Issues Related to Clinical Trials and the Clinical Trials Database
Clinical Trials Database - Discussion
Clinical Biomarkers and Surrogate Endpoints in Clinical Trials - Discussion
Summary and Conclusions
Table of Acronyms
The 77th meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on December 3, 1998. NIH Director, Dr. Harold Varmus, began by summarizing several changes to bring more public advice to NIH, particularly the creation of the Council of Public Representatives (COPR). He also reviewed several personnel changes affecting NIH as well as other U.S. Public Health agencies.
Dr. Varmus described the impact of the fiscal year (FY) 1999 appropriations bill, which provides NIH with $2 billion more than the previous year (nearly a 15 percent increase over the FY 1998 budget), bringing the total to $15.6 billion for NIH programs in FY 1999. These changes will enable NIH to: provide a 3 percent increase for inflation to current grantees; to increase the average size of new grants by about 10 percent; and to approve as many as 9,200 new modular grants in FY 1999. The appropriations bill also includes $50 million to establish a National Center for Complementary and Alternative Medicine as well as additional funding to construct the Mark O. Hatfield Clinical Research Center.
Dr. Varmus described several other legislative matters affecting NIH, which include: the review of whether a current legislative ban on human embryo research also extends to pluripotent cell lines derived from embryos; and the requirement that all data produced under Federal awards be made available through the Freedom of Information Act. The NIH reauthorizing legislation and several other bills affecting NIH programs were still pending in Congress.
Dr. Maria Freire, Director of the NIH Office of Technology Transfer (OTT), reported that guidelines are being developed concerning access to research tools. She also said that NIH recently negotiated an umbrella agreement with Dupont Pharmaceuticals guaranteeing free exchange and use of the Cre-lox technology for basic research purposes.
Dr. Larry Smarr, co-chair of an ACD subcommittee reviewing the use of computers in biomedical science, said this group plans to assess biomedical needs from computers as a science-driven, rather than a technology-driven, challenge. In addition, he said that the President's Information Technology Advisory Committee recently issued an interim report calling for a major increase in funding across Federal agencies to support research and infrastructure development in the computer sciences.
Dr. Francis Collins, Director of the National Human Genome Research Institute (NHGRI), reported that representatives from NIH and the Department of Energy (DOE) recently developed a new five-year plan for the Federal Human Genome Project, which, in some phases, is more than two years ahead of schedule. Perhaps the boldest goal in the new plan is to determine the sequence of the human genome two years early, by the end of 2003. Moreover, an international peer review process has been established to evaluate requests to revise interim priorities, an effort to catalogue common variants in human DNA also was recently begun, and other genome projects are making fast progress.
Dr. Michael Gottesman, Deputy Director for Intramural Research, reviewed progress in improving the NIH Intramural Program (IP), whose internal review procedures have been made more stringent. He also described the role of the IP in training biomedical researchers and outlined a proposal to establish a small, specialized graduate level training program within IP.
Dr. Leon Rosenberg, Professor of Molecular Biology at Princeton University, presented a summary of a report on how NIH sets priorities. The report was prepared by a panel convened by the Institute of Medicine (IOM) and focuses on scientific opportunities and public needs. It provided several recommendations to NIH, including the development of a greater public outreach and the establishment of new mechanisms for obtaining advice from the public.
Ms. Anne Thomas, Associate Director for Communications, described several recent NIH responses to the recommendations outlined in the IOM panel report. For instance, NIH has established the Council of Public Representatives (COPR) as well as an Office of Public Liaison. In addition, public contact individuals are being designated not only in the Office of the Director but in each of the NIH Institutes and Centers.
Dr. Alexa McCray, Director of the Lister Hill National Center for Biomedical Communications at the National Library of Medicine, described NIH efforts to coordinate the full array of public and private clinical trials databases, as was mandated by the FDA Modernization Act of 1997. Dr. Lana Skirboll, Associate Director for Science Policy, described related efforts of NIH to work with regulatory officials and industry representatives on developing improved methods for identifying surrogate markers and other endpoints for clinical trials that will be very useful for improving the efficiency of preliminary evaluations of therapeutic products under development.
Dr. Harold Varmus, Director of the National Institutes of Health (NIH), began the 77th meeting of the Advisory Committee to the Director (ACD) by introducing several ad hoc members of the ACD. Dr. Varmus also noted that the ACD charter was recently amended to permit the appointment of at least three new public members to the committee.
The charter amendment affecting ACD membership reflects a broader change in the advisory area, namely, the creation of the Council of Public Representatives (COPR) to advise the NIH Director and to provide NIH with an improved means for interacting with the general public. The concept for COPR arose as a response to recommendations from a report from the Institute of Medicine (IOM). To develop this concept, NIH convened a meeting of representatives from a variety of interest groups on September 23, 1998, who helped devise a procedure for selecting members of COPR. Dr. Varmus asked ACD members to consider how best to apportion advisory responsibilities of their own committee, which is rich in technical expertise, and those of the new COPR, which represents broader public interests and advocacy groups.
Dr. Varmus reviewed personnel changes affecting several U.S. Public Health agencies as well as NIH. For example, Dr. Jane Henney, a former ACD member, was recently confirmed as the Commissioner of the Food and Drug Administration (FDA), and Dr. Jeffrey Koplan became the Director of the Centers for Disease Control and Prevention (CDC).
Meanwhile, at NIH, Dr. Gerald Keusch of Tufts University Medical School in Boston was recently appointed director of the Fogarty International Center; Dr. Howard Gadlin of the University of California, Los Angeles, was appointed director of the Center for Conflict Resolution and NIH ombudsman in this area. Other searches to fill administrative positions at NIH are under way. These searchers include the positions of director for: the new National Center for Complementary and Alternative Medicine; the Vaccine Research Lab; and the National Institute of Diabetes, Digestive, and Kidney Diseases, whose Director, Dr. Phillip Gorden, is retiring after more than 11 years in that position. Searches are also under way for directors of the NIH Offices of Legislation, Equal Opportunity, and the Intramural Office of Education.
Dr. Varmus pointed out that the recent Nobel prize in medicine honors three American investigators, Drs. Robert Furchgott, Louis Ignarro, and Ferid Murad, who received NIH support for many years. They participated in a White House reception during which President Clinton spoke about the promise of science for the world.
Dr. Varmus reviewed the fiscal year (FY) 1999 appropriations bill, which provides NIH with and increase of $2 billion (nearly a 15 percent increase) over the FY 1998 budget, bringing the total to $15.6 billion for NIH programs in FY 1999. These budget increases are helping to enhance NIH investments in four broad areas--harnessing genomic information; reinvigorating clinical research; engaging other disciplines such as physics, math, and informatics; and addressing health disparities in particular population groups through research.
