Report from the Working Group on Biomedical Computing
Research Tools: Guidelines and Update
Report on Meeting of Council of Public Representatives
NIH Graduate Program
Report from the Office for Protection from Research Risks Working Group
Report from the Office of Medical Applications of Research Working Group
Report from the Stem Cell Working Group
Summary and Conclusions
Table of Acronyms
The 78th meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on June 3, 1999. Dr. Harold Varmus, Director, NIH, informed the ACD members of two new important activities at NIH involving priority setting and the evaluation of the NIH performance required by the Government Performance and Results Act (GPRA). Dr. Varmus also reviewed: recent changes in membership on the Committee, as well as changes in personnel at NIH; several developments affecting the Human Genome Project; issues involving the Intramural Program; progress toward the development of a clinical trials database; and several recent efforts to support clinical research and research training.
In addition, Dr. Varmus reported on several new developments, including: a new initiative in the area of malaria research, called "Roll Back Malaria," under the director of the World Health Organization (WHO); electronic publishing, which would allow free access to scientific literature through the Internet; consideration of how the award of new prizes might stimulate specific research activities; and the reorganization of study sections.
Dr. Varmus reviewed recent interactions between NIH and Congress, particularly concerning the NIH budget for fiscal years 1999, 2000, and 2001 appropriations. He outlined plans for exercising the Director's one percent transfer authority to fund two projects during the current fiscal year (FY). Of concern to the NIH FY 2000 appropriation is the fact that the spending caps imposed by the Balanced Budget Act of 1997, if strictly enforced, could reduce the NIH appropriation by more than $1 billion below the FY 1999 appropriation.
Dr. David Botstein of Stanford University, who, along with Dr. Larry Smarr of the University of Illinois co-chaired an ACD working group on biomedical computing, reported that its key recommendation is the establishment of a National Program of Excellence in Biomedical Computing so as to support biomedical computational research and training, build a program devoted to database development and coordination, develop an initiative in biomedical applications of computer sciences based on individual (R01) grants and supplements, and develop a system of local "clusters" consisting of several biocomputing research groups at neighboring institutions.
Dr. Maria Freire, Director of the NIH Office of Technology Transfer, described the draft guidelines to be used by investigators who develop research tools. These guidelines specify how such tools could be shared and how research materials could be more freely exchanged to further the broad interests of the research community.
Ms. Anne Thomas, Associate Director for Communications, summarized the process for selecting the 20 individuals to serve as members of the new Council of Public Representatives (COPR), which held its first meeting in April 1999. Although only 20 applicants were appointed to serve as members of COPR, approximately 200 other applicants have agreed to become COPR associates, a broader group that will also participate in similar community-related activities and will serve as a resource to individual institutes within NIH. Some of the agenda items that COPR may consider at future meetings include: NIH interactions with other agencies; research in complementary and alternative medicine; measurements of burdens of disease; and the funding and ethical issues involved in conducting research outside the U.S.
Dr. Michael Gottesman, Deputy Director for Intramural Research, presented a revised prospectus for a graduate education program at NIH. Plans include the creation of a disease-oriented integrated biology program, with emphasis on bioinformatics, genomics, and clinical research. Classes would mimic the standard graduate study with advanced degree completion expected in five years. In the beginning, the class size would be limited to 15 students per year, rising to a steady-state total of about 75 students in the program after five years. As occurred during the December 1998 ACD meeting, the proposal prompted a lively and prolonged discussion. It was agreed that the ACD will resume consideration of a refined curriculum and other changes to the proposal at the committee's next meeting in December.
Ms. Nancy Dubler, who directs the Division of Bioethics at the Montefiore Medical Center, and Ms. Renée Landers, formerly an assistant general counsel in the Department of Health and Human Services (DHHS), co-chaired a working group that reviewed the authority, resources, and bureaucratic positioning of the Office for Protection from Research Risks (OPRR). The working group recommended that OPRR be administratively relocated from its current location at NIH to the Department of Health and Human Services and that other steps be taken to ensure that it is seen as an independent entity with adequate resources, stature, and oversight.
ACD member Dr. Ezra Davidson of King/Drew Medical Center and Dr. Alan Leshner, director of the National Institute on Drug Abuse, summarized the findings of a working group that reviewed the goals and outcomes of consensus conferences held by the NIH Office of Medical Applications of Research (OMAR). The working group developed recommendations for refining the selection of topics for such conferences and adopting a more deliberative process.
In addition, Dr. Varmus established a working group to develop guidelines and an oversight mechanism in regard to the use of human pluripotent stem cells. ACD members, Dr. Shirley Tilghman of Princeton University and Dr. Ezra Davidson, co-chair the working group. The guidelines are intended not only to provide advice to researchers but also to assure the public that this research is subject to thoughtful oversight. (Note: At the time of the ACD meeting, the working group was preparing to submit final draft guidelines to NIH.)
Dr. Harold Varmus, Director of the National Institutes of Health (NIH), began the 78th meeting of the Advisory Committee to the Director (ACD) by welcoming new members of the ACD, including several who were unable to attend the June session. In addition, he introduced Mr. Phillip Williams, who served as an ad hoc member. Dr. Varmus thanked the ACD members, whose terms ended following the June meeting, for their service and contributions.
Dr. Varmus announced two new activities for the NIH for which he will be seeking help from members of the ACD. These activities will involve priority setting and the evaluation of the NIH performance required by the Government Performance and Results Act (GPRA). In response to GPRA, NIH has developed a strategic plan. A working group will be assembled that will include members of the ACD as well as members of the new Council of Public Representatives (COPR). The working group will be asked to: (1) evaluate how well NIH is meeting the terms of that plan; and (2) prepare a preliminary report to present to the ACD during its next meeting in December 1999. The second activity involves priority setting, which will be the subject of a budget retreat scheduled for June 1999. (Note: The budget retreat was held on June 17-18.) The retreat is a new concept of the budget planning process, as it represents an early effort to identify initiatives under development at the NIH institutes and centers for fiscal year 2001. During this two-day retreat, institute directors will share their proposals for program initiatives with senior administrative staff of NIH, five members of the ACD, and five members of COPR.
Dr. Varmus reviewed recent personnel changes at NIH, including the appointments of Dr. Gary Nabel from the University of Michigan to head the new NIH Vaccine Research Center and of Marc Smolonsky who was a senior policy analyst in the Department of Health and Human Services to be the NIH Associate Director for Legislative Policy and Analysis. Several searches are under way and include the positions of Director of the National Center for Complementary and Alternative Medicine and Director of the National Institute of Diabetes and Digestive and Kidney Diseases. In addition, the President of the Board of the Foundation of the NIH appointed Dr. Constance Battle to replace Ms. Ann Alexander as executive director of the Foundation.
Dr. Varmus presented a brief update on several issues discussed at the December 1998 ACD meeting:
Due to the acceleration in progress, leaders of the Human Genome Project expect to have a rough draft of the genomic sequence by 2001, with completion by 2003, well ahead of the former projected target date of 2005. The major contributors to this effort are coordinating their efforts through weekly conference calls and have strengthened their alliance with other groups in Germany, France, and Japan. In a related development, the SNPs (single nucleotide polymorphism) Consortium (TSC) has brought together ten pharmaceutical companies and the Wellcome Trust to direct a two-year program to generate 300,000 SNPs, of which about 150,000 will be mapped.
