The 82nd meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on June 7, 2001. Dr. Ruth Kirschstein, Acting Director, NIH, began by thanking all the members of the Committee and noting several who could not attend or for whom this would be their last session. She:
reviewed several matters concerning personnel at NIH;
described early steps toward implementing a new NIH loan repayment program for investigators pursuing careers in clinical research;
reported on start-up efforts revolving around the newly created National Institute of Biomedical Imaging and Bioengineering; and
described the new NIH program called the Biomedical Research Infrastructure Network (BRIN), which is intended to enable institutions in 23 states and Puerto Rico to develop infrastructure and to recruit faculty members needed to improve the competitiveness of their biomedical research programs.
The President's detailed FY 2002 budget proposal for NIH calls for an increase of more than $2 billion (13.5 percent), for a total of $23.04 billion, providing for a total of 36,143 total project grants including small business grants. The budget will allow for funding of 9,158 new and competing research project grants in the new fiscal year, the same as the year before, in part, because the size of grants has increased and also because the non-competing commitment base has grown. In addition, the stipend for research training was increased by 10 percent, with planning under way for additional increases.
Dr. Kirschstein said that the Secretary of Health and Human Services (HHS), Tommy Thompson, is meeting regularly with the heads of the HHS agencies. He has developed positive relations with NIH through several visits and frequent meetings with various NIH officials. NIH officials also have been meeting with the new Chairman, Representative Ralph Regula (R-OH) and other members of the House of Representatives subcommittee responsible for the NIH appropriations, providing them with a great deal of information about NIH programs and operations. When NIH officials appeared at a hearing on May 23 before members of the Senate Appropriations Subcommittee, much of the emphasis was on prospects for NIH support of human embryonic stem cell research.
Dr. Eric Lander described several recent developments surrounding the Human Genome Project, which led to a landmark paper being published in February 2001 that details the near completion of the DNA sequence of the genome. The goal is for the project to be completed by April 2003. Already, researchers are developing many ways to interpret genome data, learning that about 1.5 percent consists of identifiable genes and about 43 percent of the remainder consists of repetitive elements falling into four classes of transposable elements. Dr. Lander said that the experience of organizing the Human Genome Project brings some valuable lessons about conducting biomedical research. For instance, there is high value in investing in large-scale infrastructure to build analytic tools and to establish comprehensive databases. He also said that this effort is far from complete, and, during the next decade, the focus needs to shift toward developing an infrastructure for making such data more useful to investigators involved in clinical research and to epidemiologists.
Dr. Ellie Ehrenfeld, Director of the NIH Center for Scientific Review (CSR), described ways in which the peer review process is being adapted to handle changes in the way biomedical science is now being done. CSR's study sections are organized into clusters, or integrated review groups (IRGs). The Panel on Scientific Boundaries for Review (PSBR) recommended the establishment of a new set of 24 IRGs. A report incorporating the PSBR recommendations and evaluations was accepted in January 2001. The second phase of the peer review process is now underway. The first IRG taken to completion with the establishment of new study sections focuses on hematology, and plans now call for establishing new study sections for three IRGs at a time, at four-month intervals. Dr. Ehrenfeld also said that, even before the new IRG system is fully implemented, plans are being developed for evaluating it by using assessment surveys and other means.
Dr. William Brody summarized the findings of a working group that considered the need for NIH to invest in renovating and constructing extramural biomedical research facilities. The working group report recommends that:
the Federal government appropriate funds enabling NIH to sponsor direct facilities improvement grants in FY 2002 at a sum of $250 million, increasing to $1 billion per year, with grants in several categories, including relatively small sums of $2–3 million each, and larger grants of about $20 million;
a Federal loan guarantee program be established to support construction and renovation of biomedical research facilities; and
universities be reimbursed for the cost of capital associated with investing in research facilities; costs that accrue from fund-raising for such investments be considered allowable overhead costs; other rules be adjusted to permit institutions to recover indirect costs for space in research facilities that is not immediately occupied or assigned for NIH research-related purposes.
Dr. Wendy Baldwin described several recent measures by NIH to reduce the regulatory burdens imposed on researchers and said that the NIH Implementation Group for Regulatory Burden Reduction recently established four working groups to examine:
institutional conflicts of interest where by universities may hold equity positions in companies whose products are being evaluated;
cost of compliance in which NIH will reevaluate how capping of indirect costs may affect efforts by institutions to meet regulations;
human subjects protections and IRB activities; and
animal welfare issues.
She also described recent experiences in implementing modular grants in which the focus is on the scientific content of the research applications.
Dr. Greg Koski, Director of the HHS Office for Human Research Protections (OHRP), described a range of activities that signal a broad mandate within the Administration to strengthen measures for protecting patients and others who participate in research. OHRP strives toward four broad goals: simplification, uniformity, efficiency, and increased effectiveness. In addition, there are several private sector initiatives that are of great importance for efforts to improve overall protective measures.
The 82nd meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on June 7, 2001. Dr. Ruth Kirschstein, Acting Director, NIH, began by thanking all the members of the committee and noting several who could not attend or for whom this would be their last session. She acknowledged Dr. Shirley Tilghman, who, at the time of this meeting, would become the new President of Princeton University, effective June 15, 2001. Dr. Kirschstein mentioned several noteworthy NIH events scheduled for June, which included the naming of the plaza in front of the NIH Shannon Building to honor former Representative Paul Rogers and the dedication of a new laboratory building named to honor former Representative Louis Stokes. She also noted that several NIH-supported scientists recently received the General Motors Cancer Research Awards, including Dr. David Cool and Dr. Michael Phelps for their word on PET scanning, Dr. Frank Spizer and Dr. Walter Willard for their efforts in the Nurses Health Study, and Dr. Elizabeth Blackburn for her work on telomeres.
Dr. Kirschstein said that biomedical research is in the news, alluding specifically to a report that appeared in June 7 newspapers indicating that animal heart cells can regenerate — a preliminary report, but one that is heartening. Meanwhile, researchers working in the NIH Intramural Program recently reported findings indicating a genetic basis for musical pitch.
Dr. Kirschstein reviewed several matters concerning personnel at NIH, noting that Dr. Paul Sieving from the University of Michigan School of Medicine will become Director, National Eye Institute (NEI) on June 17, taking over from Dr. Jack McLaughlin, who served as Acting Director, NEI for the past six months. Dr. Audrey Penn is serving as Acting Director, National Institute of Neurological Disorders and Stroke (NINDS), while a search committee is identifying candidates to replace Dr. Gerald Fischbach, who left that post early in 2001. Dr. Barry Kramer, Director of the NIH Office of Medical Applications of Research, was named Associate Director for Disease Prevention to replace Dr. William Harlan, who retired from that position. Dr. Kramer will serve in both positions. Dr. Donna Dean was appointed Acting Director of the recently created NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB).
Dr. Kirschstein referred ACD members to follow-up reports on matters from earlier meetings, such as informational site visits to institutions conducting NIH-sponsored clinical trials and a presentation by Dr. T.K. Li and others on the Government Performance and Results Act assessment of NIH activities. She then described early steps toward implementing a new NIH loan repayment program for investigators pursuing careers in clinical research.
Dr. Claude Lenfant, Director of the NIH National Heart, Lung, and Blood Institute (NHLBI) is chairing a committee charged with developing such an implementation plan, according to Dr. Kirschstein. Since 1989, the NIH Intramural Program has featured several small-scale loan repayment programs — the first one was established to encourage investigators to do AIDS research and then other programs with more general goals were set up to encourage investigators to get involved in clinical research. In each case, these programs pay a maximum of $35,000 per year toward a participant's outstanding educational debt along with a further reimbursement to offset the tax liability of that income. Meanwhile, the NIH National Institute of Child Health and Human Development has loan repayment authority specifically geared for extramural health professionals to conduct research related to contraception and infertility. These programs will serve as models for the new NIH-wide program that Dr. Lenfant's committee has been asked to devise.
Although much about the new loan repayment program will be uniform across NIH from an administrative point of view, each of the Institutes will determine what scientific areas to emphasize and how to select individuals for specific awards, according to Dr. Kirschstein. Initially, NIH has budgeted about $28 million for the program, which, at first, will make awards to about 260 individuals, at an annual outlay of about $100,000 each. The program will start as a pilot effort, in part, because experience indicates it will be labor-intensive, involving contracts for each participant and extensive auditing and monitoring procedures. She said the current global estimate of candidates for application to this program is 4,000 or more individuals. Another reason for starting small is that no funding is specifically appropriated for this program.