The recent budget increases will enable NIH to provide a 3 percent increase for inflation to current grantees and to increase the average size of new grants by about 10 percent. Moreover, there will be as many as 9,200 new grants in FY 1999, a significant increase over the 8,000 new grants in FY 1998 and a very substantial gain over the expected level of 6,000 or fewer new grants that was under discussion only a few years ago. Meanwhile, Dr. Varmus said that while NIH is eliminating the FIRST (First Independent Research Support and Transition) grant mechanism, which awarded small amounts of money to new investigators, it is implementing modular awards in which grants are stepped up in increments of $25,000 to a ceiling of $250,000. A major purpose of the modular mechanism is to minimize detailed budget-oriented discussions during study section grant proposal reviews.
Dr. Varmus summarized his plans to use funds that are part of the Director's 1 percent transfer authority for priority projects. Pending a review by two outside groups, additional resources will be transferred into programs to support two large projects, one in which synchrotron beam lines that are used by investigators for studying structural biology will be upgraded and the other in which efforts to analyze the mouse genome will be intensified.
Dr. Varmus said that the appropriations bill includes $50 million, which may be spent over several years, to establish a National Center for Complementary and Alternative Medicine. This sum provides an increase of $30 million appropriated for the current NIH Office of Alternative Medicine. Dr. Varmus said that the director being sought for the new center should have a genuine interest in this subject as well as deep experience in the design of clinical trials. He also pointed out that NIH is supporting substantial clinical trials to evaluate alternative medicines, including a study of St. John's wort at Duke University. Moreover, several reports of other such studies were recently published in mainstream biomedical research journals.
The appropriations bill also includes funding for construction of the Mark O. Hatfield Clinical Research Center as well as other new facilities at NIH. It also includes funds to support activities of the National Foundation for Biomedical Research, which now has a director and a board of advisors. The Foundation now supports programs such as the new Clinical Research Training Program for medical students.
Dr. Varmus said that NIH and Office of Management and Budget officials are actively negotiating details of the FY 2000 budget for NIH, which will be made public as part of the President's annual budget announcement early in 1999. Health disparities and bioengineering are two categories of emphasis that will be added into the FY 2000 budget for purposes of priority setting. Although negotiations over the FY 2000 budget are not yet complete, NIH officials already are anticipating the FY 2001 budget, and thus will convene a planning forum in June 1999 to which several members of ACD and COPR will be invited.
Dr. Varmus reviewed several other legislative matters affecting NIH. For example, on December 2, 1998, he and several other witnesses appeared before the Senate Appropriations Committee's Subcommittee on Labor, Health and Human Services, Education and Related Agencies to discuss recent research leading to the isolation of human pluripotent stem cells. That work involved research by Dr. James Thomson at the University of Wisconsin Primate Center in Madison, Wisconsin, and by Dr. John Gearhart at Johns Hopkins University School of Medicine in Baltimore, Maryland, and their respective collaborators, whose efforts received support from private sources. Such cells appear very promising not only for basic studies aimed at studying differentiation but also for more applied research to do toxicity screening and for tissue and cell therapies in which pluripotent stem cells might be used to replace damaged or non-functioning differentiated cells, such as pancreatic island cells or heart tissue.
Dr. Thomson worked with materials from the inner cell mass of human embryos that had been produced at in vitro fertilization clinics and were donated by couples who otherwise planned to discard those materials. Dr. Gearhart isolated cells from the gonadal ridge region of fetuses that were obtained following therapeutic abortions. Because of Federal restrictions, Dr. Thomson's work could not be supported by NIH, whereas, in principle, Dr. Gearhart's research might have been, but, in fact, was not.
Several restrictions have kept NIH from funding research involving the human embryo, according to Dr. Varmus. Between 1978 and 1993, inactivity of the Federal Ethics Advisory Board and then its dissolution made it impossible to review, and hence, to approve, any proposals for embryo research. Subsequently, an advisory committee that was chaired by Dr. Steve Mueller of Johns Hopkins University provided a report to NIH, which was presented to ACD members in December 1994. The report outlined safeguards for going forward with such research. However, President Clinton immediately issued an Executive Order prohibiting Federal support for efforts involving creation of human embryos for research purposes but allowing research use of human embryos that had been created for reproductive purposes. About one year later, the FY 1996 appropriations bill included language banning research that would either create human embryos or destroy them during research.
Whether NIH-supported investigators are eligible to work with the stem cell materials produced by Drs. Gearhart and Thomson is now an open question, according to Dr. Varmus. Thus, the question of whether the legislative ban, instituted by the FY 1996 and subsequent appropriations bills, extends to pluripotent cell lines derived from embryos is under review by the Office of General Counsel in the Department of Health and Human Services in consultation with officials at the White House. The evaluation will depend, in part, on how "organism" is defined in legal terms and also on whether future appropriations bills contain the same or a modified amendment.
Dr. Varmus said that another potentially important legislative matter is looming for NIH and other Federal research agencies. An amendment to the appropriations bill for the Treasury Department and Postal and Civil Services includes a directive requiring all data produced under Federal awards to be made available through the Freedom of Information Act (FOIA). This directive poses a threat to biomedical investigators because it might require them to divulge even preliminary data in response to FOIA requests.
Dr. Varmus noted that the NIH reauthorizing legislation is still pending in Congress as is the legislation protecting the confidentiality of medical records, against genetic discrimination, or providing guidance on several other matters affecting clinical research and training.
Dr. Varmus called upon Dr. Maria Freire, director of the NIH Office of Technology Transfer (OTT), to review issues related to access to research tools. She has been implementing several of the recommendations outlined in a report on access to research tools. The report was prepared by a working group of the ACD, which was chaired by Ms. Rebecca Eisenberg, a member of the ACD.
Dr. Freire said that the Eisenberg report, which is being formally reviewed, is also available on the NIH Website. Based on recommendations in the report, OTT is developing a guidelines document that will be published in the Federal Register as early as February 1999. Dr. Freire said that NIH-led discussions about access to research tools have prompted similar discussions at other Federal research agencies. In addition, the National Academy of Sciences will convene a panel in January 1999 that will be considering the recommendations and findings described in the report.
Dr. Freire said that NIH has recently dealt with several specific cases involving access to research tools. For instance, NIH recently concluded an umbrella agreement with Dupont Pharmaceuticals guaranteeing free exchange and use of the Cre-lox technology for basic research purposes. Additional discussions are under way to address access to the oncomouse technology, which is also controlled by Dupont Pharmaceuticals.
In a separate development, in November 1998, the U.S. Patent and Trademark Office issued to Incyte Pharmaceuticals the first patent covering human expressed sequence tags (ESTs), which consist of partial sequence information for specific human genes. Dr. Freire said that access to this technology is a matter of keen interest to researchers at universities and in industry.