There have been a number of developments within the NIH Intramural Program (IP): (1) the Clinical Center opened a transplant unit, supported mainly by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) involving cooperation between NIH and the Department of Defense; (2) two members of the IP program, Dr. John Coffin and Dr. Robert Desimone, were elected to the National Academy of Sciences; and (3) progress in the construction of the Clinical Center was marked by the opening of the south entrance.
There have been several developments in the area of priority setting: (1) the first meeting, in April 1999, of the Council of Public Representatives (COPR); (2) follow-up Congressional hearings; and (3) publication of an article and accompanying editorial in a June issue of the New England Journal of Medicine (NEJM). (The article is an analysis done on NIH spending levels on numerous conditions and diseases as a function of various measures of the burden of disease. The authors of that article noted that there are numerous approaches to disease burden analysis, most of which are readily subject to distortion. The accompanying editorial, written by Dr. Varmus, points out that the correlation between disease burden and NIH spending is not perfect and is not intended to be as other important considerations necessarily come into play in setting spending priorities. NIH has planned a small workshop on this topic to be held at the end of June.)
Efforts at the National Library of Medicine to develop a comprehensive Clinical Trials Database are progressing, with a prototype search engine scheduled for testing during the summer of 1999. In addition, a successful conference on biomarkers was held at NIH in April, attracting 750 participants and reinforcing plans to develop biomarkers for more systematic and extensive use in clinical trials.
Several efforts are under way to support clinical research, according to Dr. Varmus. During this year, NIH will award 35 new institutional awards for the development of pedagogical programs to train clinical researchers at academic health centers. These awards will total approximately $7 million over five years. NIH expects to make about 80 awards for five-year mentored traineeships to individuals in clinical research, and another 80 five-year awards to mid-career clinical investigators. In addition, NIH is negotiating with the American Association of Health Plans to provide access to those who enroll in various health plans to participate in clinical trials.
Dr. Varmus also reviewed recent interactions between NIH and Congress concerning budget and appropriations. Because the FY 1999 appropriations bill provided NIH with $2 billion more (nearly a 15 percent increase) over the budget for the previous year, NIH was asked to provide Congress with additional information describing how the funds would be spent. In responding to these requests, NIH developed a series of pie charts that were very effective in describing to Congress how the additional funds would be used.
As part of each budget cycle, Dr. Varmus may exercise a one percent transfer authority, moving funds between institutes to fine tune priorities. As part of this process for the FY 1999 budget, $15 million was transferred to the National Human Genome Research Institute (NHGRI) and $6 million was reallocated within NHGRI to support the mouse genome project with new grants and the development of new sequencing centers. In addition, NIH allocated $18 million to upgrade synchrotron facilities at Brookhaven National Laboratory and Stanford University. These facilities are operated by the Department of Energy for use by biomedical researchers. The transfer authority decisions were reviewed by a panel, consisting of mainly outside consultants, for concurrence.
Due to a more generous budget and better paylines, another $10 million in discretionary funds is being allocated to a series of special projects rather than to Shannon Awards, which are normally used to benefit young investigators when budgets are tight.
Dr. Varmus reminded ACD members that President Clinton's FY 2000 budget requested a 2.1 percent increase for NIH over the FY 1999 budget. This increase will keep NIH more or less on track with the President's plan to increase the NIH budget by 50 percent by 2003. Meanwhile, advocacy groups and many members of Congress are seeking a faster increase for the NIH budget, with some of them calling to double the budget within five years. During presentations before Congressional appropriations committees and on the NIH Website, statements from Dr. Varmus and other information have emphasized key scientific achievements, including completion of the genomic sequence of Caenorhabditis elegans (or roundworm), determination of the three-dimensional structure of the transmembrane potassium channel, and structural descriptions of the interactions among envelope proteins of HIV and CD4 receptor proteins on host cells.
Of concern to NIH for the FY 2000 budget, is the fact that preliminary allocations to House and Senate Appropriations subcommittees under the 1997 Balanced Budget Act, if maintained, would lead to a reduction by about $10 billion below the FY 1999 spending levels for NIH. Because of these and other uncertainties, little can yet be said about the FY 2001 NIH budget, which is in a very early stage of planning and which will be sent to Congress in January 2000.
Dr. Varmus described the trans-NIH effort to bring a variety of genome projects and genetic initiatives studied by a number of different institutes into a central focus and allow interaction between institutes. Some examples of this effort are the mouse genome and the development of mouse genetic centers and zebra fish genetics and developments under the leadership of NIDDK. Early in 1999, NIH convened a research-planning workshop that focused on nonmammalian organisms, such as Xenopus, fruit fly, zebra fish, and 10 other organisms, including Aplysia. A non-mammalian coordinating group has been established to oversee these trans-NIH activities.
NIH continues efforts to strengthen international research and public health programs aimed at combatting malaria. Much of the public health effort comes under the World Health Organization's Roll Back Malaria initiative, while the basic research programs are being coordinated under the Multilateral Initiative. The latter, which was being administered under the Wellcome Trust in London, is being moved, at least temporarily, into the NIH Fogarty Center, which is under the direction of Dr. Gerald Keusch.
Dr. Varmus summarized an electronic scientific publishing proposal that he and Dr. David Lipman of the National Library of Medicine developed and recently posted on the NIH Director's Web Site. The proposal describes several key goals, including allowing free access through a single site to the world's scientific literature, enabling investigators to present their full findings in hypertext format, and establishing a flexible yet reliable electronics-based system that can adopt software and hardware innovations as they are developed.
This proposal has raised a number of issues among members of the scientific community and publishers, such as how costs will be met, how reviews will be conducted, and how to deal with international challenges. However, Dr. Varmus said that the proposal does not carry any intention of eliminating either reviews of submitted reports or existing journals. Implementation will not be immediate. He also said that NIH spends a great deal on publishing and disseminating scientific information because of its responsibility to ensure such information leads to development of effective medical interventions.
Because the proposal raises complex issues, the National Academy of Sciences (NAS) has included this topic for discussion as part of a workshop on electronic publishing scheduled in June, with additional workshops later in the summer or early fall. An update will likely be provided and more extensive discussion will take place at the December 1999 ACD meeting. In another development, Dr. Varmus participated in an NAS-sponsored workshop to address the value to research of sponsored prizes and contests. Although sponsorship of such prizes poses difficulties for NIH, advocacy groups may want to consider such activities, which, even on a modest scale, can stimulate interest and activity among well-defined communities of researchers. This matter will be brought before COPR at its meeting during the fall of 1999 and possibly before ACD during its December 1999 meeting.
Dr. Varmus reminded the committee of the A-110 attachment to an FY 1999 appropriations bill that would permit access, through the Federal Freedom of Information Act, to unpublished research findings. The Office of Management and Budget is reviewing some 8,000 comments on the provision, and an amendment is pending in Congress to delay its implementation.
The NIH Center for Scientific Review has convened a panel, chaired by Dr. Bruce Alberts of NAS, to reevaluate the organization of study sections and possibly to reshape scientific disciplines. A draft report from this panel is currently undergoing internal review. At some point, the ACD members will be asked to review the draft and there will be a discussion at the next ACD meeting. It is expected that the document will eventually be posted on the NIH Web Site for wider review and comment by the scientific community.
Report from the Working Group on Biomedical Computing
Dr. David Botstein of Stanford University and Dr. Larry Smarr of the University Illinois co-chaired a working group with diverse membership that reviewed the current role and future needs for using computers in biomedical science and the development of information technology (IT).
