therapies for many diseases, such as epilepsy, neurodegenerative disorders, and psychiatric disorders, that were once considered intractable. Moreover, while the missions of the various institutes are distinct, the basic science underlying their efforts is convergent. Each individual group would benefit greatly by interactions with others. During the past year, NINDS, the National Institute of Mental Health (NIMH), and several other institutes have been developing plans for a major new, integrated neuroscience research center within the Intramural Program at NIH. The intent in forming the Neuroscience Center is to speed the rate at which new discoveries are translated into clinically useful therapies. It is hoped that a truly integrated community at the NIH will be a useful role model for the unification of disciplines in the extramural community.
Dr. Steven Hyman, Director of NIMH, continued to describe the rationale for this new neuroscience research center. He said that it is ridiculous to separate research efforts that focus on the same neurotransmitter molecules into different buildings and institutes at NIH. Instead, there would be enormous progress in both basic and clinical areas if scientists working on the same or closely related subjects could work together. There would also be economic benefits by bringing some researchers who are now working in high-cost rented facilities back onto campus, according to Dr. Hyman. He said that a new building would be needed for several reasons. For instance, existing space is out-moded and would be costly to renovate. Moreover, much of the research being done is necessarily multidisciplinary and thus requires teamwork, which could be housed more conveniently in a building that is designed for that purpose.
Planning for such a building is at an early stage, but a facility providing 200,000 square feet of research and support space could be built by 2004, at which time renovation of Building 36 could begin and be completed by 2006.
Dr. Shirley Tilghman said that this plan was spectacular.
In response to a question from Dr. William Brody, Dr. Varmus said there is a master plan for the NIH campus.
EXTRAMURAL CONSTRUCTION
Dr. Varmus said that issues involving extramural construction programs are more complicated for NIH to face, as they raise questions about how to assess needs, what type of support to provide, and whether to build such support into the annual NIH budget requests.
Needs and Requirements of Research Institutions
Dr. David Kaufman, President of the Federation of American Societies for Experimental Biology (FASEB), said that FASEB is the largest organization representing biomedical researchers, encompassing 19 societies with some 60,000 individual members who represent 60 percent of current NIH grant holders. The FASEB leadership, who represent working scientists, traditionally gives priority to the direct support of research before facilities needs, according to Dr. Kaufman. However, as funding opportunities for investigators are expanding, the Federation's leadership is reexamining the issue of facility needs. One important premise is that a coordinated investment is needed to optimize biomedical research efforts.
Dr. Kaufman noted that the Federal government has done little directly to support construction of research facilities for several decades, leaving this responsibility to universities and academic health centers. However, early in 1999, members of the Administration and of Congress began to reconsider this policy, prompting FASEB to ask a panel, led by Dr. Richard Marchase of the University of Alabama, to review the facilities issue.
Although that review indicated a substantial need for more and better research facilities, there is disagreement about whether Federal funds are the best or most appropriate means for meeting those needs, according to Dr. Kaufman. However, a report from NSF describes a need for $11 billion for construction; medical schools report a need for 5 million square feet of new research space; and other academic institutions report the need for an additional 10 million square feet of such space. More than half these institutions indicate that construction has been deferred because funds are lacking.
Meanwhile, Congress seems poised to invest in such construction, with $75 million in the current NIH appropriation bill designated for this purpose, according to Dr. Kaufman. Moreover, the Senate approved legislation in November 1999 (S. 1268) authorizing investment of $200 million per year as part of a new NIH extramural construction program; a similar measure that is pending in the House of Representatives may raise that authority to spending up to $500 million per year.
However, the FASEB review indicates considerable complexity to the overall picture of Federal spending on construction of research facilities, according to Dr. Kaufman. For instance, some policymakers say that the Federal government is helping to meet construction needs through indirect expense recovery, including depreciation charges. In addition, construction activity during the past few years has been robust in the absence of direct Federal spending programs. The NSF survey indicates an investment of $3.2 billion in building starts during 1996 and 1997 that will yield 11 million square feet in new overall research space. In this same period, one-third of medical schools began constructing facilities, with an investment of $784 million. Nearly all these costs are being met at the institutional level. Whether these trends will continue is not known.