In addition to this general loan repayment program, the legislation creating the NIH National Center for Minority Health and Health Disparities features a similar program to encourage individuals to work within this area, and $1.9 million is being allocated for this purpose. Other programs, including the five-year K23 early career mentoring award, the K24 mid-career award, and the K30 curriculum development awards, all play a part in furthering NIH clinical research interests and activities. In fiscal year (FY) 2001, NIH made about 450 K23 awards and expects to award more than 500 K23 fellowships in FY 2002. NIH issued about 200 K24 awards in FY 2001 and will go well beyond that total in FY 2002.
Meanwhile, some 55 academic centers have received K30 curriculum development awards of about $200,000 per year for up to five years, and NIH is beginning to evaluate these efforts to determine how they may be reshaped, as necessary. Reports indicate that this program is working well, but there is some concern that the $200,000 annual funding level may need to be raised, according to Dr. Wendy Baldwin, NIH Deputy Director for Extramural Research.
Dr. Kirschstein described start-up efforts related to NIBIB, for which Congress passed authorizing legislation in December 2000, with President Clinton signing it into law shortly thereafter. Dr. Dean, who serves as Dr. Kirschstein's senior scientific advisor, was appointed as the new Institute's Acting Director. Its initial funding of $1.9 million comes through the NIH Office of Bioengineering, Bioimaging and Bioinformatics, which had been established through the NIH Office of the Director and is being transferred to the new Institute. The FY 2002 budget request for NIBIB is $40.2 million, and efforts are under way to determine which additional programs in other established Institutes and Centers should be transferred to NIBIB. Dr. Kirschstein plans to set up a search committee for a new Director and will appoint members to the advisory council for the new Institute in the near future.
Dr. Kirschstein described several NIH programs whose development has been encouraged by members of Congress from 23 states and Puerto Rico in which universities and other institutions have traditionally not had much success in obtaining NIH funds. For instance, in 1993 the NIH National Center for Research Resources (NCRR) developed the Institutional Development Award Program (IDeA Program), which includes the Centers of Biomedical Research Excellence, or COBRE Program, to help institutions in such states strengthen the competitiveness of their biomedical research programs.
To accelerate such efforts, NIH recently established a new program, called the Biomedical Research Infrastructure Network (BRIN), that will serve consortia consisting of two or more higher educational institutions in such states, enabling them to develop the infrastructure and to recruit faculty members needed to improve the competitiveness of their biomedical research programs. The program will provide $2 million per year to the institutions in each state (that sum may be divided among one or two consortia) for up to three years. Congress plans to increase the appropriation for the BRIN program from more than $40 million in FY 2001 to $135 million in FY 2002, according to Dr. Kirschstein. Plans call for about $48 million to be distributed in the first round of BRIN awards.
An important goal of the BRIN program is to recruit talented young investigators to work at institutions in the qualifying 23 states and Puerto Rico, according to Dr. Judith Vaitukaitis, Director of the NIH NCRR. She said there is marked heterogeneity among the applicant institutions within these states, but the goal is to move them toward meeting higher standards.
Resuming her presentation, Dr. Kirschstein said that the Secretary of Health and Human Services (HHS), Tommy Thompson, is meeting regularly with the heads of HHS agencies, and is developing very positive relations with NIH through several visits and frequent meetings with various NIH officials.
Dr. Kirschstein said that the President's detailed FY 2002 budget proposal for NIH calls for an increase of more than $2 billion, or 13.5 percent, to a total of $23.04 billion, providing for a total of 36,143 total project grants including small business grants. The budget will allow funding for 9,158 new and competing research project grants in the new fiscal year, the same as the year before, in part, because the size of grants has increased and also because the non-competing commitment base has grown. In addition, the stipend for research training was increased by 10 percent, with planning under way for additional increases. Also, the research contracts line has increased because of the new Loan Repayment Program, along with continuing, but expanded contracts to support databases and instrumentation. The overall success rate for grant applications is expected to be 30 percent, and the average grant will be $367,000, up by $24,000 from FY 2001. The budget for Clinical Research Career Awards has increased to $270 million. Additional resources are being sought for the oversight needed for these expanded research and research training programs.
Dr. Kirschstein said that she and other NIH officials have been meeting with the new Chairman, Representative Ralph Regula (R-OH) and other members of the House of Representatives subcommittee that has responsibility for the NIH appropriations, providing them with a great deal of information about NIH programs and operations. In addition to learning about matters such as the Human Genome Project and how elderly patients can access useful biomedical information on the NIH Web site, Rep. Regula invited Dr. Kirschstein and Directors of NIH Institutes and Centers to participate in a series of hearings on themes, such as chronic diseases, lifespan, special populations, and on infrastructure and buildings, as well as a general NIH budget overview hearing. The overall mood of these hearings was friendly and supportive of NIH.
NIH officials participated in a hearing on May 23 before members of the Senate Appropriations Subcommittee during which the emphasis was not so much on the budget proposal as on prospects for NIH supporting human embryonic stem cell research. Since the hearing, Senator Tom Harkin (D-IA) became the chair of that subcommittee, while its former chair, Sen. Arlen Specter (R-PA), became the ranking minority member. In response to a request from the President and HHS Secretary Thompson, Dr. Lana Skirboll, who is NIH Associate Director for Science Policy, and her staff are preparing a scientific review of this field, while a legal review is being separately conducted. Meantime, the meeting of an NIH stem cell advisory group that had been scheduled to review grant applications on April 25 was postponed until further notice.
In response to a question from Dr. Tom Cech, Dr. Baldwin emphasized that the K30 awards are not intended to revise medical school curricula as such, but to develop specialized course work that aims to help clinical investigators improve their research proposals and to help in revamping bioethics, biostatistics, and other programs in such a way that they are better suited for contributing to rigorous clinical research efforts. The concept behind the K30 awards seems to be working, but the funding levels might need to be raised if they are to be fully implemented. Although the long-term success of the program can be judged in terms of the subsequent success in obtaining research grants of those clinical investigators who complete these programs, it remains something of a challenge to evaluate the interim success of these curriculum-development programs.
Dr. Victor Dzau said that Harvard Medical School's K30 award is successfully bringing several clinical research-facilitating programs together, which is helpful; however, stimulating young clinicians to pursue research careers involves a broader and more complicated set of issues. For example, the loan repayment program will be particularly valuable, but other stimuli and other programs will be needed to induce such young people to follow careers in clinical research.
In response to a question from Ms. Eisenberg about stem cell research prospects, Dr. Kirschstein said that both Senator Specter and Senator Harkin are strong advocates of such research and have introduced legislation that would mandate it. This issue now is requiring more time than she and other NIH officials spend on any other activity. Despite the attention being paid to this research by the news media, little in detail is known about it because all such efforts are confined to the private sector and there is no requirement that researchers publish their findings or follow proposed NIH guidelines.
In response to a question from Dr. Cech about BRIN, Dr. Kirschstein said that the 23 states will not compete among themselves for these awards and, instead, each state can count on $2 million per year. Dr. Cech said that this direction is dangerous for NIH because it diverges from the peer review process and could amount to wasting resources. In response, Dr. Kirschstein said that the program represents a short-term nurturing effort, not a long-term entitlement, and that NIH will require applicant consortia to describe in some detail how they plan to develop their new research-strengthening programs. In response to several questions from Dr. Linda Waite, Dr. Kirschstein said that the consortia may consist of any number of institutions from one or more states but that funding levels available to any one state will remain limited to the $2 million ceiling. However, so far, most of the applications come from consortia formed within a state and consisting of several institutions, and NIH has provided the applicants with technical assistance and guidance, including holding a special workshop.
In response to questions from Dr. Eric Lander about the immediate intent of the BRIN program and whether it would be evaluated, Dr. Kirschstein said that its resources will go mainly for infrastructure build-up but limited additional resources might go for pilot research projects or as start-up funds for hiring faculty, with the goal of helping institutions address their most urgent needs. Dr. Yvonne Maddox, NIH Acting Deputy Director, said that the program will help establish networks and develop cores, which are to develop infrastructure and may lead to acquisition of necessary equipment as well as staff, building needed administrative functions, and procuring other resources that institutions need to develop competitive grant proposals.
In response to a question from Ms. Rebecca Eisenberg concerning multiple applications from single qualifying states, Dr. Kirschstein said that NIH is prepared to consider up to two applications from separate consortia within any one state. Educational institutions are free to organize their consortia as they see fit, and it is conceivable that all the higher education institutions within a given state might join in a single consortium. However, even in such cases where there would be no competition for BRIN support as such within the state, NIH will still review and work closely with applicants to ensure plans are sound. Dr. Lander said that careful evaluations will be needed to make sure the program does not become a set-aside.