Dr. Botstein said that the working group reviewed its mandate and identified four principal issues to address: (1) the current infrastructure and developmental needs over a five-year period, (2) hardware and software along with high-end computing needs, (3) algorithm development, and (4) training needs. He also briefly described the diverse make-up of the committee and their scientific interests, including complex imagery analysis in structural biology, clinical sciences and clinical database development as well as surgical decision making, neurosciences, electronic handling of the scientific literature and research databases, modeling of scientific problems such as how the heart beats or how proteins fold, population genetics, and industry needs across a wide range of applications. Representatives from other Federal agencies and departments, including the National Science Foundation (NSF) and the Department of Energy (DOE) also participated in these deliberations.
Dr. Botstein said that the members of the working group agreed that, although many NIH-supported biomedical researchers will need access to high-end computers, the main responsibility for developing and building such facilities rightly belongs more to NSF and DOE than to NIH. Hence, the leadership from these Federal agencies will need to work out appropriate collaborative arrangements.
The key recommendation of the working group is for NIH to develop a substantial new training program to build a cohort of individuals with various levels of expertise in computing and in its biomedical applications. Dr. Botstein pointed out that the need for skilled individuals includes those who work at the support level as well as others who are faculty members in academic settings.
To meet these needs, the working group offers the following recommendations for NIH to consider:
i) create National Programs of Excellence to support research, tool development, the requisite infrastructure, and teaching programs needed for building computation skills in biomedical applications, with the understanding that many more traditionally trained biologists are also going to acquire these skills;
ii) build a program explicitly devoted to database development, coordination, and management, while making such tools universally accessible and "interoperable," meaning usable and interchangeable when going from one database to another;
iii) develop an initiative in biomedical applications of computer sciences based on competitive individual R01 grants and supplements to such grants, thereby encouraging software and related developments in individual laboratories; and
iv) explore a system for developing local "clusters," consisting of several biocomputing research groups at neighboring or regional institutions whose members share development and use of mid-scale computing devices, which are higher-powered than conventional systems but do not involve super computers.
Dr. Smarr said that the participation of biologists on the working group was highly valuable and that the consensus reached by its members corresponds closely to recommendations being developed by the President's Information Technology Advisory Committee. He also emphasized that improvements being made or that are being contemplated for this field will significantly influence the way science is done. He also predicted that increased reliance on information technology will lead this field to expand rapidly.
Dr. Marc Kirschner of Harvard University asked for a fuller description of how the committee envisions NIH stimulating information technology developments through training. In particular, he asked whether the main impact would involve training computer scientists or biologists. In response, Dr. Botstein said that training should be directed to members of both groups, with an emphasis on undergraduate and graduate students interested in computer-intensive areas of biology. In addition, R01 grants should be used not only to fund innovative research on bioinformatics projects but also to build IT infrastructure and to support the hiring of appropriate personnel, including systems managers and programmers.
Dr. David Lipman from NLM pointed out that there is a scaling problem to be faced in developing IT training programs and centers of excellence. Dr. Eric Kandel of Columbia University suggested that undergraduate students from physics departments might help to fill this pipeline.
In response, Dr. Botstein said that there is a serious scarcity of such students. Dr. Smarr said that, for this field to benefit biology fully, it needs centers where physicists and other IT specialists can come together with biologists who are seeking their expertise. Dr. Botstein agreed, noting that young people with IT expertise and knowledge about biology are difficult to retain in academic positions because they receive higher pay and greater opportunities in industry and other settings.
Dr. Philip Needleman of Monsanto said that fostering this discipline at academic institutions will entail instituting appropriate peer review at NIH and elsewhere as well as enlightened tenure criteria at universities. Many IT efforts do not follow the traditional hypothesis-driven model for doing science. In response, Dr. Botstein said that engineering departments come closest to providing an appropriate model for academic IT careers.
In response to Dr. Shirley Tilghman from Princeton University, who requested clarification on the committee's second recommendation, Dr. Botstein described some of the typical difficulties faced in handling biological databases. Those difficulties include inconsistent nomenclature when describing similar genes or proteins in different species, fuzziness in distinguishing between process and function for particular molecular entities such as proteins, and descriptive problems arising because of the multifunctionality of some of those molecules. Another problem, based on database searching experience, is that Medline searches based on gene names prove more efficient and comprehensive than do searches based on other means that supposedly are more specific.
Dr. Shankar Subramaniam from the University of Illinois, a member of the working group, said that an interdisciplinary approach is key to addressing IT challenges. Biological databases are organized around unorganized data sets; once compiled, a great deal of complex computational effort may be needed for fully analyzing those data. In addition, he said that biologists are accustomed to dealing with information in a piecemeal fashion, much like chemists were before they had organizational tools such as the periodic table.
Mr. Arthur Ullian, from the National Council on Spinal Cord Injury, said that the demands biologists are making on the computer industry represent a means for pushing the general economy forward. Mr. Phillip Williams, of the Times Mirror Company, said that the existence of two time frames makes it necessary for bold and radical action to meet the IT challenge. Because of long-range needs, he said that specialized training will also be needed earlier during elementary and secondary education as well as at the community college level. Dr. Botstein agreed, saying that computer literacy and interests in biology should be actively fostered among young children. He also said that curricula at universities should be adjusted — for instance, to emphasize statistics rather than calculus for biologists.
Dr. Eric Lander, of the Massachusetts Institute of Technology, praised the general recommendations in the committee report but said that the central recommendation for training could prove challenging to implement. In addition, establishing IT Centers of Excellence to foster both research and training may require unconventional arrangements, such as building centers that actually are networks linking several institutions to reach the critical mass of people needed to carry out such activities. Another critical need is to develop new curricula.
Dr. Varmus said that NIH will need to decide whether a single institute or many institutes will support such centers. He also noted that he favors the second of those two options, based in part on the recent experience of NIH establishing mouse genetics research centers. In any case, implementing the recommendations in the IT committee report will entail trans-institute coordination.
In response to a comment from Dr. Smarr about NSF experience forging alliances between computer experts and other scientific disciplines, Dr. Varmus said that he will be discussing such matters with NSF Director Rita Colwell, who is a biologist and also has major responsibility for the Federal IT initiative.
Dr. Kirschner said that universities will likely continue to distinguish between individuals doing IT support work and those doing tenure-track work in this area. In response, Dr. Botstein said that NIH reviewers will be capable of making such distinctions but that both kinds of efforts will need NIH support. Dr. Kirschner also said that designing the recommended NIH-sponsored training program will be difficult because one of its principal goals is to build a cadre of individuals who are knowledgeable about computers and biology, but the outcome of this effort could be different if the mechanism involves training grants rather than R01 research grants.
Dr. Mark Ellisman, who is the coordinator for a cross-disciplinary supercomputer center at the University of California, San Diego, said that funding incentives will bring together computer specialists and biologists to build interdisciplinary teams at other institutions, thereby overcoming some of the traditional discipline-based barriers between such specialists. He also said that, if NIH channels resources through disease-oriented institutes, the outcomes are likely to be less generalizable. In response, Dr. Smarr noted that NIH should take a portfolio approach to foster very broad-based IT developments, with some of that portfolio including collaborations with NSF and DOE.