Dr. Varmus called on ACD member Dr. Larry Smarr, who, along with geneticist Dr. David Botstein of Stanford University, co-chairs a working group of the ACD that is reviewing the current and future role of computers in biomedical science. The working group plans to assess biomedical needs from computers as a science-driven rather than a technology-driven challenge. Hence, the members of the panel were chosen for their strength in particular areas of biomedical science and for their ability to develop a vision of what specialists in diverse research fields will need from computer science and related disciplines. The NIH working group met recently for the first time and is compiling information and developing recommendations. It plans to deliver a report to Dr. Varmus by June 1999.
Dr. Smarr, who is also a member of the President's Information Technology Advisory Committee (PITAC), said that members of PITAC recently issued an interim report calling for a major increase in funding across Federal agencies to support research and infrastructure development in the computer sciences.
In response to a question from Dr. Eric Lander over whether the recent embryonic stem cells deliberations have any intellectual property ramifications, Dr. Varmus said that Senator Tom Harkin (D-IA) of the Senate subcommittee expressed concern about the terms under which researchers might gain access to this emerging technology and said that he plans to convene another hearing devoted to this topic. Dr. Varmus noted that Dr. Thomson and Dr. Gearhart have applied for patents to cover their research on human stem cells. He also said that, although the terms under which materials will be made available are not yet clear, NIH is interested in how access to this technology will be regulated.
REVIEW OF HUMAN GENOME PROJECT
Dr. Francis Collins, Director of the National Human Genome Research Institute (NHGRI), said that representatives from NIH and the Department of Energy (DOE) recently developed a new five-year plan for the Federal Human Genome Project, which began in 1990. The project involves a global cohort of investigators, several of whom attended the ACD meeting in December. The visitors included Dr. John Sulston of the Sanger Centre in England, which is committed to analyzing one-third of the human DNA sequence, Dr. Ari Patrinos of DOE, and Dr. Craig Venter of the Institute of Genome Research and Celera.
Dr. Collins said that the five-year goals set in 1993 for the Human Genome Project have been exceeded, with some phases of the overall project more than two years ahead of schedule. For instance, efforts at Genethon in France led to a detailed map of human genes, which contains more information than was called for in the 1993 plan. Similarly, the physical map of human genes contains as many as 50,000 markers rather than the 30,000 called for in the 1993 plan. In addition, more than 30,000 gene transcripts have been assigned to chromosomal loci. Also, there has been more large-scale EST sequencing than had been anticipated, and full sequencing of DNA pieces that exceed 30,000 basepairs now is in excess of 200 million basepairs. Thus, about 7 percent of the human genome is in completed form, with a fairly high rate of accuracy.
Dr. Collins compared the current approach for determining the sequence of the human genome to taking a book apart page-by-page. According to this analogy, each page corresponds to a bacterial artificial chromosome, which contains a linear fragment of human DNA containing as many as 150,000 basepairs. These "pages" are duplicated, enabling investigators to cut them into smaller pieces for actual sequencing and, subsequently, to "tape" them back together to reassemble the "page-size" sequences, which are then assembled page-by-page.
This strategy is responsible for producing more than 200 million basepairs of high quality sequence information, according to Dr. Collins. He said that Dr. Venter and his collaborators plan to omit the page-by-page approach and, instead, move directly to the sequencing of much smaller fragments and then assembling the resulting sequence information into finished level information. This alternative "shotgun" approach has been used successfully to analyze several bacterial genomes.
Dr. Collins outlined the extensive efforts entailed in revising the five-year plan for the Human Genome Project. The NIH efforts, which were overseen by Dr. Aravinda Chakravarti of the NHGRI council, entailed extensive deliberations of several advisory groups as well as a series of 10 workshops involving more than 300 scientists. DOE conducted a similar review process under an advisory group chaired by Dr. Ray Gesteland. These efforts then were combined to develop a joint plan. In addition, Dr. Leroy Walters chaired a group that reviewed the five-year plan in terms of its ethical, legal, and social implications (ELSI).
The new five-year plan lays out bold new goals for the Human Genome Project, according to Dr. Collins. Perhaps the boldest is the decision to determine the human genome sequence by the end of 2003 (instead of 2005), which will mark the 50th anniversary of the DNA double helix structural discovery. An interim goal is to finish one-third of the sequence--roughly 1 billion basepairs-- by the end of 2001, emphasizing the gene-rich regions of the genome. As part of this effort, because scientists may want to alter the priority of specific sequencing projects, an international peer review process has been established to evaluate such requests and recommend which ones to address.
Dr. Collins said that a modified shotgun approach to sequencing also will be scaled up, one that entails continued reliance on bacterial artificial chromosomes that can be mapped by conventional means. This effort is expected to produce a "working draft" of the human genome sequence containing 90 percent of the sequence information but also significant gaps and ambiguities. He said that there is great potential in this phase of the genome project for collaborating with private sector groups, such as the one at Celera, and thereby accelerating overall progress.
Because the Human Genome Project is publicly funded and international in scope, genome sequence information needs to be freely accessible, according to Dr. Collins. Thus, NIH and its national and international collaborators continue to follow a policy of releasing, on a daily basis, sequence assemblies that are one to two kilobases or more. Patenting of such sequences is being strongly discouraged.
Dr. Collins pointed out that the DNA sequences of several model organisms, including Escherichia coli, yeast, and (in December 1998) Caenorhabditis elegans, have been completed, leading NHGRI to develop plans for additional mapping and sequencing projects, including analysis of the mouse, rat, zebrafish, and chimpanzee genomes. Other institutes and agencies are involved in some of these efforts, including the National Heart, Lung, and Blood Institute in the rat genome initiative, the National Cancer Institute on studying full-length cDNAs of humans and mice, and NIDDK on zebrafish. Additional projects that are well under way include efforts to analyze the genomes of Arabidopsis, which is being supported by the National Science Foundation (NSF), and Drosophila melanogaster.
An effort to catalogue common variants in human DNA also has begun, according to Dr. Collins. He said that a good rough estimate is that there are 200,000 common variants with functional significance within the human population. To assemble this catalogue within the next five years, improved technologies are needed for identifying single-nucleotide polymorphisms (SNPs) and for generating a SNP map containing 100,000 markers within three years, as well as improved means for analyzing large data sets. In addition, a public resource of 450 DNA samples that have been stripped of all identifiers for these analyses is being assembled.
Dr. Collins said that the goal of this project is restricted to discovering variations; only later will they be correlated with phenotypes, such as disease. Because this catalogue of SNPs will be assembled without disease or other phenotypic information, plans call for this information to be made fully public for basic research purposes.