Mr. Phillip Williams said that, although members of Congress may want to move away from the peer review system, the BRIN program represents a relatively small portion of the overall NIH budget being used in a non-peer review fashion to promote institutions becoming more competitive for future research proposals that will be peer reviewed. Mr. Arthur Ullian said that those goals of the program are terrific and deserve support. Dr. Barrie Carter said that the program could be considered as providing seed capital to the participating state consortia. In response to questions he posed about the way participants are organizing themselves, Dr. Kirschstein said that they have considerable latitude to develop their own plans, but these plans also were reviewed by a group of outside experts. In response to Dr. Lander, who called for the program moving towards being competitive, she said that additional NIH programs, such as the COBRE and IDeA Programs, will be involved and that BRIN will be reevaluated in three years.
Dr. Bette Sue Masters asked whether there are safeguards to ensure that no one institution within a state would take over its BRIN resources. Dr. Donald Wilson asked whether the allocations per state in BRIN would grow in proportion to growth in the overall NIH budget. Dr. Baldwin said that other NIH programs are providing funding to institutions in states that are not receiving a great deal through competitive NIH grants, noting that these alternative programs provide students in weaker institutions with valuable research experience and thus strengthen the overall research enterprise. Dr. William Brody agreed and said that such programs can be valuable for individual students early in their careers. However, he also said that some states are unwilling to invest in their own institutions of higher learning and thus it seems unfair to rely on a Federal program to overcome such shortsightedness.
In response to comments from Ms. Eisenberg, Dr. Kirschstein said that the standards and agenda for BRIN are not vague and that additional details about this planning program will be made available at a forthcoming meeting. In response to a question from Dr. Cech about the NIH AREA Program, she said that the program provides relatively small resources nationwide and that conclusions about its success are mixed.
In response to a question from Mr. Ullian about the approaching end (by FY 2003) of the five-year NIH budget-doubling period, Dr. Kirschstein said that NIH and several constituencies are beginning to plan for the post-doubling period. For example, NHLBI Director Dr. Lenfant is heading a group of NIH officials, informally called the "Soft Landing Committee," who are helping to develop future budget objectives.
Dr. Lander said that the campaign to double the NIH budget within five years, while welcome, did not represent an optimal increase of this Federal investment in biomedical research. He said that a separate effort is needed to assess what continued increase could be considered appropriate for NIH once the five-year budget doubling period is completed. In response, Dr. Kirschstein said that she has reminded the Congressional Appropriations Committee members that biomedical research will not halt in FY 2003 when the NIH budget-doubling effort is completed, and that there will be many important questions still to address. In response to a comment from Ms. Eisenberg about comparing the public and private investments in biomedical research, Dr. Kirschstein said that the Government, University, and Industry Research Roundtable of the National Academy of Sciences has an ongoing interest in addressing such questions.
In response to a question from Dr. Waite, Dr. Kirschstein said that Congress does not appear to be targeting, or earmarking, more of the overall NIH budget for specific spending programs. Nonetheless, more thought is going into changes in the way science is done and how it affects budgeting strategies for NIH. For instance, modern biomedical research relies increasingly on the availability of very costly instruments, which need to be shared among research groups, and complex databases that need to be maintained and updated while remaining accessible to the broad scientific community; both are costly ventures.
Dr. Eric Lander said that NIH discussions about the Human Genome Project date back to at least 1986, when the mapping of specific disease-related genetic traits led to broader plans to build more comprehensive genetic and physical maps of the human genome. At that time, disease markers could be located only by very tedious procedures, known as chromosome walking. Recognizing the inefficiency of this process, efforts were made to build a big-science project that would also serve the interests of individual researchers. In effect, the goal was to build the equivalent of the chemical periodic table for human genetics.
By the late 1980s, these efforts led to a genetic map of the human genome containing some 400 discrete markers, a landmark at the time, according to Dr. Lander. By the middle 1990s, researchers were also assembling fairly comprehensive physical maps of the human genome, leading researchers to begin several three-year, pilot-scale genomic sequencing projects aimed at completing about 10 percent of the overall genome. By 1999, this effort was accelerated to production-level sequencing that quickly moved to complete 90 percent of the human genome — reflecting, in part, the development and wide availability of highly automated DNA sequencing techniques. For example, researchers working at Dr. Lander's center produce about 65 million bases of DNA sequence per day and, on a worldwide basis, perhaps 1,000–2,000 bases per second are now being sequenced.
The public-sponsored human genome sequencing effort made a point of being inclusive and, for example, added the Beijing Genome Center in 1999, which, after completing its work in the human genome, is now working on the pig genome in cooperation with a Danish group. All members of the human genome sequencing public consortium agreed to release data to the Web site without restrictions within 24 hours of assembling the data.
These sequencing and data assembly efforts led to a landmark paper on the human genome being published in February 2001. Gaps remain in the sequence data, but the members of the international consortium continue to refine the data. Some 43 percent is in finished form with no gaps and 10-4 accuracy and, by the end of 2001, the vast majority of the genome will be in a near-finished state of completion, with a gap about every 100 Kb or so, Dr. Lander predicts. The goal is to essentially be completed by April 2003, the 50th anniversary of the Watson-Crick paper disclosing the double helical nature of DNA.
Dr. Lander said that there are many ways to go about interpreting the data from the genome project. For instance, the genome contains notable gene-rich and gene-poor regions, whose distribution appears to correlate with light and dark bands on chromosomes, with the GC content of the DNA being relatively low in gene-poor regions and relatively high in gene-rich regions. Indeed, there are many other ways to scan the genome by using browsers that enable users to focus on particular features of the genome, including browsers developed by researchers at the University of California, Santa Cruz, by a group at the NIH National Center for Biotechnology Information (NCBI), and by a group at the European Bioinformatics Institute, called Ensembe. Information and correlations with other genomes, such as those for the mouse and zebra fish, are being added to databases on a daily basis.
The genome consists of about 1.5 percent genes, according to Dr. Lander. Of the remainder, about 43 percent consists of repetitive elements falling into four classes of transposable elements. One is called LINE, which are long interspersed repeats that make RNA molecules of about 7 Kb that go to the cytoplasm, each one carrying two open reading frames (ORFs) encoding two proteins that bind that RNA, return it to the nucleus, and reverse transcribe it into the genome. This parasitic genetic element, which is about 1.5 billion years old, is found throughout eukaryotic genomes.
A second set of genetic elements, called SINE, encodes RNA transcript molecules that do not encode proteins. However, SINE RNA can bind LINE-specified proteins that then deliver SINE RNA from the cytoplasm to the nucleus for retro-transcription into the genome. In addition to LINE and SINE, there are retrovirus-like elements that have some essential genetic elements, namely gag and pol, but lack a gene specifying an envelope protein. In addition, there are DNA transposons that move about without an RNA intermediate but with a DNA intermediate.
It is possible to put dates on the repeat elements within the human genome and to estimate when they moved from one locus to another, according to Dr. Lander. This activity was very high for some period but seems to have slowed a great deal during the past 30–40 million years, suggesting that the overall human genome is shrinking (although at a minuscule rate). Moreover, the last time that a DNA transposon moved within the human genome appears to be 40 million years ago, with no evidence of new elements since then. However, the mouse genome appears to be different, with at least 11 actively moving sets of transposons. He speculates that species with smaller populations that are more subject to genetic drift may have transposons that die out more rapidly.
Other information comes from analyzing transposons. For instance, researchers measured the differential rates of mutation in sperm and eggs by examining transposers that jumped to either the X or Y chromosomes. Sperm appear to have twice the rate of mutation as eggs, according to Dr. Lander.
Investigating gene content has several challenges, with an important one being that the noise to signal ratio is about 20:1, according to Dr. Lander. By several different estimates, there seems to be 30,000–40,000 genes in the human genome, far fewer than the 100,000 figure that appears in most text books and which apparently arose from a rough calculation in the early 1980s. Nonetheless, because the human genome allows for a good deal of alternative splicing of genes, the estimate for how many different kinds of proteins the genome specifies is considerably higher.
Based on an analysis fo the human genome, most protein domains are not particularly innovative compared to those encoded by genes of invertebrates, but vertebrate proteins are inventive in terms of domain architecture, according to Dr. Lander. The human genome contains genes for about 1,000 smell receptors, many of which are non-functional pseudo-genes — unlike the mouse genome in which many more of these smell receptor genes appear to be functionally intact.