Dr. William Brody, of Johns Hopkins University, said that computer science differs fundamentally from other engineering disciplines, making it more difficult for biologists to collaborate with computer science faculty members, who tend to see biology problems as representing uninteresting challenges within that discipline. Dr. Botstein agreed, noting that IT-based research on biological problems often is not viewed as appropriate for issuing graduate degrees in computer science. Dr. Elaine Fuchs, of the University of Chicago, said that NIH investment in this area can make a difference. However, over the short-term, universities are not well situated to respond quickly to a mandate for non-traditional interdisciplinary training and research programs. Hence, she suggested that NIH serve as an initial, model center to offer such training. She also said that the overall training program should provide means for established investigators to develop IT skills during sabbatical-length or shorter-term stints. Both Dr. Varmus and Dr. Botstein agreed that new resources such as grants supporting research in this area can provide a powerful incentive for universities to develop new interdisciplinary programs of their own.
Dr. Hamilton Smith, of Johns Hopkins University, endorsed the report and said that because huge volumes of data are being generated throughout biology, the need for training of scientists with sophisticated IT capabilities will be essential for the biomedical sciences in the near future.
Research Tools: Guidelines and Update
In 1998, Ms. Rebecca Eisenberg , of the University of Michigan and a member of the ACD, presented a report from the ACD Working Group on Research Tools. It recommended that NIH establish guidelines for investigators who develop such tools, indicating how tools could be shared, and materials exchanged, to further the broad interests of the research community. Dr. Maria Freire, Director of the NIH Office of Technology Transfer, led a group whose members drafted such a guidelines document.
Dr. Freire said that she and her colleagues have worked closely with representatives of universities, companies, and patient advocacy groups to draft a set of guidelines for the use of research tools. Two versions of these guidelines were published in a May 1999 Federal Register: one using precise legal terms, and the other using more simplified language. The guidelines are divided into two parts: (1) outlines of four principles of highest concern to NIH, and (2) sample terms of agreement that universities and other grantees may use to develop research tools agreements of their own.
Dr. Freire described the four basic principles that are outlined in the draft guidelines: (1) ensure academic freedom and publication, with a 30–60 day limit on publication considered reasonable; (2) ensure appropriate implementation of the Bayh-Dole Act, which mandates the use, public access to, and commercialization of inventions developed with federal funds; (3) minimize administrative impediments to academic research and, ideally, use a generic one-page material transfer for this purpose; and (4) ensure dissemination of research resources developed with NIH funds and ensure that other sponsored agreements are consistent with these NIH basic rules and principles.
NIH is receiving thoughtful comments from technology university officials who handle technology transfer issues as well as from biotechnology and pharmaceutical industry representatives, according to Dr. Freire. The public comment period will end on August 23, 1999, and NIH expects to issue a final set of guidelines soon thereafter.
Dr. William Brody of Johns Hopkins University said that the patenting and licensing of inventions are separate activities, and that patenting a technology does not mean that it should be licensed. In response, Dr. Freire said that NIH does not encourage the practice of defensive patenting but favors rapid publication to prevent others from patenting a similar or the same technology. Thus, she encourages universities to patent strategically rather than defensively. She also said that how a patent is licensed can prove extremely important.
Dr. Varmus said that the guidelines will come to be better understood as they are implemented in specific situations. He promised to report back to ACD on how the guidelines are applied, particularly in cases of alleged abuse.
Dr. Freire called upon industry representatives to adopt similar guidelines, noting that it is a continuing challenge for university and industry researchers to exchange materials. Dr. Varmus added that the application of the guidelines to academic researchers who receive support from NIH and industry poses further uncertainties and also could further encourage defensive patenting and licensing practices.
Dr. Brody pointed out that industry is far from uniform in terms of the patenting strategies that its members follow, with a major distinction appearing in the goals being pursued by smaller start-up companies versus larger, well-established corporations. This difference often forces universities to choose whether to license on an exclusive or non-exclusive basis. He suggested that resolving such differing practices is a matter of Federal policy.
In response, Dr. Freire said that industry is even more complex than he described, noting that tool providers see things differently from tool users and also that other industries subscribe to very different practices. Dr. Varmus added that industry representatives from diverse sectors were involved in the development of the working group's report.
Report on Meeting of Council of Public Representatives
Ms. Anne Thomas, Associate Director for Communications, said that NIH chose 20 members from more than 250 applicants to serve on the new Council of Public Representatives (COPR). These members represent a diverse cross-section of interests, who pledged to set aside their professional and personal interests in favor of broad and global thinking in regard to the issues that NIH presents to them. COPR members are expected to help explain NIH policies to their constituencies, to act as a sounding board for NIH proposals under consideration, and to funnel views of the public into NIH.
COPR met for the first time on April 21, 1999. Among the highlights of that meeting were presentations by four institute directors about how they involve the public in their activities and by other NIH officials on topics such as barriers to clinical trials, clinical trials databases, and disparities in health care. COPR members will be participating in a variety of other NIH activities, including the budget retreat (scheduled to be held in June 1999), performance reviews, and deliberations of the peer review oversight group.
Although only 20 applicants were appointed to COPR, at least another 200 of the other applicants have agreed to belong to COPR Associates, a broader group of individuals who will participate, to some extent, in similar community-related activities and as a resource to individual institutes within NIH. For example, three members of the associates group have agreed to participate in a July workshop on human genetic diversity being sponsored by the National Institute of General Medical Sciences.
Ms. Thomas reported that electronic means are being developed to facilitate communications among COPR members and associates. In addition, NIH launched a Web page called "Public Liaison" that is aimed at making NIH more accessible to members of the general public.
Ms. Thomas said that COPR is building its agenda, adding topics such as NIH interactions with other agencies, protection of patients involved in research, research in complementary and alternative medicine, burdens of disease measurements, and the funding and ethical issues involved in conducting research outside the U.S.
Dr. Eric Kandel of Columbia University praised the COPR program and recommended that its members be encouraged to disseminate information about NIH to the members of their respective communities. He also suggested that knowledgeable representatives of advocacy groups be invited to make presentations at COPR meetings. Dr. Varmus noted that advocacy groups might also establish prizes to stimulate such activities and suggested that this topic be part of the agenda at the next COPR meeting.
In response to a question from Dr. Victor Dzau of Brigham and Women's Hospital, Ms. Thomas said that initial term of membership on COPR is for one year, but many members of this first group will have their terms extended to develop a system of three-year terms, with an annual turn-over of one-third of the membership. She said that COPR members and associates are supplying many suggestions for future agenda items. Dr. Varmus added that he chairs COPR meetings and decides on the agenda, keeping in mind the concerns expressed by COPR members and the potential for overlap between COPR and the ACD. Some issues will be appropriate for consideration by both groups, whereas others will not. From time to time, because some overlap will be useful, some members of each group will be invited to attend the other group's meeting.
In response to a question from Dr. Ting-Kai Li of Indiana University School of Medicine, Dr. Varmus said that information about the COPR associates will be made available to ACD members who may want to seek them out on a regional basis. Dr. Varmus suggested that this information be made available electronically through a list-serve mechanism, provided that the individual associates agree to such information being made public.
Mr. Arthur Ullian from the National Council on Spinal Cord Injury suggested that COPR members be presented with readily accessible news of breakthrough research. In response, Ms. Thomas said that there are plans for giving COPR members a tour of NIH and taking other steps to familiarize them with NIH research activities.