Plans to begin (or in some cases accelerate) some of these newer projects are predicated on developing improvements in the technologies needed to conduct such studies. Hence, considerable resources are being invested in developments intended to reduce the time and costs of determining DNA sequences. Investments are also being made in other technologies, such as building collections of cDNAs, that will provide benefits more generally to investigators studying basic biology.
Dr. Collins said that the ELSI program within NHGRI not only is sponsoring research projects but also is developing policy positions and seeking ways to develop legislative initiatives. An ELSI panel is also considering some of the consequences of producing such a wealth of human genetic information so quickly. NHGRI is also investing resources in bioinformatics in partnership with the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM), and in training investigators in the range of specialty areas required for genome analysis and interpretation.
Dr. Shirley Tilghman suggested that Dr. Ari Patrinos of DOE and Dr. John Sulston of the Sanger Centre in England comment on the recently revised five-year plan. In response, Dr. Sulston said that he and his colleagues are in full agreement with the plan, which calls for them to take responsibility for determining the sequence of one-third, or about 1,000 megabases, of the human genome by 2003. Dr. Sulston said that nearly half the clones needed for this undertaking have been prepared and some 64 megabases of DNA sequences have been determined. Investigators at the Sanger Centre do not see these efforts as part of a race.
Dr. Patrinos also emphasized the cooperative nature of the Human Genome Project, noting this cooperation is particularly important at interfaces with other disciplines such as physics and computational science. As part of its specific involvement in the five-year plan, DOE will merge its laboratories at Los Alamos, Berkeley, and Livermore into a virtual center to be called the DOE Joint Genome Institute. Moreover, DOE components of the genome program have been opened to tough external review by several advisory bodies. Dr. Patrinos said that DOE plans to meet its responsibilities for 2003 as outlined in the five-year plan.
In response to a question from Ms. Rebecca Eisenberg about plans for disseminating genomic information from the private sector, Dr. Craig Venter said that the Celera plans for publishing sequence information that were described in a recent issue of Science have not changed. He said that Celera plans to sequence the human genome by 2001 and to make that information freely available to the scientific community.
Dr. Susan Horwitz pointed out that there are serious shortages at universities of people trained in bioinformatics because they are being hired quickly by industry. Dr. Eric Kandel agreed and suggested that NIH participate more actively in training young people in bioinformatics, perhaps bringing them to the NIH campus during summers in programs like those held at the Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and at the Marine Biological Laboratories in Woods Hole, Massachusetts.
Dr. Collins said that NHGRI is funding a number of interdisciplinary training programs, with some of them being joint programs between biology and mathematics or engineering departments. To overcome a continuing supply problem, NIH is working with DOE and the Sloan Foundation to stimulate further growth in this area. One major obstacle is that there is no well defined academic track for such trainees, one that would encourage them toward pursuing long-term careers in academic settings. Dr. Collins also said that NCBI is helping to train people and to furnish talented investigators in this area to universities.
In noting that universities tend not to consider such individuals as suitably trained for independent careers as researchers, Dr. Varmus invited ACD members to comment on whether academic institutions are developing career tracks to attract such individuals into university settings. Dr. Marc Kirschner said that some such specialists may play important roles in academic research without developing independent tenure-track positions at universities. Thus, their security depends in large part on the steadiness of NIH funding.
Dr. Ting-Kai Li suggested that secure funding for such individuals might come from indirect costs from research grants to institutions. Dr. Larry Smarr pointed out that specialists in information technology are often being lured into the private sector because of very favorable economic opportunities, including lucrative stock options for very rapidly growing companies. In part because of this gulf in compensation packages, universities cannot compete effectively for information specialists. Moreover, this challenge extends beyond the biomedical sciences and affects other Federal agencies that support university-based research.
Dr. Varmus said that the problem of job and salary security for such individuals is part of several broader issues, including the willingness of grant reviewers to approve of high salaries for such investigators who then might take positions away from several graduate students or postdoctoral researchers. A broader issue is how NIH might sustain careers of scientists who do not choose to work independently.
Dr. Eric Lander identified two separate issues, one involving research scientists not seeking independent tenure-track careers at universities and the other involving researchers who work in interdisciplinary areas without identified departmental homes in academic institutions. In both cases, there is a need to discuss the development of novel career tracks. Dr. Lander pointed out that, even at MIT, it often proves difficult to appoint individuals specializing in bioinformatics to tenure-track positions.
Dr. Victor Dzau said that the development of genomic information poses an immense challenge to clinicians and clinical researchers, who may benefit from access to individual patient genetic information but whose needs in this and other areas are being thwarted by developments in the health care delivery system that discourage expansion of physician activities.
In response, Dr. Collins agreed that the educational challenge in human genetics awaiting physicians and other health care providers is immense. He said that NHGRI has joined with several other organizations to establish the National Coalition for Health Professional Education in Genetics, which now has 120 member organizations. He also noted that there is a continuing challenge to assure the privacy of the medical and genetic records of individual patients.
Dr. Varmus said that NIH is consulting with managed care organizations about how to optimize the use of genetic information such as SNPs and other clinical information that may be useful to researchers while still safeguarding the privacy of patients.
In response to a question from Dr. Li about defining pharmacogenomics, Dr. Collins said that it entails correlating human genetic variation with responsiveness to particular pharmacologic interventions. He noted that some people use the term to describe the development of designer drugs that are based on disease-related genes.
Dr. Kirschner raised several questions about setting priorities for using Federal resources for specific genome-related projects when the private sector is also investing resources in some of these projects. For instance, does it make sense to accelerate Federally- sponsored human genome sequencing efforts when investigators in the private sector have said they will complete their efforts even sooner? He also asked whether NIH is satisfied with overall coordination among the various institutes on genome-related projects.
In response, Dr. Varmus said that few programs have higher value than determining full-length cDNA sequences for humans, mice, and other organisms. Dr. Collins said that the capacity for doing DNA sequencing in general is great enough to permit continued production of high value projects, such as those based on analyzing ESTs and full-length cDNAs. Nonetheless, there are on-going concerns about overall DNA sequencing capacity. Thus, part of the five-year plan calls for building that capacity during a period of exponential growth.
In response to a question from Dr. Shirley Tilghman about the status of the Human Genome Diversity Project (HGDP), Dr. Collins said that the collection of 450 human cell lines, which is part of the Human Genome Project, is an altogether separate enterprise. Several years ago, critics of HGDP raised concerns that its research activities would exploit minority populations. Although the Institute of Medicine endorsed the scientific goals of HGDP, it recommended a scale-down version of the initial undertaking to overcome some of those ethical concerns.