Dr. Lander said that the experience of organizing the Human Genome Project brings some valuable lessons about conducting science. For example, it indicates that there is high value in investing in large-scale infrastructure to build analytic tools and to establish comprehensive databases. Although individually developed R01 grant mechanisms are still at the core of NIH-sponsored biomedical research, there is value in sponsoring large-scale projects, such as the Human Genome Project, that spur the development of cooperative efforts among many groups of scientists from several different disciplines and in the public and private sectors, and working in an international, often highly competitive arena but also involving cooperation and teamwork. Dr. Lander said that data-sharing is tremendously important for the project, proving that scientists could receive credit for their work without retaining it.
Dr. Lander said that more investment is needed for the genome project to yield full information about each and every gene. Future efforts are needed in several broad areas, including structural genomics, chemical genomics, medical and population genomics, and comparative genomics. For instance, it will be helpful to do full one-to-one comparisons of regions between the human and the mouse or rat genome — a technique that dramatically boosts the ability to detect potential protein-encoding sequences along the genome. Hence, there is significant progress in sequencing the genome of the mouse, with 90 percent of that genome already being available in public databases.
Some sequences in the mouse genome that do not encode proteins overlap substantially — with 90 percent sequence identity — with parts of the human genome, according to Dr. Lander. What these stretches of homologous DNA do is generally not known, but they are plentiful. Good examples occur in the homeobox, or HOX, clusters, which in insects and vertebrates are genes involved in controlling overall development. Mammalian genomes contain four HOX clusters that are highly conserved, with many regulatory elements, and line up spectacularly closely across the human, baboon, mouse, and rat genomes. Moreover, these segments are missing repeats that are commonplace in many other regions of the genome.
Dr. Lander said that many other valuable genomic analytic efforts are under way, including the sequencing of several dozens of bacterial genomes; a number of fungal genomes such as Neurospora crassa, whose genome contains 40 Mb of DNA; Tetraodon, the pufferfish, whose genome contains 380 Mb of DNA; Fugu, another distantly related pufferfish; the zebrafish; and various examples from the Chordates, such as the tunicate, whose genome contains 180 Mb.
Comparative sequencing of DNA among humans also will be valuable, particularly for learning how genetic variation contributes to and correlates with various diseases, according to Dr. Lander. In general, one base in 1,300 within the human genome is polymorphic, which represents little variation and can be explained by theory developed by Dr. James Crow and Dr. Moto Kimura. The theory also predicts that there are only two to four common variants in most genes throughout the entire human population, and this prediction seems to hold.
Many geneticists believe that these retained and well distributed common variants account for a lot of the risk of developing common diseases, according to Dr. Lander. If this notion holds up, it could simplify efforts to catalogue the gene variant combinations that will account for disease risk throughout the population. There are two ways to go about this — testing gene variants by direct mapping or by indirect mapping, looking along ancestral DNA segments of possibly about 1 million base pairs or perhaps only 60,000 base pairs, depending on which human population group is under consideration.
Meanwhile, efforts to catalogue single nucleotide polymorphisms (SNPs) also are expanding at a rapid rate, with more than 1.5 million SNPs now reported. Some parts of the genome are more polymorphic than others. SNPs should aid researchers as they attempt to map specific diseases to genes and chromosomal regions. For instance, inflammatory bowel disease susceptibility has been mapped to regions of chromosome 5 and 16, one of which regions encodes genes for several cytokines, including interleukins-4, -5, and –13.
Such preliminary findings suggest the need for ongoing collaborative, comparative genomics studies, according to Dr. Lander. Indeed, the Genome Project is far from complete, and there is a continuing need to invest in more infrastructure, tool development, and comprehensive analysis to fulfill the promise of genomics.
Dr. Shirley Tilghman asked whether sequences from the pufferfish line up with the homologous mouse and human non-ORF-encoding sequences. In response, Dr. Lander said that very few fish sequences appear to line up with the large homologous noncoding mouse and human sequences, suggesting that regulatory elements mutate or are lost more quickly during evolution than are coding sequences. He predicted that analyzing such sequences will lead soon to insights about gene regulation.
Dr. Allen Spiegel, Director, National Institute of Diabetes and Digestive and Kidney Diseases, said that some intron sequences in the mouse and in humans may be retained to enhance splicing. He asked whether DNA sequence differences between African and Northern European populations will provide insights about differences in disease trends between these two populations. In response, Dr. Lander said that studying DNA sequences of African Americans could prove useful because they consist of mixtures of ancestral African and Northern European haplotypes and studying variants could provide insights about disease trends and disease-related gene segments. Ultimately, however, analysis of multiple ethnic groups will be needed to ensure that the medical benefits are broadly applicable to all populations.
Dr. Victor Dzau asked Dr. Lander to comment on what genomics can contribute to the scientific understanding of ethnic- and race-based variations to drug responses. In response, Dr. Lander said that data addressing such questions are still scarce. He also said that, although the variation is relatively small between groups and that most variants occur in all groups, frequencies of those variants differ, and those frequencies could account for observed differential responses to drug treatments. Each population likely has its own mix of such variants, making it useful to study certain variants within a particular population group. However, there is nothing fundamentally different in terms of DNA sequence among population groups.
In response to a question from Mr. Ullian, Dr. Lander said that the tools for using genomics to make progress against diseases are in place, with information about the mechanism of diseases coming from genomics and that information about mechanism, in turn, being applied mainly by industry to develop new approaches to therapies. The Genome Project provides information that enables a wide range of biomedical researchers to attack disease problems more efficiently.
In response to a question from Ms. Eisenberg about who is using genomics data, Dr. Lander said that about half of the inquiries come from industry and the other half from university researchers. Users in industry tend to download more comprehensive volumes of data.
In response to a question from Dr. Dzau about whether clinical investigators are properly equipped to use genomic data, Dr. Lander said that a great deal needs to be done to meet future needs of such investigators. The Genome Project initially focused on how it would meet its internal goals — developing physical and genetic maps of human chromosomes and then sequencing genomic DNA. During the next decade, the focus needs to shift toward making information from such analyses available and developing an infrastructure for making such data useful to different kinds of investigators, such as those doing clinical research and also epidemiologists. It will take considerable planning and ingenuity to develop such plans and to meet these goals.
UPDATE ON STUDY SECTION REORGANIZATION ACTIVITIES IN THE CENTER FOR SCIENTIFIC REVIEW
Dr. Ehrenfeld, Director of the NIH Center for Scientific Review (CSR), said that the peer review process may need to accommodate changes in the way biomedical science is being done, pointing to the Human Genome Project as a prime example of research being organized in a very different fashion from the traditional, investigator-initiated approach. This change is one among several that Dr. Ehrenfeld noted from many visits to members of the extramural scientific community soon after she arrived at NIH in 1997. They told her, for example, that some emerging fields of science had no appropriate study sections for reviewing research proposals and that some existing study sections had become too narrow to accommodate multidisciplinary proposals, while other study sections were too broad to provide expert review.
The NIH grant review system had not been systematically evaluated since it was developed about five decades ago, according to Dr. Ehrenfeld. To do so, she appointed a Panel on Scientific Boundaries for Review (PSBR), a working group of 15 distinguished researchers constituted as a subcommittee of the CSR Advisory Committee. The PSBR identified principles and guidelines for organizing science for the review process during the first phase of their activities. CSR's study sections are organized into clusters, or integrated review groups (IRGs), as a way of providing structure within the CSR, serving much like academic departments within universities. Procedures for periodically reviewing the performance of study sections within each IRG have recently been implemented in CSR. The Panel recommended establishing a new set of 24 IRGs.
The recommendations and evaluations were incorporated into a report. According to Dr. Ehrenfeld, the report delineates how IRGs are to emphasize a mechanisms-to-disease review of research applications. It accommodates the advent of molecular medicine and acknowledges that research is not only hypothesis-driven but may also, for instance, be design- or problem-driven. It also acknowledges that some research will not fit into designated categories but is cross-cutting. A draft of this report was made available to the wider research community and extensively reviewed and updated based on comments from individuals and from professional scientific societies, and eventually accepted as final in January 2000.
The second phase of the PSBR initiative is to design and establish study sections for each of the new IRGs, according to Dr. Ehrenfeld. To prepare, CSR officials compiled a database from approximately 10,000 applications received by NIH for the May 2000 review round. Although already reviewed, these applications were re-sorted according to the proposed IRGs and the new CSR guidelines, and this distribution was reviewed by the CSR staff to identify overlaps and ambiguities.
From these experiences, CSR officials developed a procedure for the second phase in which a CSR division director appoints a steering committee for each IRG of CSR review staff and program staff from Institutes and Centers who, in turn, identify the scientific communities that are relevant and involved with that IRG. Then, a boundary team is appointed from those relevant communities to work out the composition of study sections within the IRGs. The team members come to NIH to redefine the study sections, and their proposal is posted on the CSR Web site to permit an iterative refinement process before the new study sections are presented for approval to the CSR Advisory Committee and fully implemented — a process that takes at least one year.