Dr. Marc Kirschner of Harvard University asked about the expectations of the COPR members. For instance, do they see themselves as helping to make policy or of merely communicating more effectively with their respective constituencies? Will they become frustrated if their expectations are not met? In response, Ms. Thomas said that there seems to be a mix of expectations, but she anticipates that COPR members will have a substantial impact on NIH. At this stage, most of them are very engaged and enthusiastic with the council's prospects. Dr. Varmus added that, in specific terms, they are engaged in many of the same tasks as are ACD members, including the GPRA review, the budget retreat, and reviews of institute directors.
NIH Graduate Program
Dr. Michael Gottesman, Deputy Director for Intramural Research, presented a revised prospectus for a graduate program at NIH and additional information to address some of the questions raised during the December 1998 ACD meeting as part of a broader discussion of NIH education programs. He noted that proposals for such a graduate program have come up earlier at NIH, including 25 years ago when Dr. Dewitt Stetten Jr. was serving as Deputy Director for Intramural Research. Six years ago an ACD external advisory committee, which was co-chaired by Dr. Paul Marks of Memorial Sloan Kettering in New York and Dr. Gail Cassell, then of the University of Alabama in Birmingham, reviewed the NIH Intramural Program (IP) and agreed that a graduate program at NIH could be considered once the committee's recommendations were implemented.
Dr. Gottesman said that there now are 145 graduate students at NIH, representing 44 universities. NIH has formal agreements with four of those universities, allowing it a bigger role in selecting the students who do their research on the campus while receiving their graduate degrees from their respective universities. Altogether, some 700 graduate-level researchers are at work on the NIH campus, many of them engaged in research as they consider their next career moves either into graduate or medical education programs.
With many of the reforms recommended in the Marks-Cassell report now in place, NIH officials began early in 1998 to discuss what would be required to build a graduate program. These discussions led to formation of a working group consisting of 20 NIH scientists. It met regularly to develop concepts and to outline a model curriculum. Moreover, some 100 principal investigators recruited to work at NIH over the past five years have said they are enthusiastic at the prospect of having a graduate education program and of interacting with students. In addition, NIH consulted, among others, Roger Chalkley from Vanderbilt University and John Perkins from the University of Texas Southwestern Medical Center, who are graduate deans at their respective institutions. These discussions led to a campus-wide "town meeting" in May 1999 during which more than 500 members of the NIH staff, representing diverse interests, responded to the draft proposal.
Dr. Gottesman outlined several reasons why NIH should sponsor a graduate program, including: (1) there are unmet graduate education needs in the U.S., such as in bioinformatics, clinical research, and genomics, in which fields NIH has particular strengths and could usefully contribute; (2) NIH has a talented research staff, many of whom are eager to develop and participate in a graduate education program; (3) the presence of graduate students would enliven the atmosphere and bring many intellectual benefits to NIH; and (4) NIH is well situated to recruit graduate students from diverse backgrounds and its scientists could provide quality mentoring and serve as role models.
At this stage, plans call for creating a curriculum emphasizing a highly rigorous, disease-oriented, integrated biology program, with specialties in bioinformatics, genomics, and clinical research and with small-group tutorials as well as class work, followed by thesis research, all to be completed within five years. At the start, the class size will be set at 15 students per year, rising to a steady-state total of about 75 students in the program.
Students will begin with courses in the biology of complex systems, bioinformatics, genomics, and molecular imaging, with tutorials that expose them to examples of bench-to-bedside clinical research. In addition, students will do research rotations before choosing a laboratory in which to conduct their thesis research, which will begin during the second year. Although formal classes would not be required after the first year, a variety of specific disease-oriented tutorials would continue through the second year while other elective courses would also remain available for students throughout their studies at NIH. Future plans also call for a social and academic center as well as residential facilities for students in the program.
Dr. Gottesman noted that NIH has experience establishing and running highly mentored graduate and undergraduate programs, with four such programs under way: (1) the Howard Hughes Medical Institute NIH Scholars Program, now in its 13th year, providing laboratory research experiences to medical students; (2) the new Clinical Research Training Program that brings third-year medical students to NIH to do clinical research; (3) the Undergraduate Scholarship Program, now in its third year, that brings disadvantaged students to NIH during summers for lab experiences; and (4) a Bioengineering Summer Program, beginning in 1999, for undergraduate students pursuing this specialty.
In addition to these on-going programs, the intramural researchers have developed a training and mentoring set of guidelines that is now used widely outside NIH. Several programs have established solid track records and also attract high numbers of underrepresented minority group members.
In terms of implementing this program, NIH faces several critical steps:
(1)writing a plan, including a detailed proposal to be reviewed by outside experts; (2) securing support for the plan from the Department of Health and Human Services as well as obtaining legislative authority for a degree-granting program from the Congress; (3) recruiting a dean and administrative staff to oversee the program; (4) obtaining accreditation for it; and (5) developing a budget to pay for the program. Dr. Gottesman noted that $150 million of the annual $1.6 billion in the IP budget supports overall training efforts. At the steady state, the graduate program operating budget would be below $3 million, representing a modest fraction of the overall training budget within the IP.
Dr. Eric Kandel praised the revised proposal, saying that it brings a unique capability to national graduate education needs in fields such as bioinformatics and clinical investigation. He also said that recent improvements in the NIH Intramural Program draw attention to the additional value that a graduate program would bring to it. In addition, he noted that the initial low numbers of students who would enroll in the program address concerns about adding to the overall volume of Ph.D.s being produced throughout the country.
Dr. Philip Needleman agreed with Dr. Kandel, but said that the proposed program would likely have problems with focus because of the large size of the IP research staff and would also compete with graduate education programs at neighboring institutions. In response, Dr. Gottesman said that the main graduate faculty would likely consist of about 100 individuals within the IP from appropriate specialty areas, and that their commitment to this program would ensure its focus.
Dr. Elaine Fuchs agreed with Dr. Kandel about the importance of emphasizing bioinformatics, genomics, and clinical translational research. She said that to develop the curricula in these specialty areas, as well as the detailed plans to advise students who come to NIH to work in these specialties, will entail a great deal more in the way of time commitments than anticipated. Dr. Gottesman agreed, noting that the descriptions of the proposed curricula are at an early stage of development.
Dr. Shirley Tilghman said that, although there is a national need for increased training of researchers in bioinformatics and clinical investigations, NIH should consider options other than establishing a graduate education program to meet those needs. She said that NIH should, instead, consider providing such specialized training to the hundreds of graduate- and postdoctoral-level researchers who now work on the campus in the IP. In other words, NIH could help to meet those specialized training needs without instituting its own degree-granting program.
In response, Dr. Varmus noted that many of the graduate-level students at NIH are pursuing full programs, many of them as medical students and others as graduate students who have met course requirements of their sponsoring institutions.
Dr. Gottesman added that NIH does provide lecture series and course work for these graduate-level students, but the current arrangement is not as highly structured as it would be in a formal, degree-granting program.
Dr. Tilghman said that some of the goals outlined in the proposal could be achieved without establishing a formal program and adding new students but, instead, retraining students and postdoctoral fellows who are already present at NIH. Later, she challenged NIH to develop ways of enriching its informal programs that train graduate-level students who already are present at NIH. She also expressed skepticism that the addition of a small, formal graduate program would invigorate the atmosphere at NIH.
Dr. Varmus responded that the proposed graduate education program would not depend so much on recruiting outside students as on providing a formal degree-granting program to graduate-level students who already spend time at NIH.