Dr. Kaufman said that FASEB concluded that the rapid expansion of biomedical research anticipated for the next decade will require a change in existing facility construction support mechanisms. As the NIH-sponsored research build-up continues, the availability of adequate research space will become a limiting factor--a challenge that needs to be addressed quickly because of the inherent lag that new construction entails. Thus, the FASEB leadership recommends that resources be allocated soon to building the infrastructure of the future, particularly because planning for major construction projects involves a multi-year effort.
Dr Kaufman said that, because many specific issues are not resolved, FASEB proposes a study to clarify needs for construction, evaluate whether current construction investment mechanisms are adequate during this period of expanding research efforts, evaluate the potential for political involvement and change, assess the effects of funding mechanisms on different kinds of institutions, and take into account the impact on institutions that have less of a track record in receiving research support. The study also should examine whether construction should be funded through competitive grants, loan guarantees, or through adjustment of support for research overheads. However, whatever the funding mechanism, FASEB recommends that peer review and formal oversight should be in place to establish how best to meet these needs.
NIH Expenditures and a Legislative Proposal
Ms. Susan Quantius, Associate Director for Budget, said that at NIH the National Center for Research Resources (NCRR) plays a dominant role in authorizing funds for extramural construction. Until this year, the high point for such activity was in the 1960s, when outlays sometimes were about $60 to $70 million per year, the equivalent of 5 to 10 percent of the overall budget. During most of the past decade, however, extramural construction amounted to less than 0.5 percent of overall NIH spending. It was also dwarfed by the intramural budget for construction.
Ms. Quantius said that Federal law mandates that proposals for NIH-supported construction be peer-reviewed and that Federal funds are matched on a 50-50 basis. Moreover, the law reserves 25 percent of whatever is appropriated for "institutions of emerging excellence," a category that is defined as a group of 25 minority health professions schools, which have been designated by the Health Resources and Services Administration.
During the past three years, NIH awards for extramural construction have remained modest, and typically serve as "seed" money, according to Ms. Quantius. The success rate for the emerging excellence institutions is substantially higher than the overall rate. As much as one-half the funding goes to schools that are in the top 50 NIH grantees, according to an analysis by NCRR.
Meanwhile, Congress frequently earmarks appropriations bills for projects that bring resources to particular districts. The leadership, particularly in the Senate, is dominated by members from have-not states. Although the NIH appropriations bill typically remains free of such earmarks, that practice would likely change if NIH began to provide substantial funding for facilities construction, according to Ms. Quantius.
Moreover, Congress is showing an increased interest in infrastructure spending--for example, S. 1268, sponsored by Sen. Tom Harkin (D-IA), recently passed the Senate. If passed by the House and signed by the President, it would authorize $250 million for facilities construction in FY 2001 and similar amounts for the following two years. It also would authorize spending of $100 million per year for a shared instrumentation grant program. The bill would require that 25 percent of the first $50 million of funds be allocated to institutions of emerging excellence and an additional 25 percent of remaining funds be allocated to these institutions if approved applications exist. Because of participation among the emerging excellence institutions, it could be difficult to allocate all the funds in this set-aside. Other provisions in the bill could be at cross purposes with the needs of the have-not states. The outcome for S. 1268 during the next session of Congress is far from certain, according to Ms. Quantius.
Role of NIH Funding
Dr. Wendy Baldwin, Deputy Director for Extramural Research, said that one new way in which NIH provides for extramural construction through cost recovery under indirect costs, which are now known as facilities and administration (F and A) costs. The administration component of F and A is capped at 26 percent. The facilities component covers depreciation and use allowances as well as institutional operation and maintenance costs. Tabulation of indirect cost rates is complicated, and they reflect where an institution is located, its size, the breadth of research activities it sponsors, and whether it belongs to the public or private sector.
Dr. Baldwin said that indirect cost rates changed substantially during the past half century, moving from 8 percent in 1947 to the 26 percent cap for administrative costs imposed in 1991. During the late 1980s, interest was included along with depreciation and use as factors used for tabulating the overall rate. Interest can be a substantial contributor to such costs, particularly for private sector institutions that finance new construction through borrowing. Although the aggregate average for indirect costs is 52 percent, the interest factor is so variable that the actual figure ranges from 15 percent to 115 percent.