Dr. Ehrenfeld said that the first IRG taken through to completion with a full set of new study sections focuses on hematology. Since this first set of study sections was completed, plans now call for working through study sections for three IRGs at a time, at four-month intervals. The next three sets of boundaries groups were expected to meet in July 2001, and the entire process of setting new study sections should be completed within three to four years.
Dr. Ehrenfeld said that, even before the new IRG system is fully implemented, plans are being developed for evaluating it. For instance, assessment surveys are being designed for applicants, program staff, and for reviewers. She and others also are faced with a concern that the underlying science is changing so rapidly that it may prove necessary to revise the study section boundaries soon again. It is hoped that the teamwork fostered by the IRG structure and the periodic external assessment of each IRG will permit fine-tuning and adjustments that will make another wholesale revamping of the system unnecessary anytime soon.
Dr. Cech said that the opportunity for investigators to recommend the IRG and study section to which their applications are sent for review is a useful means for reducing anxieties over the new system. He also urged CSR to have a Web site that lists the study sections, indicating the area(s) of research reviewed and the meeting schedules. In response, Dr. Ehrenfeld said that the Web site is being redesigned toward that purpose, and it already includes schedules and rosters of reviewers who have served for the past three rounds, making the entire assignment-and-review process more transparent. She said that the issue of investigators recommending where to send their applications is complicated, but that ultimately they may be encouraged to list first and second choices of where their applications might be sent. Typically, CSR heeds such requests, except where there are obvious conflicts of interest or in instances where the investigator seems misguided, in which cases the matter is usually discussed with the applicant to find a solution.
Dr. Bettie Sue Masters praised Dr. Ehrenfeld for her efforts in reforming CSR and asked about CSR efforts to bring the most highly qualified reviewers into the new system. Dr. Ehrenfeld said that a great deal of effort is being put forth to meet this challenge, particularly in some fields where senior scientists are reluctant to commit to reviewing grants. The CSR Advisory Committee is planning a long-term study of this issue, and will gather information on what are seen as obstacles to doing this service. Dr. Masters suggested that members of disadvantaged research communities be recruited to study sections.
In response to questions from Dr. Brody and Dr. Lander, Dr. Ehrenfeld said that the entire process will require several years to set up a total of about 160 study sections and to allow for ample comments from the scientific community and further fine-tuning of the IRGs. She said that plans call for simply phasing in new study sections whenever possible, allowing ample time for implementation and for members of the community to develop a sense of comfort for the changes under way. In response to questions from Dr. Kirschstein, Dr. Ehrenfeld said that the hematology IRG is waiting, in part, until another one or two new IRGs are established before it can be considered complete.
Dr. Barrie Carter asked about developing study sections with a more visionary approach to reviewing innovative research proposals, suggesting that senior researchers might be best suited for this service. In response, Dr. Ehrenfeld said that the CSR Advisory Committee is considering scientific creativity issues in very broad terms. Dr. Kirschstein pointed out that senior researchers can sometimes prove very conservative when reviewing innovative, high-risk research proposals.
Ms. Eisenberg said that CSR will need to identify reviewers with breadth of vision but that going to professional societies for guidance tends to select more conservative individuals. In response, Dr. Ehrenfeld said that professional societies represent only one of several sources of advice and of recommendations for individuals to serve on IRGs. CSR also receives advice from staff in the NIH Institutes and Centers, who typically have a good sense of where progress and innovations are being made. However, during this reform period, CSR has received a good deal of valuable input from professional societies, while improving its interactions with them as a way of disseminating information to their members.
Dr. Cecil Pickett asked what NIH expects from the many changes being implemented in CSR. For instance, will resources move away from R01 mechanisms and more toward project and centers grants? In response, Dr. Ehrenfeld said that changes in the reviewing mechanisms should not affect decisions by Institutes in regard to their pattern of investment in R01 or other grants and contract mechanisms. The patterns vary considerably from one Institute to another, but the changes at CSR are not expected to influence the patterns significantly. In more general terms, the changes at CSR are intended to sharpen the review process and to result consistently in the best applications being identified for funding. Judging this success will be difficult, but efforts are under way to develop surveys and other evaluation procedures for this purpose. Moreover, it is important to build in flexibility to adjust and refine the new system as its new procedures are being implemented.
In response to a comment from Dr. Donald Wilson about using deans of research within the university community for advice and referrals for reviewers, Dr. Ehrenfeld said that CSR is in the process of developing such a database.
REPORT FROM THE EXTRAMURAL CONSTRUCTION WORKING GROUP
Dr. Kirschstein said that the former NIH Director, Dr. Harold Varmus, appointed a working group to study how NIH should support extramural construction. This issue is of particular interest to Senator Tom Harkin (D-IA), who introduced legislation that passed as part of the Public Health Improvement Act, authorizing $250 million for such construction in FY 2001 and at higher funding levels, in FY 2002 and 2003. Meanwhile the appropriations bill for NIH sets such spending levels at $75 million for FY 2001.
Dr. William Brody thanked several NIH staff members for help in preparing the working group's report, including Dr. Vaitukaitis, Dr. Belinda Seto, and Ms. Victoria Conte, and he also acknowledged two members of the working group who were attending the ACD meeting, Mr. David O'Brien from Stanford University and Mr. Gary Talesnik of KPMG. He said that preparing the report proved challenging and time-consuming, even without considering complex issues such as accelerated depreciation rules, the details of Federal Circular A21, and tax incentives for industry to finance construction at tax-exempt institutions.
The working group's mandate was to consider needs for, and to develop new concepts for constructing extramural biomedical research facilities, according to Dr. Brody. The working group intended to survey some of the top one hundred NIH grantees, but ended up conducting a more limited, anecdotal review. It indicates that institutions with particular difficulty in financing new research facilities may be grouped into three main categories: emerging institutions that currently do not have much support for their research programs; minority-serving institutions; and special category institutions such as the regional primate centers.
Additional data that proved especially helpful to the working group are contained in a 1998 report from the National Science Foundation (NSF), "Scientific and Engineering Research Facilities at Colleges and Universities." This report, which NSF plans to update biennially, estimates that U.S. biomedical research facilities at such institutions face a deferred maintenance total of $5.6 billion. In terms of building new research facilities, existing mechanisms have proved inadequate over the past several decades, even among top-notch institutions. Hence, the preponderance of research facilities now in operation are antiquated, inadequate, and extremely expensive to retrofit and upgrade.
To meet the needs dictated by the ongoing NIH budget doubling, some 12 to13 million net assignable square feet of usable lab space will be needed nationwide, according to Dr. Brody. Such space costs about $500 per net square foot, amounting to an overall investment for new construction of $7 billion, which if added to the NSF estimate of $5.6 billion to meet deferred maintenance needs, indicates a substantial amount of pent-up demand for new and improved research facilities.
The Federal government is investing in research facilities in several ways, including through direct construction or renovation grants and indirectly through facilities and administration reimbursement mechanisms, according to Dr. Brody. Moreover, state governments, private funds from foundations and endowments, and various gifts are being used for construction and renovation of such facilities. The NSF report indicates that 28 percent of such funding comes from state governments, 27 percent by debt financing, 8 percent from the Federal government, and the remainder from private donations and institutional funds. These figures vary widely from private to public institution and from one state to another. Renovation funds tend to be generated at the institutional level, whereas new construction is more likely to come from donations or from debt financing.
Dr. Brody said that NIH sponsors a competitive facilities improvement program, encouraging institutions of emerging excellence and Regional Primate Centers to apply for such support. The program asks applicants to find matching funds, but this requirement can be waived. These NIH funds are provided up-front rather than as a long-term reimbursement, but they are generally kept to a ceiling of $1.7 million per award, which is not enough for new construction or even large-scale renovation. For many institutions, the matching fund requirement presents a difficulty that often is all-but-insurmountable. In addition, for many other institutions, NIH involvement comes with certain additional administrative requirements, such as NIH oversight during the architectural design stage. Prior to 1970, NIH funded construction through a direct grant program, but switched primarily to a facilities and cost reimbursement program thereafter except for a brief period of construction financed under auspices of the war on cancer.