Dr. Kandel said that, although there is wide agreement about the risk in training too many graduate students, concerns about creating additional surpluses do not apply to the specialized areas, such as bioinformatics and clinical research which the contemplated NIH program will be targeting. Those areas represent unmet national needs. Moreover, the small numbers of graduate students who will be trained at NIH will not significantly change the overall numbers of Ph.D.s being produced.
Later, Dr. Tilghman pointed out that the main problem is not the actual numbers of graduate students in the proposed program; instead, the problem arises from the symbolism of NIH establishing a new program that is not all that different from those offered at other such institutions, which now are producing an excess of Ph.D.s. However, she also voiced enthusiasm if NIH were to develop a genuinely innovative Ph.D. program in bioinformatics.
Mr. Phillip Williams said that it is an important positive symbol for NIH to move to fill a national need, such as for expanded training in clinical research and bioinformatics.
In recalling the research training he received at NIH early during his career, Dr. Kandel said that he would have been better off if lectures and courses on campus had been structured as a formal program. He pointed out that students greatly benefitted when Rockefeller University established formal graduate degree-granting programs and noted that this transition served its first groups of students particularly well.
In response to a question from Dr. Victor Dzau about the need to train more M.D.s rather than Ph.D.s to do clinical research, Dr. Gottesman said that some of the medical students at NIH would like to complete Ph.D.s as well. He said that there is also a need for Ph.D.s to contribute to clinical research, such as by designing protocols, seeing proposals, doing reviews, and conducting laboratory analyses, without being able to care directly for patients at the bedside. Thus, a component of the proposed NIH graduate program might entail qualifying for a certificate in clinical research.
Dr. Marc Kirschner said that, although he has both practical and philosophical qualms about the proposal, its implementation would benefit the NIH intramural program. His qualms include: (1) concern that creating a new graduate program accentuates a broader problem having to do with trainees conducting the bulk of research work; (2) doubt as to whether any program can train people in specialties such as bioinformatics without first providing them with an extensive background in conventional disciplines, such as biochemistry and genetics; and (3) concern that NIH no longer supports programs, such as a program at Harvard, that exposes upper-level graduate students to an additional year of course work in clinically-oriented disciplines. He pointed out that NIH might better serve the national training need by supplementing established programs than by establishing a new one.
In response, Dr. Varmus noted that curriculum development efforts for the NIH program are at an early stage and that core, discipline-oriented teaching needs can, and will be, met. He also said that IP initiatives should not be held up because of what may happen to similar programs at extramural institutions following critical reviews of them. Dr. Kandel said that an important duty of ACD members is to set aside their parochial interests when reviewing proposals, such as the one to establish a training program that could strengthen the NIH intramural program. He suggested that the program be subject to periodic review to ensure that it continues to meet timely training needs.
Dr. Kirschner said, and Dr. Tilghman agreed, that the more fundamental question is whether to enrich existing graduate education programs at universities versus establishing a new one at NIH. Dr. Christine Cassel asked whether establishing a graduate education program would significantly change the culture at NIH and, if so, would the benefits outweigh the downside risks. In response, Dr. Gottesman said that the proposed IP program would have a positive impact on the culture at NIH. The proposed program is not intended to compete with extramural graduate programs but, instead, to optimize the resources at NIH and to pilot ideas for graduate training in areas of special national need. He also said that the addition of 15 Ph.D.s to the total national pool of 5,700 Ph.D.s per year will not have a practical or detrimental effect on pool size.
Dr. Jane Menken asked how NIH could build flexibility into its program, noting that needs for researchers with specialized training tend to shift. In response, Dr. Gottesman said that the graduate program could be flexible but would be limited by the overall range of expertise represented by the NIH scientific faculty. Dr. Kandel said that the future flexibility of the NIH training program will be a measure of the scientific leadership in the intramural program. He also said that advances in certain fields, such as psychiatry and neurosciences, will depend primarily on Ph.D.s rather than on M.D.s doing research.
Dr. Larry Smarr said that, in light of the national need for training researchers in bioinformatics, NIH represents a unique national resource to provide critical leverage to eventually build a nationwide effort in this area. Thus, the NIH graduate program with an emphasis on bioinformatics could provide a starting point for a national program.
Dr. Elaine Fuchs agreed, saying that starting with a graduate education program that is too broad would be mistake. Instead, the proposed NIH program should focus narrowly on training in bioinformatics and clinical research. As the programs develop and prove successful, NIH could consider expanding into other areas of training need.
Dr. Varmus asked if the committee members felt that the proposed program might adversely affect NIH or pose a threat to extramural institutions. He said that, if the proposal is widely deemed to be an inappropriate activity for NIH, then seeking authorization for it from Congress would not be beneficial. Dr. Varmus later requested a "straw vote" of whether ACD members wanted to drop the proposal or, instead, to refine the proposed curriculum for the graduate training program and take other steps to resume discussion of the proposal at a later meeting. A majority of ACD members agreed to further discussion of the proposal at the next ACD meeting in December 1999.
Further discussion will be held with several ACD members before the December meeting in an effort to modify the proposal and to seek a consensus in regard to this proposed program. In addition, Dr. Kandel later recommended that a subcommittee of ACD be established to further develop this proposal, which he considers to be a good one. He said that the more general issue of graduate education and non-conventional research career paths also should be addressed, a suggestion with which Dr. Marc Kirschner agreed. Along similar lines, Dr. Elaine Fuchs recommended that NIH enhance training and mentoring for post-doctoral fellows on campus.
In response, Dr. Varmus noted that several issues, such as careers of researchers who do not become independent investigators and the general treatment of post-doctoral fellows, should also be discussed. Another matter for consideration is the use of senior scientists rather than trainees in projects that involve technology development instead of hypothesis-driven research.
Report from the Office for Protection from Research Risks Working Group
Dr. Varmus noted that because questions have been raised regarding the oversight role of the NIH Office for Protection from Research Risks (OPRR), a working group was established to review the administrative placement of OPRR within NIH and to recommend changes that might be appropriate.
Ms. Nancy Dubler, who directs the Division of Bioethics at the Montefiore Medical Center, acknowledged committee and staff members who helped produce the working group report. The group's mandate included: (1) ensuring that OPRR is located appropriately within the Department of Health and Human Services to fulfill its mission, and (2) advising whether OPRR should be delegated additional authority to accomplish its mission.
Much of the working group's review was carried out in the context of research involving human subjects, an area of research that has accelerated rapidly over the past several decades and that has, in turn, stimulated extensive discussions about ethical conduct. OPRR also shares responsibilities with officials in the U.S. Department of Agriculture (USDA) for ensuring the humane care of animals being used in research.
Ms. Dubler said that, amid these expanding research activities, OPRR plays a critical role in helping to protect the rights of human subjects. However, because OPRR oversees activities sponsored by NIH while also being located within NIH, this dual role contributes to public distrust and to a perception that OPRR may favor researchers over its other duties.
Ms. Dubler outlined several additional areas in which OPRR plays an important role, which includes helping to provide a balance between providing individuals with opportunities to participate in clinical research protocols and protecting certain types of individuals from participating in ways that might be detrimental to them. For instance, the young or the mentally ill may need such protection, but their exclusion from research may also reduce the likelihood that they benefit from its eventual outcomes.
Ms. Dubler pointed out that OPRR does not have jurisdiction over privately funded research activities and that conflicts can arise over whether the Federal or state and local governments have lead jurisdiction over various research activities. Members of the working group urged that OPRR exert leadership to prevent balkanization of regulations and guidelines affecting such research.