According to a study by DHHS in 1990, the top 90 institutions vary widely in terms of indirect cost rates. However, the depreciation and use allowance, which then was about 7 percent, is what funds construction. During the past decade, that allowance has gone up by more than 5 percentage points, but it also varies widely. From such figures, Dr. Baldwin estimates that perhaps 17 percent of the NIH extramural budget now goes for facilities costs. This percentage represents about $3.5 billion for F and A in an overall budget of $11 billion, meaning about $500 million for depreciation and use costs. She said that these costs are real and providing funds for them is essential for the conduct of research.
Dr. Baldwin said that direct costs for construction through an appropriation is a prospective process whereas indirect cost accounting is retrospective in nature. Direct support recently has been available to a relatively few institutions and is targeted, whereas indirect cost recovery is available universally and generally is more diffuse, although there are reviews for renovating facilities, particularly for those that are large. Direct and indirect support mechanisms represent such different strategies for construction, and their uses need to be carefully planned.
DISCUSSION
Dr. Varmus said that officials at DHHS have been asking NIH to consider incorporating plans for construction spending into its budget request. That plan could describe a direct grant mechanism, a loan, or a matching program. There are other options to consider, including whether the program should be peer-reviewed and whether it should emphasize institutions that have high success rates in the NIH system or those with poorer track records. Such a program also raises concerns about congressional earmarking and whether NIH should divert funds from research into construction, when those facilities needs may be met through other resources.
Dr. William Brody said that funding construction through the indirect cost recovery method subjects an institution to considerable risk, which provides some positive incentives and enforces discipline in computing construction needs. However, direct funding might be helpful to institutions operating in new areas. Dr. Varmus said that, even with a budget of $500 million for construction, NIH would likely not pay the full costs of specific buildings. More likely, NIH will provide loans or matching grants.
Ms. Rebecca Eisenberg asked about the impact on indirect cost rates if NIH or another Federal agency provides funding for an extramural facility. In response, Dr. Baldwin said that the investment is backed out, meaning the Federal government does not pay twice for particular projects. She also said that NIH is considering changing its depreciation scale, which could raise the indirect cost rate. In general, depreciation is computed as a straight line, 50 years for buildings and 15 for equipment.
Mr. Frank Kutlak, an architect and Project Officer in charge of the Louis Stokes Laboratories building, said that the initial construction costs of a research facility typically represent only 5 percent of its total costs over its useful life-time, and that provisions need to be made to meet those long-term costs. Dr. Varmus noted that the initial construction costs are a fraction of follow-up renovation costs. Dr. Baldwin said that NIH funds very little in direct renovation costs, and that calculating how much it funds through indirect costs is far from straightforward.
Dr. Eric Lander said that important questions revolve around economic inefficiencies in the system. Do institutions not build facilities they need? At the margins, NIH might help by remedying situations where market forces fail. Mr. Phillip Williams agreed, noting that NIH funds could be used to support special construction needs.
Dr. Varmus said there are two immediate questions for NIH to address: One, should NIH evaluate these questions about extramural construction more deeply, particularly as they relate to the FY 2002 budget? Two, should NIH support S. 1268, an issue that will likely come up again in Congress during the first months of 2000?
Mr. Steven Chu pointed out that facilities that are renovated or built to serve biological research purposes at a high cost sometimes fail to receive long-term support and may be under-used or abandoned. He also said that donors and foundations may help to build a facility, but they rarely will provide funds for its maintenance. In response, Dr. Varmus said that NIH pays salaries and other costs for maintaining such facilities, but typically ceases to do so when the grants providing such support fail. Ms. Leslie Christovich, from NSF, said that about 20 percent of respondents to a foundation survey indicated that facilities needed to be renovated or replaced to continue supporting research.
In response to a question from Dr. Ruth Kirschstein about institutions that could not meet matching grant requirements, Dr. Lander said that legislation, such as S. 1268, or a construction support proposal from NIH would need to provide several options and overall flexibility as to how such funding would be used. Dr. Varmus said that there seemed to be a consensus that NIH should convene a group to develop a long-term plan for construction spending and to report their findings during the budget planning retreat in June 2000.