After the early 1970s, the NIH direct budget for extramural construction all but disappeared, whereas facilities reimbursement costs and administrative costs grew steadily, rising to about $3.5 billion of the total $13 billion NIH extramural budget in FY 1999, according to Dr. Brody. These figures encompass allowable costs for recovering interest on debt, depreciation, and operation of the buildings. To the extent that an institution raises construction funds by other means, it is not reimbursed for those efforts or funds, but only for debt service on money borrowed to complete a project. For the most part, NIH funds construction and renovation costs by reimbursing for related facilities and administrative costs on a pay-as-you-go basis, requiring no separate grant-application mechanism while providing support (and, in effect, conducting reviews) through R01 and other competitive research grants and contracts.
Logical and workable though this system is for those institutions with a proven track record, it puts other institutions with fledgling research programs at a distinct disadvantage, according to Dr. Brody. Such institutions often do not have capital for new construction or the credit rating needed for borrowing such funds at reasonable rates. Another problem with the current NIH system for paying for such expenses is that it attracts criticism at the political level, which led officials in the Clinton Administration to set caps on administrative reimbursable costs. Such political decision making, in turn, undermines confidence among those at institutions who are responsible for maintaining and constructing such facilities because they can no longer count on such costs being recovered over the extended — for example, 20-year — period that was agreed on during the construction or renovation-planning phase. Seldom are those costs recovered in full, and full costs certainly cannot be recovered for multi-use facilities because only research space, but not teaching space, is eligible for NIH support.
Debt financing accounts for about 30 percent of the capital being invested in research facilities, according to Dr. Brody. How much debt and the interest rate that can be negotiated vary from one institution to another. Because some required capital can be reimbursed by NIH through indirect cost recovery, NIH in effect encourages institutions to use debt financing for construction purposes. However, the Federal government often is penalized when it uses this approach for underwriting construction and renovation projects at institutions that are forced to borrow at high interest rates.
Dr. Brody said that the working group made three general recommendations:
The Federal government should appropriate significant funds to NIH for the purpose of direct facilities improvement grants because of the substantial backlog in unmet renovation and new construction needs and because many institutions cannot make the needed investments. For FY 2002, that sum should be the authorized at $250 million, and officials should consider increasing that total to $1 billion per year. Grants for such projects should be divided into several categories, including relatively small sums of $2–3 million, and sums of about $20 million per institution for more substantive projects. Thought should be given to easing matching requirements, asking grantee institutions to submit information about their research facility master plans, and establishing special competitive categories for minority and emerging research institutions.
A Federal loan guarantee program should be established to support construction and renovation of biomedical research facilities. The program would provide institutions a source for borrowing money at competitive rates, which would also provide savings for the Federal government.
In terms of the current facilities and administrative reimbursement mechanism, the working group recommends that universities be reimbursed for the cost of capital associated with investing in research facilities. In addition, the costs that accrue from fund-raising for such investments should be considered an allowable overhead cost. Also, rules should be adjusted to permit institutions to recover indirect costs for space in research facilities that is not immediately occupied or assigned for NIH research-related purposes.
Dr. Brody said that perhaps the fundamental message from the working group is that expanding the NIH budget necessitates a comparable investment in facilities in which that biomedical research will be conducted.
Dr. Lander asked whether an institution, if given a sum of money for construction, would be better off handing that sum to a private corporation and borrowing it back. In response, Dr. Brody said that transactions of that sort would not be approved by trustees at his university and, under some circumstances, could be considered illegal arbitrage. Moreover, he said that there are incentives to use gift money directly for construction rather than to assign it a different use while relying on borrowed funds for construction. The more troubling question, he added, is whether an institution should receive some credit from NIH for raising sizable donations for the purpose of constructing research facilities.
In response to a question from Mr. Williams, Dr. Brody said that about $3.5 billion in the NIH budget now goes for facilities and administrative costs in the extramural community, and half that sum goes for facilities maintenance and operation costs. About $1.2 billion per year from NIH is being spent on depreciation and interest costs associated with extramural biomedical research facilities, according to Mr. Talesnik of the working group. Dr. Brody said that the working group's recommendations would amount roughly to doubling the current NIH investment in research facilities. A difficulty with continuing to rely on indirect cost recovery for this purpose is that these costs were repeatedly the focus of political debates during the 1960s and 1970s and, again, in the early 1990s.
Dr. Baldwin asked whether increasing the direct investment from NIH into constructing and renovating extramural research facilities would lower needs for recovering such costs through indirect means. In response, Dr. Brody said the working group did not undertake such elaborate calculations and modeling efforts, but agreed that analyzing data and reviewing additional options would be helpful. Dr. Lander added that these two funding mechanisms do not simply offset one another, but interact in more complicated ways because of effects on planning and risk-taking at the institutional level.
Along similar lines, Dr. Lander asked Dr. Brody and other working group members what the budget impact would be if NIH were now allowing grantee institutions to recover more or full capital costs through indirect means. In response, Dr. Brody said that allowances for interest costs would nearly double from current levels, but the overall impact on capital flow could prove difficult to estimate.
Mr. Talesnik said that some commercial contractors that do business with the Federal government have worked with such rules for several decades and, generally, accept a blended rate that does not precisely reflect the true interest rate on borrowed funds. In response to a question from Dr. Kirschstein, he said that many of the changes recommended by the working group could be implemented by changing policies outlined in the A21 and A122 Federal documents, which apply to many Federal agencies besides NIH.
In response to questions from Dr. Cech, Dr. Kirschstein said that, although Congress authorized $250 million in capital spending by NIH, only $75 million was appropriated for this purpose for FY 2001 and the President's budget request for FY 2002 calls for a little more than $100 million for this purpose, making it unlikely that Congress will raise that $100 million request to anywhere near $250 million.
Dr. Lander asked whether current depreciation schedules are appropriate for biomedical research facilities. If they are slow relative to real building replacement needs, they create economic disincentives. Dr. Brody said that there are several issues to consider in terms of technology and buildings becoming obsolete and also of new technologies costing more than the obsolete instruments that they replace. Mr. Talesnik said that institutions are allowed to renegotiate and write-off facilities more rapidly if obsolescence rates are more rapid than actual facility deterioration.
Mr. Talesnik also said that there is a practical limit to using the indirect cost accounting system for recovering building and maintenance costs. If the overall average indirect cost rates, now at about 50 percent of the NIH extramural budget, were to go much higher, the institutions whose indirect costs come in at the higher end of those rates would attract undue attention. Hence, he strongly recommends finding other means to finance research facilities construction.
Dr. Cech said that this issue is important for NIH, agreeing with Dr. Brody and the working group that current increases in the overall NIH budget necessitate improvements and expansion of the NIH investment in extramural research facilities. He called this investment critical and urged that it be made as a separate, competitively distributed capital investment fund, not as part of indirect overhead costs.
Dr. Kirschstein asked ACD members to reread the working group report and to discuss it with colleagues. She also promised to discuss these matters again at the ACD meeting next December. Dr. Brody said again that trying to finance new construction through the indirect cost mechanism, which has served extramural researchers very well in general, would not be workable at the increased levels recommended in the working group report. Dr. Kirschstein and Mr. Williams alluded to current research and health-related construction activity on university campuses, noting the widely held impression that such activity is widespread. She also pointed out that any substantial request from NIH for increased funding for such construction, however much it may be needed, could offset budget increases in other programs.
UPDATE ON REGULATORY BURDEN AND REVIEW OF MODULAR GRANTS
Regulatory Burden Reduction
Dr. Baldwin said that, in 1998, Congress asked NIH to review regulations that might be burdensome to researchers, following up on an earlier review by the Government Accounting Office. The review identified approximately 60 regulations affecting researchers but concluded that, although some of the regulations were burdensome, they were appropriate and necessary. In response to the 1998 request from Congress, NIH focused on five areas where these burdens could be reduced and sought advice from representatives of the extramural research community to identify problem areas and ways to address them.
Dr. Baldwin said that NIH learned that regulations limiting flexibility, or that specify how to meet goals rather than simply prescribing the goals themselves, tend to be the most burdensome to the extramural research community. Regulations that are administered by more than one Federal agency, particularly by non-science agencies, also tend to be viewed as particularly burdensome. One major step to reduce such burdens has involved recent efforts to harmonize policies and oversight of the NIH Office for the Protection from Research Risks (OPRR) — now reestablished within HHS as the Office for Human Research Protections — and the Food and Drug Administration (FDA), particularly with respect to their jurisdiction over Institutional Review Boards (IRBs).
According to Dr. Baldwin, the NIH has developed some IRB-related policies that streamline procedures and thus reduce regulatory burden. For instance, "just-in-time" IRB reviews give institutions the flexibility to postpone evaluations until a decision is made as to whether a pending application may be funded, thus avoiding IRB-level reviews for applications that will not be going forward. In regard to animals used in research, reporting requirements are now better coordinated and synchronized among agencies — here again, reducing regulatory burden for researchers. Recent proactive compliance site visits by OER and other NIH staff are also meant to reduce regulatory burdens, mainly by improving communications between NIH and many of the institutions whose research it supports.