The working group provided several specific recommendations. The first and foremost is that OPRR be administratively relocated from its current location at NIH to ensure that it is seen as an independent entity, according to Ms. Dubner. Hence, moving OPRR outside NIH will help to overcome four difficulties: (1) perceived conflicts of interest, as well as a widely held view that OPRR favors researchers over research subjects; (2) OPRR is perceived as remote and unresponsive to complaints rather than engaged in and leading a robust dialogue; (3) because it lies within NIH, OPRR does not appear to represent the Secretary of Health and Human Services and thus is compromised in its dealings with other agencies and departments within the Federal government; and (4) oversight of OPRR is compromised by being located within NIH.
However, because removing OPRR from NIH could also generate certain problems, efforts are needed to maintain OPRR's continued understanding of the research enterprise, to provide sufficient resources for it to fulfill its mission, and to insulate OPRR from inappropriate political influences.
Working Group co-chair Ms. Renée Landers, of Ropes and Gray, outlined its remaining recommendations. The second recommendation is that OPRR be moved into the Department of Health and Human Services, where it would report either to the Surgeon General or the Assistant Secretary of Health. By moving outside NIH, OPRR will be better positioned to enhance its leadership role and to interact more freely with other Federal departments and agencies. Ms. Landers said that this relocation would also signal the importance of OPRR's overall activities to all the parties affected by its actions.
The third recommendation is that the OPRR director be a member of the Senior Executive Service and have national stature in the scientific, ethics, and legal communities, according to Ms. Landers. This change would also enhance OPRR's leadership capabilities.
The fourth recommendation is that the HHS Secretary establish an independent oversight or advisory committee to review OPRR performance and to help in setting its standards. The advisory committee should have a diverse membership, including scientists, ethicists, former research subjects, animal welfare experts, and members of the public. Such a committee could also guard OPRR against inappropriate political intrusions.
The fifth and final recommendation notes that, although the authority delegated to OPRR is adequate, the resources allocated to exercise that authority do not seem to be adequate and thus should be increased. Ms. Landers said that with increased resources and reinvigorated authority, OPRR can play a critical role enhancing the ethical consciousness of the national research community.
Dr. Varmus said that he and institute directors agree with the conclusions and recommendations of the working group report, and if endorsed by the ACD, would plan to send the Secretary of HHS a memorandum advising her of the report's recommendations. She, in turn, would need to settle administrative questions such as where to relocate OPRR, to what office it would report, and how to adjust its resources to meet its augmented mandate.
In response to a question from Dr. William Brody about the budget and scope of OPRR operations, its director Dr. Gary Ellis said that its annual budget is between $2 to $3 million and it has the equivalent of about 28 full-time employees.
Dr. Ezra Davidson praised the working group for its thoughtful report, noting that implementing its recommendations will benefit the research enterprise.
Dr. Varmus said that moving OPRR will resolve prevailing ambiguities about conflicts of interest and will enhance its ability to deal with other agencies.
Dr. Elaine Fuchs asked for more information regarding the working group's fourth recommendation, namely that an OPRR advisory committee be formed, in part, to insulate the office from undue political influences. In response, Ms. Landers said that OPRR decisions have been subject to NIH review. However, with a shift to HHS, there will be less filtering of its decisions and this change would likely promote more effective communication, particularly in the case of disagreements.
Ms. Dubler added that an advisory committee would also help to keep OPRR in close touch with the research community even after it is removed from NIH. Thus, NIH could be expected to play a continuing role in OPRR activities by partaking in the activities of this new advisory committee. The committee would also provide helpful advice to OPRR on complex ethical issues.
Dr. William Brody expressed concern that some of the conclusions embodied in the working group report could have profound effects. Part of his concern is that OPRR could become too independent and yet might have insufficient resources. In response, Dr. Varmus said that the new OPRR reporting responsibilities have not been set and that, in physical terms, its offices may remain on the NIH campus, close to a scientific base.
In response to a question from Dr. Ting-Kai Li about the relationship of OPRR and USDA over animals, Ms. Dubler said that this issue was not a major focus of the working group. Its members concluded that a better working relationship with USDA would develop if OPRR were to become more independent of NIH.
Dr. Brody asked whether thought was being given to enhancing the OPRR budget. Dr. Varmus said that the OPRR workload is heavy. Ms. Landers added that the working group did not attempt to assess the OPRR budget or to provide advice on how it could be optimized. However, the working group concluded that the budget would not be adequate for OPRR to expand its activities in areas such as training and public education. She also said that, although NIH might continue to fund OPRR, other options, such as assessing fees from other research agencies, should be considered.
Dr. Varmus said that he will send a memorandum conveying the report's recommendations to the Secretary of HHS.
Report from the Office of Medical Applications of Research Working Group
A working group was asked to review the NIH Office of Medical Applications of Research (OMAR), which runs consensus development conferences.
ACD member Dr. Ezra Davidson said that OMAR, which was established in 1978, is the focal point for health technology assessments within NIH by holding consensus development conferences and advising the clinical community about the status of specific new technologies arising from research. OMAR was last evaluated in 1994.
For the current evaluation, Dr. Varmus asked the working group to review the goals and outcomes of the consensus conferences held during the past five years, particularly in light of the changes occurring because of expanded research and also within the health care delivery system. To conduct this review, members of the working group met several times.
Dr. Alan Leshner, director of the National Institute on Drug Abuse, summarized the recommendations of the working group. Its members concluded that the consensus development conferences continue to serve important roles for the public and for health care providers, educating them about new developments and clarifying inconsistencies in medical practice. However, he said, selecting topics is a critical part of the process, with the general goal being to target the moment when the science behind a new technology is ready but practitioners have not yet adopted it. Sometimes a practice is adopted before the body of scientific evidence supporting it is evaluated, and such conferences can play an important role in dealing with such cases.
Dr. Leshner outlined the working group recommendations, including: (1) an advisory group with diverse expertise should be formed to help in choosing topics for consensus conferences; (2) topic selection should be a more formalized process; (3) there should be a process for systematically reviewing evidence; (4) the entire consensus development procedure should be made more deliberate, allowing ample time for full discussions and reviews; (5) the consensus development process need not adhere to a single model but should be kept flexible; (6) the conference and consensus development activities should be separated from the public release of conclusions to avoid any rush to judgment; and (7) efforts to disseminate information based on consensus development conferences should be broadened.
Dr. Leshner said that an idealized approach to consensus development has been incorporated into a schematic diagram, which outlines the range of interactions that go into this procedure.
Dr. Varmus said that, in general, the consensus development format has proved highly successful. For example, he pointed to new treatments of gastric ulcers based on an emerging understanding that a microorganism, Helicobacter pylori, can be their cause. However, this format cannot overcome scientific disputes over clinical issues that need further research before they can be resolved.
Dr. Christine Cassel praised the report, particularly its recommendation to slow the consensus process. She also noted that a more sophisticated understanding of what constitutes evidence for the purposes of consensus development is available, pointing to an international electronic network known as the Cochrane Collaboration and based in Oxford, England. Dr. Leshner said that an endorsement of this approach appears as part of the report.
Report from the Stem Cell Working Group
In November 1998, several research groups reported that they had generated human pluripotent stem cells from human fetal tissue and from human embryos that had been donated for research purposes from materials generated in private clinics as part of infertility treatments. Researchers in the private sector subsequently established cell lines for a broad range of follow-up studies, addressing whether such cells can be developed into replacement tissues and organs.