DIRECTOR'S CLOSING COMMENTS
Dr. Varmus said that the NIH is in good health in terms of its recent budget increases, that biomedical science is flourishing, and that these factors are encouraging plans for building projects and for expanding research into new areas.
However, there are areas of concern. One involves how NIH will sustain budget growth, which is important because of the expanding commitment base. During FY 2000, NIH will award 10,000 or more new grants, but if the budget ceases to grow, the research community will face a situation like that in the early 1990s when the proposal success rate fell and new investigators were stymied. To maintain the current budget growth momentum, powerful voices and better ways of explaining NIH programs to Congress will be needed. Interest in funding other Federal programs and a changed political environment are but two of the challenges that NIH will face.
Dr. Varmus said that a second concern is what will happen to medicine and health as NIH-sponsored research leads to more elaborate and expensive medical technologies. If technology-based advances deepen the divisions between those who can afford health care and those who cannot, NIH will have failed its mission of improving public health. Moreover, it will appear to be an agency intended mainly to serve the elite.
Dr. Varmus said that, from his point of view, a third issue involves how NIH is structured, noting that its current structure makes it difficult to manage. NIH now consists of 25 institutes and centers, but if current trends continue, it could grow to 50 or more during the next several decades. Yet, there is a correlation between the age of an institute and the size of its budget, and larger institutes typically can out-perform smaller institutes. Dr. Varmus said that a different way of organization might need to be considered.
SUMMARY AND CONCLUSIONS
The Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) met on December 2, 1999, to consider a series of recent developments affecting its budgetary growth, recent successes in the Human Genome Project, plans for implementing an electronic system of disseminating the scientific literature, several recent workshops and review or guideline-development activities, activities involving research facility construction and related planning activities.
The ACD acknowledged and commented on these reports, and ACD members recommended that a working group be convened to develop a long-term plan for construction spending and to report their findings during the budget planning retreat in June 2000. As he closed the meeting, Dr. Varmus pointed to several areas of concern as indicated above.
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
Ruth L. Kirschstein, M.D. Acting Director, NIH
Table of Acronyms
ACD — Advisory Committee to the Director
AIDS — Acquired Immunodeficiency Syndrome
BACs — Bacterial artificial chromosomes
cDNAs — Copy DNAs
CDC — Centers for Disease Control and Prevention
COPR — Council of Public Representatives
CRC — Clinical Research Center
CSR — Center for Scientific Review
DALYs — Disability adjusted life years
DHHS — U.S. Department of Health and Human Services
DOE — Department of Energy
ELSI — Educational, Legal, and Social Implications
ESTs — Expressed Sequence Tags
F and A — Facilities and administration costs
FASEB — Federation of American Societies for Experimental Biology
FDA — Food and Drug Administration
FOIA — Freedom of Information Act
FY — Fiscal Year
GPRA — Government Performance and Results Act
GROW — Genetic Resources on the Web
HIV — Human Immunodeficiency Virus
HGDP — Human Genome Diversity Project
IOM — Institute of Medicine
IRB — Institutional Review Board
IRGs — Integrated review groups
IP — Intramural Program
IT — Information technology
NAS — National Academy of Sciences
NBAC — National Bioethics Advisory Commission
NCI — National Cancer Institute
NCBI — National Center for Biotechnology Information
NCRR — National Center for Research Resources
NIAMS — National Institute of Arthritis and Musculoskeletal and Skin Diseases
NIDA — National Institute on Drug Abuse
NIDCR — National Institute of Dental and Craniofacial Research
NIDDK — National Institute of Diabetes and Digestive and Kidney Diseases
NIH — National Institutes of Health
NIMH — National Institute of Mental Health
NINDS — National Institute of Neurological Disorders and Stroke
NHGRI — National Human Genome Research Institute
NLM — National Library of Medicine
NSF — National Science Foundation
OMAR — Office of Medical Applications of Research
OPRR — Office for Protection from Research Risks
ORMH — Office of Research on Minority Health
OSP — Office of Science Policy
OTT — Office of Technology Transfer
PNAS — Proceedings of the National Academy of Sciences
QALYs — Quality adjusted life years
SNP — Single Nucleotide Polymorphism
TSC — The SNPs (single nucleotide polymorphism) Consortium