Meanwhile, individuals involved with HGDP are said to be disappointed with the Human Genome Project's SNP-based genetic variation survey because it will not include ethnic or racial identifiers, according to Dr. Collins. However, the absence of such information will help to safeguard the project against anyone using its findings to issue inaccurate or otherwise premature statements and conclusions linking genetic and phenotypic findings.
Mr. Bradley Margus asked whether the human genome project will lead to a bottleneck of sequence information for biologists and if NIH is planning a similar broad undertaking to identify corresponding proteins and their roles in cells. In response, Dr. Varmus pointed out that genome efforts account for about 1.4 percent of the NIH budget and that there is not a simple correspondence between scientific advances in genetics or other areas and clinical applications. He also noted that gene therapy has not proved a simple corrective to apply to corresponding damaged or abnormal genes. Nonetheless, NHGRI does include plans to study proteins identified through the genome efforts, and there are also major NIH-sponsored efforts under way in structural biology. Genome-based research thus represents a formidable but highly promising challenge to all of biology.
Dr. Kandel agreed that genome analysis will be very helpful in developing a basic understanding of complex organisms, including fundamental behavioral and psychiatric disorders in humans — in part because it will provide a means for methodically comparing genes and evidence of their activities between species such as mice and humans.
ISSUES REGARDING THE INTRAMURAL PROGRAM
An NIH Academy
Dr. Michael Gottesman, Deputy Director for Intramural Research, reminded ACD members of the principal recommendations outlined in the report from an earlier panel that reviewed the NIH Intramural Program (IP). The panel was co-chaired by then ACD members, Dr. Paul Marks of Memorial Sloan Kettering in New York and Dr. Gail Cassell of the University of Alabama in Birmingham. Dr. Gottesman said that, in response to the recommendations in the Marks-Cassell report, NIH has increased the stringency of IP internal review procedures, effectively reduced the IP budget to about 10 percent of the overall NIH budget through improved management and other efficiencies, and has been adopting other recommendations concerning the training and mentoring of postdoctoral fellows and researchers at other levels in their careers during their time at NIH.
The rigors of the revamped review process within the Intramural Program as well as other changes have affected the demographics within IP, according to Dr. Gottesman. In 1990, the IP had 1,200 tenured scientists, several hundred senior staff fellows, and was giving tenure to about 36 scientists per year. Since then, the number of tenured scientists was reduced by about 25 percent, the tenure rate was lowered to about 15 scientists per year, and several new types of appointments are being made within the IP. One type involves tenure-track appointments that are parallel with those of assistant professors at universities. Another involves non-tenure track, renewable appointments of staff scientists and clinicians.
Dr. Gottesman said that, although the possibility of NIH developing a specialized graduate training program has been under discussion for many years, plans were suspended after the Marks-Cassell report was completed and while broad IP improvements were being implemented. Nonetheless, the NIH Intramural Program has had a steady role in training biomedical researchers, accounting for about 15 percent of the total cadre of NIH-supported postdoctoral fellows in the United States.
The IP continues to train a large group of post-doctoral fellows--with about 1,000 visiting from other countries and 80 percent of whom return home after their training. Of the entire group, about 1,000 may be classified as training associates and the others are clinical fellows, some with outside support. A Fellows Committee at NIH works in partnership with the Office of Education to help meet the needs of this large group of young researchers. In addition, there is a special award program for the fellows, as well as workshops aimed at meeting their professional needs. Participation and performance in mentoring these fellows are criteria that are reviewed during the regular reviews of NIH senior scientists in the IP.
The IP also sponsors a very active summer training program, bringing to the campus each year more than 1,000 individuals from diverse backgrounds, including some 30 percent from underrepresented minorities, according to Dr. Gottesman. A new component of this program brings students who have just completed their bachelor-level education to the campus. As part of this program, a good deal of attention now focuses on bringing an even more diverse group of trainees into the program, enabling it to serve as a national model for encouraging young people from underrepresented minorities to pursue careers in biomedical research.
Dr. Gottesman noted that NIH has always had graduate students working in the IP--currently there are about 100-- as part of joint programs with other institutions. In addition, the Howard Hughes Medical Institute supports medical students who come to NIH to work in basic research laboratories. Moreover, NIH instituted a Clinical Research Training Program two years ago that now includes some 65 students. Other training programs include several loan repayment programs for clinical-level researchers as well as the new Undergraduate Scholarship Program for Disadvantaged Students, which is administered by the Office of Loan Repayment and Scholarship. The latter program provides such college students full tuition and brings them to NIH to do research during the summer.
Collectively, these training programs amount to something like the NIH Academy that was envisioned in the Marks-Cassell report, according to Dr. Gottesman. To be successful, this program needs to provide intensive and effective mentoring. Moreover, the program would benefit from a residential facility, one in which students at different stages of their training could mentor one another. In addition, the program would benefit from various partnerships and if there were more continuity between NIH and extramural sites.
Dr. Gottesman said that, although the NIH IP includes many training components from the high school to the postdoctoral level, it does not include a formal graduate program, which is an important link among these other components. Instituting a graduate degree-granting program thus could be a way of improving the diversity of the overall IP training program while helping to energize the staff as well as provide a more academic-like atmosphere at NIH. Further, a formal graduate training program would permit IP staff to develop a new curriculum and new approaches to graduate education, particularly with an emphasis on clinical and translational biomedical research, and could broaden the diversity of the IP research staff. The aim would be to focus on training a small and select group of students in clinically-oriented research and other specialized areas, including bioinformatics.
To establish such a program, appropriate approval is needed from Congress and the Administration as well as from appropriate state-level authorities and accreditation institutions. Moreover, NIH will seek advice from universities and from advisory committees such as the ACD before moving forward with this proposal.
Clinical Research Training
Dr. Gottesman said that the Clinical Research Training Program was instituted following a recommendation of the NIH Director's Clinical Research Panel, which was chaired by Dr. David Nathan of Dana-Farber Cancer Institute in Boston. It recommended establishing a program to enable medical students to participate in modern medical research. The first group of nine students to participate in this program arrived at NIH early in 1997. The second group of 15 in 1998, plus two who stayed over from the first year, are being supported by the Foundation for the NIH with help from Pfizer.
Students — typically students who have completed their third year of medical school — who join this program are immediately assigned to a clinical tutor at NIH, who works with them throughout the year. Participating students also work with a laboratory supervisor, usually someone other than their tutor, on clinical research projects that entail working with patients, designing protocols, and other phases of clinical research. Plans call for expanding this program to accommodate cohorts of 30 students and to provide living space for them on the NIH campus.
Dr. Shirley Tilghman said that it is important for NIH to identify unmet national needs, such as educating clinical researchers, and that the new Clinical Research Training Program is valuable but too small. However, she said that there is not a strong need for a new NIH-based graduate training program to educate more Ph.D.'s, even one intended to attract underrepresented minority students. She also said that the training of specialists in bioinformatics could be done at the postdoctoral level within the NLM at NIH.