Dr. Varmus notes that several congressional committees have held hearings on this subject. Although a provision in the NIH appropriations bill stipulates that Federal funds may not be used for research that damages or destroys human embryos, HHS general counsel Harriet Rabb concluded that this provision does not prohibit use of Federal funds for research on stem cells derived from such materials. Meanwhile, President Clinton asked members of the National Bioethics Advisory Board (NBAC), which is headed by Princeton University president Harold Shapiro, to review the ethical issues surrounding such research.
Dr. Varmus emphasized that NIH and HHS have restricted their analysis to the legal implications of stem cell research, whereas the NBAC analysis focuses on its ethical implications. He noted that, although NIH sponsored an extensive review of embryo research in 1994, it has not funded research on human embryos. The 1994 NIH-sponsored report divided embryo research into three broad categories, including projects deemed appropriate for NIH support, projects that would be inappropriate, and those that should await further consideration. The report recommended that NIH funds be used for research on embryos donated for such purposes, including for studies intended to produce stem cells.
Soon after the 1994 report was made public, President Clinton issued an executive order stating that Federal funds could not be used for research involving the creation of embryos for such purposes. However, the administration endorsed research outside the ban, including on stem cells derived from embryos that were generated for other purposes. Subsequently, through an amendment to the NIH appropriations, Congress has expressly prohibited use of Federal funds for research on human embryos of any origin.
In an effort to deal with these complex issues, NIH established a working group, under the guidance of ACD members Dr. Tilghman and Dr. Davidson, to develop guidelines for researchers seeking Federal support to study human stem cells. These guidelines are intended not only to serve researchers but also to assure the public that this research is subject to thoughtful oversight.
Dr. Tilghman reported that the working group met in April 1999 and has a broad-based membership, including researchers such as developmental biologists, physicians, ethicists, lawyers, and religious leaders. (At the time of the ACD meetings, the working group was in the process of preparing its final draft guidelines and expected to submit them to Dr. Varmus within a matter of weeks.)
The principal mandate for the working group was to develop guidelines and an oversight mechanism for two areas of research: (1) the derivation and use of human pluripotent stems cells from fetal tissue; and (2) the use of pluripotent stem cells derived from embryos produced in excess of clinical needs. Dr. Tilghman noted that the charge was to decide how such research could be done in an ethically responsible manner, not whether it should be permitted or prohibited.
Before the April meeting of the working group, Drs. Tilghman and Davidson, along with NIH staff members, drafted preliminary guidelines for the purpose of discussion. Before the meeting, and for some time thereafter, members of the public were invited to comment on these issues.
During the meeting, the working group separated its discussion of stem cells derived from embryos from its consideration of stem cells derived from fetal tissues. The group also identified types of experiments with stem cells that should be considered ineligible for Federal funding (for example, reintroducing pluripotent stem cells into a human embryo). The working group also extensively discussed informed consent issues and how to provide additional oversight of grant proposals following their review for scientific merit.
Dr. Varmus said that the final draft from the working group will be published in the Federal Register for public comment and that, after further changes are made, will be presented to ACD members for their review sometime prior to the next ACD meeting scheduled for December 1999. Once the guidelines are approved, NIH will assemble an oversight panel to review research proposals in this area.
In response to a question from Dr. Marc Kirschner about the breadth of discussions over the development of stem cell guidelines, Dr. Davidson said that representatives from organizations advocating research on chronic diseases have expressed special interest in stem cell research because they envision important potential benefits from such studies. However, he added, interest in this research continues to grow in diverse directions. Dr. Varmus said that there is a distinction between the broader debate involving legal and ethical concerns over this research and the more narrowly defined guidelines developed by the NIH working group.
Dr. Elaine Fuchs asked for more information about what the working group identified as stem cell research that would not be eligible for Federal funding. In response, Dr. Tilghman said that such research would include use of human stem cells for human reproductive cloning, making human-animal chimeras, or for producing any other form of intact organism. However, uses for producing tissues or organs are viewed as appropriate.
NBAC executive director Dr. Eric Meslin said that the commission, which was to meet late in June, had not completed its report, a draft of which was available to the public. Dr. Varmus told the ACD members that the draft guidelines will be sent to them for their comments as soon as they are published in the Federal Register. (A final recommendation will be sought from the ACD at its next meeting in December 1999.)
Mr. Norman Francis, president of Xavier University of Louisiana, said that both short- and long-term strategies for training young investigators need to be considered, particularly as efforts are made to include underrepresented groups, such as women and minorities. For instance, there are relatively low numbers of women who have training in the area of computer science. He encouraged NIH to develop a graduate program to help to overcome such training gaps. He also said that the broader research and education system needs to be brought to bear on this challenge.
In response, Dr. Varmus referred to a report presented by Dr. Harold Slavkin, Director of the National Institute of Dental Research, during the June 1998 ACD meeting. The report summarizes efforts to enhance the diversity of the biomedical research community and encourage participation from the entire pool of available talent, particularly members of underrepresented minorities, by establishing an academy within the NIH Intramural Program. He said that efforts at NIH are likely to succeed because many minority students spend time at NIH and there is also a relatively high number of researchers from minority groups to serve as mentors and role models for those students. In addition, NIH investigators are planning clinical research intended to address health disparities among minority groups.
(NOTE: During the general discussion, ACD members returned to the subject of the proposed NIH graduate program; those comments are integrated into the discussion section under that heading.)
Summary and Conclusions
The Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) met on June 3, 1999, to consider: a recommendation from a working group for NIH to develop a substantial new training program in biocomputing; a proposal to develop a graduate training program at NIH; several sets of guidelines that are being developed, including the use of research tools and the use of stem cells in research; the results of the first meeting of the NIH Council of Public Representatives; and reports from working groups reviewing the Office for Protection from Research Risks (OPRR) and the Office of Medical Applications of Research.
The ACD acknowledged and commented on these reports, agreed through a "straw vote" to resume discussion of the graduate education program, and also agreed with recommendations to move OPRR from NIH to the Department of Health and Human Services (DHHS).
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Ruth L. Kirschstein, M.D. Executive Secretary Advisory Committee to the Director, NIH
Harold Varmus, M.D. Director, NIH
Table of Acronyms
ACD/Advisory Committee to the Director
AIDS/Acquired Immunodeficiency Syndrome
CDC/Centers for Disease Control and Prevention
COPR/Council of Public Representatives
CRC/Clinical Research Center
DHHS/U.S. Department of Health and Human Services
DOE/Department of Energy
ELSI/Educational, Legal, and Social Implications
ESTs/Expressed Sequence Tags
FDA/Food and Drug Administration
FOIA/Freedom of Information Act
GPRA/Government Performance and Results Act
HIV/Human Immunodeficiency Virus
HGDP/Human Genome Diversity Project
IOM/Institute of Medicine
NAS/National Academy of Sciences
NBAC/National Bioethics Advisory Committee
NCI/National Cancer Institute
NCBI/National Center for Biotechnology Information
NIAMS/National Institute of Arthritis and Musculoskeletal and Skin Diseases
NIDA/National Institute on Drug Abuse
NIDDK/National Institute of Diabetes and Digestive and Kidney Diseases
NIH/National Institutes of 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
OTT/Office of Technology Transfer
PITAC/President's Information Technology Advisory Committee