With these measures in place, the NIH Regulatory Burden Advisory Group has established four working groups to examine other significant issues:
institutional conflicts of interest where, for example, universities may hold equity positions in companies whose products are being evaluated, chaired by Arnold Smith of the University of Missouri;
costs of compliance in which NIH will address how facilities and administrative cost caps may affect efforts by institutions to meet regulations and consider alternatives, chaired by Robert Rich of Emory University;
human subjects protections and IRB activities, chaired by Ada Sue Selwitz of the University of Kentucky; and
animal welfare issues, including proposed regulations regarding the pain and distress, and regarding rats, mice, and birds used in research, which is chaired by Janet Greger of the University of Wisconsin.
Dr. Baldwin also described NIH experiences with modular grants, which came into use in January 2000. Modular grants change the requested budget strategy in dealing with research projects — mainly funded through R01 awards, but also R03, R15, and R21 awards. The new approach is limited to applications that request up to $250,000 (including indirect costs) per year, which, in modular form are budgeted in $25,000 increments. In regard to modular grants, less attention is paid to specific budgeting details in an application and no longer does the NIH set rigid categories for expenditures or for revising budget items during the course of the research project. Thus, instead of NIH attempting to micro manage how a researcher spends money on a grant, the investigator is given a good deal of freedom in managing the project budget.
Before modular grants were implemented on a large scale, the NIH worked through many of the details of this transition in pilot phase. In turn, although investigators put less in the way of budgetary details in their modular grant research proposals, reviewers expect the information that is included to correspond closely to the actual scientific needs, the general costs of materials and methods, and the number and type of personnel required to perform the research being proposed. The review itself now focuses more sharply on the merits of the research being proposed. Data have been provided to reviewers on the historical average awarded costs by category as a guide to aid them in their understanding of the budget request.
The NIH continues to stress the education of its research constituency in regard to the new terms of the modular grant system. The transitional effort began with a pilot of 25 requests for applications, but the follow-up educational effort has extended to regional meetings, mass e-mails, staff training, and other comparable programs to explain modular grants to members of the extramural research community. Dr. Baldwin indicated that 97 percent of the applications that could fall within the modular umbrella are now arriving at NIH in that form and, as soon as modular grants with their $250,000 ceiling were made available, the number of R01 applications seeking higher total budgets dropped. Indeed, much to the surprise of NIH officials, modular grant proposals do not routinely request the top figure but, instead, on average, tend to request $175,000–200,000.
The change to modular grants also is affecting peer review, according to Dr. Baldwin. Reviewers are told to consider budget issues as part of the overall assessment of applications and, when appropriate, to recommend changes in the number of modules that might be recommended. However, the central message is to keep the review focused on scientific merit. NIH-wide analysis indicates that about 70 percent of R01 budgets go to support personnel, with most of the rest for supplies and equipment. Although the average cost of grants is going up, the changeover to modular grants did not disrupt or dramatically affect that trend; moreover, the modular process has not in itself affected the average cost of NIH grants. Another change during this period is a significant increase in applications requesting more than $500,000, but this change is not affected by the modular grants process because the large-sized grant proposals lie outside the modular limits.
Dr. Baldwin said that the NIH plans to evaluate the modular grant system after it is in operation for a full two years, allowing universities and other research institutions to streamline their internal reviews and to adapt fully to the new system before trying to evaluate how well the modular grants process is working. For one thing, it took awhile before administrators and researchers at many institutions came to understand that applications no longer need to include elaborate budgetary details. To conduct the forthcoming evaluation, Dr. Baldwin is asking the Peer Review Oversight Group to convene this fall to develop a strategy for evaluating the modular grant experience. The goal is to include the full spectrum of stakeholders in conducting this evaluation.
Commenting on research-associated regulatory burdens, Dr. Wilson said that the Veterans Administration Hospitals are addressing regulatory burdens and conflicting messages in terms of intellectual property ownership between the requirements of the Bayh-Dole Act and current policies within the agency.
Dr. Bette Sue Masters said that Dr. Baldwin addressed many of the concerns that she hears from researchers. However, Dr. Masters continues to question whether the modular grants process may contribute to inflation of research budgets, and the consequent reduction in the number of new grants being funded. Moreover, she added, some reviewers from the research community are concerned that NIH staff members, rather than peer reviewers, are deciding on appropriate budget levels for R01 proposals. Hence, some reviewers feel disenfranchised.
Dr. Masters asked as to how NIH obtains a meaningful assessment of grant budgets and how it can ensure consistency across study sections. In response, Dr. Baldwin said that ensuring such consistency is a constant challenge because the NIH review process involves a large and complex organization; moreover, its Institutes and Centers sponsor very different research programs
Dr. Masters also asked about accountability, particularly in reference to Congress and the move to double the NIH budget within a five-year period. Because Congress appears to accept the validity of investigator-initiated research, it behooves NIH to show that it is supporting young investigators and increasing the numbers of new grants, she said. In response, Dr. Baldwin said that, although there are inevitable inconsistencies across NIH, there are no data indicating that modular grants are draining the system of resources or leading to fewer numbers of R01 awards. There are broad changes taking place that affect extramural grants, but these changes are occurring mainly with proposals seeking support of $500,000 or more. Dr. James Battey, Director of the National Institute on Deafness and Other Communication Disorders, pointed out that such large-budget proposals tend to receive the best priority scores in part because high-priority science costs more to do. This factor appears to be a principal driver behind the rising cost of R01 grants.
Dr. Greg Koski, Director of the HHS Office for Human Research Protections (OHRP), said that he is chairing the Human Subjects Research Subcommittee (HSRS) of the Committee on Science, the operating arm of the National Science and Technology Council. These activities signal a broad mandate within the Administration to strengthen measures for protecting patients and others who participate in research. Both NIH and FDA play particularly prominent roles in these basic efforts and recent efforts to build a better protective system.
This recent reform activity stems from concerns that the system for protecting human subjects in research has not kept pace with other changes in the research environment, and that IRBs perhaps needed shoring up, according to Dr. Koski. The revamped system emphasizes responsibility, greater flexibility and accountability, and prevention rather than post-hoc compliance efforts.
Dr. Koski said that OHRP is providing support for HSRS, which is the working group that is developing policies and coordinating patient protective efforts among several Federal agencies and departments. His office also interacts with the National Human Research Protections Advisory Committee (NHRPAC), which was established in the fall of 2000. OHRP also evaluates reports from and implements recommendations developed by the National Bioethics Advisory Commission, which was established in 1994.
OHRP strives toward four broad goals under the acronym SUEE: simplification, uniformity, efficiency, and increased effectiveness, according to Dr. Koski. The past system for protecting human research subjects was based on confrontation and enforcement, thereby separating patients and other volunteer subjects from researchers and their sponsors. OHRP now is emphasizing an alternative collaborative and programmatic approach in which all the participants acknowledge their common goals, especially the effective protection of research subjects, and OHRP improves overall coordination as a way of shifting some burdens away from IRBs.
Dr. Koski said that IRBs need effective administrative staffs and communication systems, adequate resources, and appropriate mechanisms for compliance oversight, focusing on quality of the programs rather than on punishing those who do not precisely meet every rule. Monitoring and reporting adverse events are important responsibilities, but there is a need for greater emphasis on identifying and effectively managing communications of critical information surrounding such events. Education is the single most important step needed to improve the overall program, he said.
Several private sector initiatives are of great importance for these efforts to improve the overall program, according to Dr. Koski. For instance, individuals involved in human research need to be properly trained in certified programs within the private sector, the cornerstone of which is a private, voluntary system of accreditation for these activities. An over-arching goal is to develop uniform national standards for human research protection programs. A report from the Institute of Medicine (IOM) last April outlines the initial steps needed for implementing such a program. He said that once most individual programs are certified and accredited, OHRP will be in a better position to meet its oversight and regulatory responsibilities, focusing more of its resources on those programs that still need help in attaining full accreditation.
OHRP also is looking for additional opportunities to reduce costs and improve effectiveness of human subject protections, according to Dr. Koski. One idea is to shift partly to a multicenter consortium model for IRBs, establishing regional review boards to serve several local institutions instead of the current system in which each institution has its own IRB. Such a change might improve efficiencies and reduce costs. For instance, in Kansas City, several academic institutions are pooling resources to establish a separate foundation under the Midwest Bioethics Center that will have the responsibility of operating a human subjects protection program for all the participating institutions. Another possibility calls for several geographically separated universities to develop cooperative agreements in which they rely on the IRB at one of the member institutions to serve the needs of them all. Dr. Koski also plans to meet with National Cancer Institute representatives to consider developing a national human research review board for protocols conducted under cancer cooperative groups.