In response, Dr. Gottesman said that a diverse staff and other resources put NIH in a good position to help in attracting underrepresented minority students and training them for careers in biomedical research, particularly in clinical areas. Dr. Tilghman responded by noting that many other institutions provide ample capacity for such training.
Dr. Eric Kandel pointed out that, although there may be many reasons for establishing a graduate training program at NIH, the proposal for doing so appears to contain contradictions. He also said that a strong case could be made for a very focused graduate program in clinical research that would serve as a national model.
In response, Dr. Gottesman said there seemed to be some confusion about the NIH proposal for developing a graduate education program amid its other on-going training activities. In fact, a virtual NIH Academy already exists as a series of formal and informal training programs at all levels, for high school students through senior fellows, according to Dr. Gottesman. The new proposal calls for adding to this virtual academy a small-scale training program that will focus on providing graduate students with specialized clinical research skills.
Dr. Varmus said that the proposal envisions graduate students participating fully in activities at the new Clinical Center, where they would receive specialized training to prepare them for careers in clinical research. The new program would also take advantage of NIH resources to encourage minority trainees, including through peer-level interactions with other NIH-based trainees who are at other stages of their education. Moreover, this program would benefit the NIH staff. However, it would not dramatically affect the national pool of biomedical investigators.
Ms. Rebecca Eisenberg said that the committee's discussion of the proposal suggested there is a larger underlying question about the relationship between intramural and extramural NIH-sponsored activities. In response, Dr. Gottesman pointed to the example of the Clinical Research Training Program, which NIH was able to establish very rapidly. He described this as a special feature of the Intramural Program. He also said that NIH has many other resources at its disposal for establishing additional high-quality training programs.
Dr. Susan Horwitz said that establishing a graduate training program involves complex efforts and deserves careful consideration. Moreover, faculty members and administrators at many universities are seriously considering reducing the size of their graduate training efforts. However, she agreed that the presence of graduate students in a training program could provide valuable stimulation for the permanent staff and that the development of a more academic atmosphere at NIH also would be valuable.
Dr. Tilghman said that it would not be good to establish a graduate program for the sake of having students to augment the research workforce at NIH. She also said the current relationship between training and research may not be in balance nationwide. In response, Dr. Varmus said that the demographics implicit in the NIH proposal would not entail bringing in graduate students as an exploitable workforce. Instead, the benefit envisioned for the NIH staff would be much more in terms of having an atmosphere energized by inquisitive trainees who also would stimulate NIH staff to develop a new graduate level curriculum and otherwise participate in intensive teaching efforts.
In response to a question from Dr. Eric Lander, Dr. Varmus said the proposed graduate program would bring in 15-20 new students per year to a maximum of about 100 in the entire program. Dr. Lander said that the ratio of so many staff to such a low number of students would help to making the program distinctive. He also noted that this small group of students would not have a significant impact on the national pool. Moreover, the development at NIH of a new curriculum for training clinical researchers would provide a national benefit.
Dr. Varmus said that it would be a mistake not to take full advantage of the NIH clinical research program, the largest in the world, for training purposes. Dr. Marc Kirschner agreed, noting that following through on the proposal could prove beneficial for the NIH Intramural Program, which at 10 percent of the total NIH budget does account for significant resources and thus should be enhanced. He asked whether there might be other ways to accomplish some of the goals outlined in the proposal without establishing a formal, degree-granting program. He also suggested that NIH test smaller-scale pilot programs for several years before moving ahead with a formal graduate education program.
Dr. Kandel noted that the unusually animated discussion about the NIH proposal was due, in part, to the way in which it was presented. He said that it is important to realize that there is a nationwide crisis in clinical investigation, albeit amid a period when amazing new research opportunities have appeared across wide areas of biomedical interest. He also said that NIH is uniquely positioned to provide leadership in this important area and that a graduate program is one way of demonstrating that leadership.
In response, Dr. Tilghman said that training individuals to do clinical research would be consistent with meeting an identified national need, but that could be done without granting Ph.D. degrees. Dr. Kandel said that providing Ph.D. degrees as part of the program would be valuable for the participants and that developing a program that emphasized the clinical relevance of research would be exemplary.
Dr. Ezra Davidson expressed concerns over the diversity issue, saying that expanded opportunities for underrepresented minority students are welcome but that justifying the program in this way might distract attention from other valuable aspects of the proposal.
Dr. Jane Menken agreed that NIH should take full advantage of the diversity among its staff to mentor trainees from underrepresented minorities. Dr. Gottesman pointed out that the NIH Academy activities, many of them focused on building diversity, already are in operation and will continue to operate regardless of what happens with the graduate program proposal.
Dr. Victor Dzau said that because physicians typically accumulate large debts as they complete their M.D. degrees, perhaps any new program in which some of them are trained for clinical research could include a means for reducing or eliminating those financial burdens.
Ms. Katherine Graham pointed out that the proposal sounded grandiose and that teaching can entail a full-time commitment. Dr. Varmus said that many NIH investigators are eager to spend some of their energy teaching, which can prove stimulating and intellectually broadening for them. However, there are no plans to develop the proposed graduate training program into a full-fledged university at NIH.
Mr. Arthur Ullian asked how individuals who come to NIH for training now acquire Ph.D. degrees. He said that individuals who receive training at NIH undoubtedly deserve to earn credentials that reflect the efforts that they have invested while working on the campus.
Dr. Kandel said that a residential component would add value to the IP training programs. Dr. Varmus said the model for the residential program of the NIH Academy is the Meyerhoff Program at the University of Maryland Baltimore County, which has been developed by Freeman Hrabowski. The concept of peer education has proved very successful there and at other institutions.
Dr. Varmus said that the discussion was very helpful and that he would plan on resuming it in six months with the focus more narrowly on the graduate training proposal rather than on the full range of activities within the NIH Intramural Program.
PRIORITY SETTING AT NIH
Report: Scientific Opportunities and Public Needs
Dr. Leon Rosenberg, Professor of Molecular Biology at Princeton University, presented a summary of a report on how NIH sets priorities that was prepared by a panel convened by the Institute of Medicine (IOM) of the National Academy of Sciences (NAS). The report, which was mandated by Congress and completed in mid 1998, focuses on two critical issues, namely scientific opportunities and public needs, according to Dr. Rosenberg. In addition, it contains a concise description of how NIH conducts its main activities.
Dr. Rosenberg said that the IOM report is premised on the panel's strong belief that NIH is a successful government enterprise, but one like any other that must set priorities and make difficult choices about how to marshal its resources. The IOM panel described the NIH mission as including: identifying public health needs; reducing the burden of disease by developing better methods of prevention, diagnosis, treatment, and rehabilitation; extending the basic knowledge base; and communicating to the public and health providers the state of scientific knowledge and the implications of biomedical research advances for improving health.
The challenge faced by NIH in setting priorities is awesome, according to Dr. Rosenberg. NIH must be responsive to the Administration, Congress, disease group constituencies, researchers and medical care providers, the news media, the general public, and to a changing environment that gives rise to new and unexpected public health problems, such as emerging or reemerging infectious diseases. Meanwhile, some members of Congress continue to question whether there is a strong enough correlation between research allocations made by NIH and disease burdens being faced by the general population.
In response to its mandate from Congress, the IOM panel provided four principal recommendations in its report, according to Dr. Rosenberg: First, the IOM recommended that NIH continue to use the criteria it now has in place for priority setting in a balanced way to cover research related to human health, including activities that go beyond the study of specific diseases. NIH set forth its five main criteria for setting priorities in a booklet prepared in 1997, he noted.
Second, NIH should make its mechanisms for implementing those criteria clear and should evaluate their effectiveness. This effort will help to make NIH procedures more transparent, according to Dr. Rosenberg.
Third, in setting priorities, NIH should strengthen its analysis and use of health data, including information describing the burden and costs of diseases, and of data describing the impact of research on public health. Dr. Rosenberg emphasized that the strengthening of such analyses should not replace other priority-setting activities at NIH.
Fourth, NIH should improve the quality and analysis of its data describing research funding by disease categories, including both direct and related expenditures. Dr. Rosenberg noted that including related expenditures in such presentations may appear to inflate the NIH budget beyond actual outlays, but this approach to describing how funds are being spent in specific disease areas could provide a truer picture of the NIH overall investment on important public health problems.
Dr. Rosenberg said that the IOM panel also provided two recommendations on NIH processes for setting priorities. The first involves expanding the use of ACD by the director, particularly as NIH grows and the value of supporting cross-cutting research increases. To help in this task, the diversity of ACD should also be expanded, and the number of members representing the general public on ACD should be increased.
The second of these recommendations involves NIH developing additional mechanisms to receive advice from the public. Dr. Rosenberg said that NIH should establish an Office of Public Liaison in the Office of the Director to document public outreach, input, and response mechanisms. In addition, the Director should establish a Council of Public Representatives to facilitate NIH interactions with the public.
Finally, NIH should provide Congress periodically with reports and analysis of its programs, including descriptions of how changes in its organizational structure are affecting NIH interactions with the public.
Enhancing Public Participation in NIH Activities
Ms. Anne Thomas, Associate Director for Communications, described part of the NIH response to the recommendations in the IOM panel report. She said that NIH immediately established the Council of Public Representatives (COPR), is setting up an Office of Public Liaison, and will be adding information about these activities to the NIH Website. In addition, public contact individuals are being designated not only in the Office of the Director but also in each of the NIH Institutes and Centers.
The public liaison offices among the NIH Institutes and Centers are to serve as contact points for the public, conduct outreach efforts with constituency groups, educate the public on NIH activities, and implement recommendations from the COPR. The liaison office in the Office of the Director is intended to respond to public inquiries, share best practices across the institutes, help in staffing COPR, evaluate this array of activities, and report to Congress as needed.
To gather advice on implementing the IOM recommendations that called for enhanced interactions with the public, NIH convened a public meeting on September 23, 1998, inviting a diverse group of individuals from across the country, including ambassador Charles James and Mr. Bradley Margus, who participated in the December 1998 meeting of the ACD. Participants at the September meeting said that COPR would bring public views to NIH, serve as a sounding board, identify issues for NIH consideration, and would be influential in dealing with NIH accountability.
Ms. Thomas said that the COPR charter has been published in the Federal Register and that it establishes a broadly based membership of twenty for the committee, who will be selected by the Director. COPR is expected to meet twice yearly, will be chaired by the Director, and may form working groups as needed. The membership of COPR is to include individuals who communicate with the broader public, who can set their program-specific interests aside, and who can think broadly and constructively. COPR as a whole is also expected to reflect the multicultural and geographic diversity of the public it represents.
Ms. Thomas said that NIH already has received many nominations to membership in COPR and the process will remain open until January 15, 1999. Dr. Varmus is expected to select the first slate of members by the end of February, and the committee should meet for the first time in April 1999. The committee's agenda is expected to be broad, as NIH seeks advice on a wide variety of issues, including privacy and confidentiality of research data, informed consent, the clinical trials database, the budget, and NIH compliance with the Federal Government Performance and Results Act.
Dr. Varmus said that NIH already has a very rich set of interactions with the public, including members of advocacy groups, the scientific community, and the general public. In establishing COPR, NIH faces a challenge to ensure that the new committee's overlap with ACD is not too great. Nonetheless, both ACD and COPR can make contributions to NIH on many of the same issues, including embryo research and GPRA-related evaluations of NIH. However, he added, some issues are expected to fall exclusively to COPR.
Dr. Varmus also described two distinct models for how NIH may set priorities for spending its resources--one in which the Director decides which diseases deserve special priority funding and the other model in which many, many individuals play small parts but collectively decide how the bulk of NIH funds will be allocated. He pointed out that the IOM report's recommendations primarily address the first model, even though to some degree NIH practices also follow that second model for assigning spending priorities.
Dr. Eric Kandel suggested that COPR and ACD sometimes meet jointly, perhaps once per year, to address issues of shared concern. He also said that NIH is not as visible as it might be and could do a better job to present its scientific vision to the public. He cited Dr. Alan Leshner, Director of the National Institute on Drug Abuse, as an example of someone who successfully articulates his institute's scientific vision.
Dr. Kandel also said that some patient advocacy groups function very effectively, and that COPR might help others to improve their own efforts. In response, Dr. Varmus noted that Ms. Sharon Monsky has proved an extraordinarily effective advocate for sclerodoma, in large part, by personally campaigning to interest individual researchers in this medical problem.
In response to a question from Dr. Susan Horwitz, Ms. Thomas said that NIH has used many different means to notify the public about COPR and to invite nominations for membership on the new committee. Dr. Horwitz suggested also using the New York Times Tuesday science section as a vehicle for notifying the public about COPR's nomination process.
Dr. Susan Donaldson, who served on the IOM panel, said that the membership should be reserved for individuals who are not specialists in the sciences but are truly representatives of the general public. In response, Dr. Varmus said that during the September planning meeting, participants concluded that individuals with scientific credentials should not be excluded from COPR but that their service there would be as representatives with general interests, not as specialists. He guaranteed that COPR would not become a committee that depends on special scientific language even though it might be called on to consider the public and ethical impacts of scientific topics such as embryo research.