Dr. Koski described his three-phase, two-year remodeling plan for OHRP in which the first phase emphasizes networking across the entire system to build a strong foundation. Thus, for example, he has been traveling widely, speaking to many stakeholders about current efforts and forthcoming changes. The second phase, which is beginning, involves implementing changes, focusing on education and support, enhancing oversight, and taking advantage of technological advances to improve efficiencies of IRBs within the system. The third and final phase will entail fine-tuning these many changes and consolidating the improvements by early 2002. During the first phase, OHRP was formally established within HHS and, subsequently, NHRPAC. In addition, the charter for HSRS was developed and approved in January 2001, and its members are implementing a simplified Federal-wide assurance process for human subjects protection programs and plan to develop a registration system for all IRBs, including those at institutions that do not receive Federal funding.
Other important activities are under way, according to Dr. Koski. IOM completed its first report to OHRP on the proposed accreditation process, and a pilot test of the process is beginning. A working group of OHRP is examining financial relationships and conflict-of-interest questions. OHRP is also involved in international deliberations over human subject protections, including a move to revise the Declaration of Helsinki. Meanwhile, the single most important effort during the second phase of the OHRP three-phase reform efforts will be to implement a quality improvement program to replace past practices in which quality assurances were renegotiated, according to Dr. Koski. The new approach involves visiting many institutions and analyzing about 60 separate programs across the country. In addition, a Federal manual for human research is being written.
In the fall of 2001, a SUEE Task Force will assemble representatives of Federal agencies and stakeholders from throughout the country to identify and review opportunities for achieving greater efficiencies, uniformity, and for simplifying the system, according to Dr. Koski.
Dr. Brody said that, although the Office of Management and Budget apparently does not favor a program of Federal loan guarantees for constructing research facilities, such a program would enable institutions to borrow at favorable rates and could save the government in terms of lowered interest payments on construction loans.
The third set of recommendations in the report addresses changing facilities and administrative (F&A) rates to capture construction costs, according to Dr. Brody. However, changes that tend to increase F&A rates are likely to prove untenable politically. He said that a policy statement indicating that the Federal government was committed to reimburse F & A costs and that the increasing facility costs to fund new construction and renovation would be reimbursed. Such a policy would encourage institutions to continue to make long-term commitments to invest in facility construction.
In response to a question from Dr. Brody about the challenge of educating researchers across the country about OHRP-mandated changes and the possibility of centralizing these efforts, Dr. Koski said that a major goal identified during a meeting in February 2001 was to establish a national educational council for pooling information resources that could be shared — downloaded from various Web sites — locally by institutions that conduct research involving human subjects. Since NIH mandates education of investigators conducting such research, institutions are making extensive efforts to obtain such materials. OHRP, NIH, FDA, and other Federal and private Web sites, such as that of the Association of American Medical Colleges, now post a great deal of such information that is frequently augmented.
In response to a question from Dr. Vaitukaitis about the role of private partners in the accreditation process, Dr. Koski said that the system is based on one developed and used by AAALAC, with plans for a single and uniform standard for both private and public institutions. Meeting that goal will be tricky because the Department of Veterans Affairs began to develop its own privately situated accreditation program before OHRP began its efforts, and that effort involves the National Council of Quality Assurance and the Association for Accreditation of Human Research Protection Programs. However, he is working to develop reciprocity and avoid redundancy between that effort and the one under OHRP. He said that they share a common vision, and perhaps the system being devised will involve several organizations accrediting IRBs under uniform standards across the entire program.
In response to a question from Dr. Vaitukaitis about costs of the accreditation program, Dr. Koski said that OHRP will have little or no influence over costs of these programs within the private sector but those costs likely will resemble those now seen in established accreditation programs. It is still an open question whether those costs will be considered allowable under Federal research funding mechanisms. Of course, there is a very high cost to non-compliance when it comes to meeting human subjects protections goals and standards, he said.
Dr. Baldwin said that, although standards are not entirely uniform across agencies when it comes to adverse event reporting, certainly officials in each agency respond to those reports as a critical part of their efforts to ensure appropriate protection to human subjects. Dr. Koski said that he over-simplified his description of that set of activities. He also said that such reports sometimes accumulate before there is any response to them, particularly in cases of large-scale, multicenter trials, indicating that reforms are needed to make responses more effective and efficient. Dr. Baldwin pointed out that the Data Safety Monitoring Boards are now required to send summary reports to all IRBs as a way of improving efforts to monitor patient safety.
Dr. Kirschstein commented on an earlier statement by Dr. Koski, saying that efforts are under way to improve the management of adverse event reporting, not the management of adverse events themselves. Dr. Koski agreed, saying the goal is to monitor such events in a very timely fashion, analyze them, and respond appropriately to avoid further harm to participants.
In response to a question from Dr. Maddox about protecting children who are participating in research protocols, Dr. Koski said that a report being prepared for Congress on this subject does not contain a great deal of solid data, indicating a need to study this subject more thoroughly. However, available evidence indicates that institutions are doing what they should to protect children who participate in research protocols.
The Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) met on June 7, 2001, to consider reorganization activities within the Center for Scientific Review, recommendations from a working group on NIH investments in extramural research facilities, efforts to reduce regulatory burdens placed on extramural researchers, initial experiences with modular budgeting of research grants, and HHS efforts to improve measures for protecting patients in clinical research and others who participate in studies.
The ACD acknowledged, commented on, and endorsed some of the recommendations in these reports, and ACD members agreed to reconsider extramural construction technology transfer issues, among others, at its next meeting.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Yvonne Maddox, Ph.D. Acting Executive Secretary Advisory Committee to the Director
William R. Brody, M.D., Ph.D. President Johns Hopkins University Baltimore, Maryland 21218-2688
Bette Sue S. Masters, Ph.D. The Robert A. Welch Foundation Professor in Chemistry Department of Chemistry The University of Texas Health Science Center San Antonio, Texas 78229-3900
David R. Burgess, Ph.D. Professor Department of Biology Boston College Chestnut Hill, Massachusetts 02167
Cecil B. Pickett, Ph.D. Executive Vice President for Research Schering-Plough Research Institute Kenilworth, New Jersey 07033
Barrie J. Carter, Ph.D. Executive Vice President and Director of Research and Development Targeted Genetics Corporation Seattle, Washington 98101-1823
Larry L. Smarr, Ph.D. California Institute for Telecommunications and Information Technology University of California, San Diego La Jolla, California 92093-0405
Christine K. Cassel, M.D. Professor and Chairperson Department of Geriatrics and Adult Development The Mount Sinai School of Medicine New York, New York 10029-6574
Shirley M. Tilghman, Ph.D. Lewis Thomas Laboratory Department of Molecular Biology Princeton University Princeton, New Jersey 08544
Thomas R. Cech, Ph.D. President Howard Hughes Medical Institute Chevy Chase, Maryland 20815
Arthur D. Ullian Chairman, Task Force on Science, Health Care, and The Economy Boston, Massachusetts 02116
Steven Chu, Ph.D. Professor Physics Department Stanford University Stanford, California 94305-4060
Linda J. Waite, Ph.D. Professor National Opinion Research Center University of Chicago Chicago, Illinois 60637
Yank D. Coble, Jr., M.D. Physician Jacksonville, Florida 32205
Phillip L. Williams Vice Chairman (Retired) The Times Mirror Company Pacific Palisades, California 90272
Victor J. Dzau, M.D. Chairman Department of Medicine Brigham and Women's Hospital Boston, Massachusetts 02115
Donald E. Wilson, M.D. Vice President for Medical Affairs Dean, School of Medicine University of Maryland, Baltimore Baltimore, Maryland 21210-1559
Rebecca S. Eisenberg, J.D. Professor of Law University of Michigan Law School Ann Arbor, Michigan 48109-1215
Charles K. Francis, M.D. President Department of Medicine Charles R. Drew University of Medicine and Science Los Angeles, California 90059
Executive Secretary Yvonne Maddox, Ph.D. Acting Deputy Director National Institutes of Health Bethesda, Maryland 20892
Eric S. Lander, Ph.D. Member, Whitehead Institute for Biomedical Research Professor of Biology Massachusetts Institute of Technology (MIT) Director, Whitehead Institute/MIT Center for Genome Research Cambridge, Massachusetts 02139-1561