Dr. Eric Lander said that interactions between COPR and ACD on scientific issues in which there are also important public policy implications will be valuable. He suggested that a once-annual joint meeting might not be adequate for the purpose of setting NIH priorities for spending. Dr. Varmus said that some interactions of this type already take place in the council meetings of the Institutes and also in the working groups in which patient advocacy group representatives participate. In addition, NIH has stimulated research in areas where real opportunities for progress have been identified.
Dr. Marc Kirschner asked whether the IOM panel intended to endorse the criteria used by NIH for setting priorities or meant NIH to change those criteria--perhaps modestly, or perhaps fundamentally-- on the basis of new analyses of health and disease burden data. In response, Dr. Rosenberg said the panel endorsed NIH criteria without giving them blanket approval and that NIH did not always make best use of information describing public health needs. Thus, NIH could be doing a better job of implementing several of its own criteria for priority setting.
In this same context, Dr. Varmus said that the third IOM recommendation is not clear and may suggest to some observers that NIH needs to use disease burden data and the impact of research progress on particular diseases-- setting priorities in a mechanical fashion. In fact, he said, such information about diseases is not easy to obtain in itself. Moreover, that process is different from trying to apportion research dollars on the basis of some measure of disease burden.
In response, Dr. Rosenberg said that the IOM panel based this recommendation on its reading of particular NIH materials, which seem to say that disease burden analysis cannot be used effectively to set priorities. However, he said, members of the IOM panel thought NIH should pay more attention to this area of analysis. However, Dr. Varmus pointed out that those NIH materials were intended to simplify NIH positions on this matter. Moreover, Institute directors have had lengthy discussions with economists over burden of diseases analyses and related issues, indicating that NIH has not been ignoring such data. Dr. Rosenberg said that the IOM panel was not fully aware of those NIH discussions, suggesting that here have been some communication shortcomings.
Ms. Rebecca Eisenberg said that the IOM report could be taken to mean that NIH should seek to redirect public input, which now is directed mainly toward Congress, into priority setting at the agency itself. However, because it may be beneficial for Congress to continue hearing public messages about disease burdens without trying to micromanage NIH, perhaps more of that information could be transmitted through NIH.
In response to Ambassador Charles James, who asked whether COPR and ACD might sometimes work at cross purposes, Dr. Varmus said that deciding what issues to bring before the two groups and whether they should meet together or separately are more likely to be problematic issues. Ambassador James also asked whether COPR could become a lightening rod for highly vocal advocacy groups rather than a vehicle to serve the broader interests of the general public. Dr. Varmus acknowledged this potential problem and said that the outcome will depend in part on whether COPR becomes more inward- or outward-looking.
Dr. Kandel pointed out that, although the public may be adept at identifying problems that are medically or public health related, its members are unlikely to devise appropriate solutions or research approaches that could lead to solutions. Hence, COPR's main function is to identify and bring ideas about medical and public health problems before NIH. In response, Dr. Rosenberg said that he agreed and thus it would be important not to confuse the agendas before ACD and COPR. Dr. Varmus noted that COPR is not meant to be a policy-making body, a point with which Dr. Thomas Kelly of the IOM panel agreed.
Dr. Varmus pointed out that the IOM panel report provides a series of recommendations, not a blueprint, and that NIH will implement some of them and adapt others as proves appropriate.
Mr. Bradley Margus said that it would have been helpful to have invited representatives from the IOM panel to explain some of their recommendations to participants who attended the September COPR-planning meeting. He asked whether the purpose of COPR is to make the public feel listened to, to learn from COPR members about the concerns of the general public, or to communicate about NIH to the public.
Mr. Arthur Ullian pointed out that members of Congress and the general public readily recognize the importance of dollar figures used to describe specific disease burdens. He said that the National Long-Term Health Care Survey, which measures decline and disability, provides a useful means for assessing progress toward reducing the costs of chronic health problems or disabilities. He also said that the American public likes to see measures of progress.
In response, Dr. Varmus said that having consistency of measurements across different diseases remains a challenge, with available measurement systems unable to make fine distinctions. He also said that he has been trying to stimulate research on disease such as malaria, which is studied very little in comparison to the enormous human toll it exacts. In such an extreme case, where disease burdens and scientific opportunities are both high, the criteria for boosting research investments are readily satisfied.
Dr. Donaldson said that the members of the IOM panel distinguished between "health needs of the public" and "public health needs," and preferred the former term. She also pointed out that some of the research funding by NIH relates to health rather than disease.
Dr. Kelly said that, while the IOM panel supported the NIH criteria for setting priorities, the health needs of the public are primary. The real challenge is to achieve an appropriate balance among that and the several other criteria. However, the panel endorsed the idea that the responsibility for making this balancing judgment belongs within NIH, and that it should not be done by formula, other outside agencies, or by Congress. The perception of the IOM panel was that the data needed for assessing public health burdens are incomplete or inaccurate, and that inadequate resources are available for compiling those data.
In response, Dr. Varmus said that COPR can help to air these issues. He also said that NIH will spend additional resources in FY 1999 in ways that are not disease specific but instead address broad issues such as harnessing genomics and correcting health disparities.
Dr. Kirschner called the IOM panel report recommendations disappointing because they do not allay the public's misunderstandings about how resources are allocated for biomedical research. He pointed out that unintended health benefits from such research often prove greater than the expected benefits. Even so, NIH might not be setting priorities in an optimal way. The IOM panel did not address this complex and difficult issue, according to Dr. Kirschner.
Dr. Kandel said that American biomedical research has been far-sighted in not being too targeted and that even the war on cancer has entailed broad support for research across a wide array of activities rather than, say, highly focused efforts to improve chemotherapy. He said that it is not possible to predict where clinical insights will arise.
Dr. Kandel, during the discussion near the end of the meeting, said that NIH should consider educating science writers about biomedical research to help them improve their communication skills —for instance, by developing an aesthetic for science. Ms. Katherine Graham noted that communicating complicated scientific topics can be very difficult. Dr. Susan Horwitz said that sports are much more thoroughly covered by newspapers than is science. Dr. Varmus suggested that this topic might be more suitable for a discussion by COPR than by members of the ACD. He also noted that these issues of communicating science touch on the broader question of general science literacy.
CLINICAL TRIALS AND THE CLINICAL TRIALS DATABASE
Clinical Trials Database
Dr. Alexa McCray, Director of the Lister Hill National Center for Biomedical Communications at the National Library of Medicine (NLM), described NIH efforts to coordinate the full array of clinical trials databases. This effort is mandated by the FDA Modernization Act of 1997, which requires NIH to establish a single database cataloguing both federally and privately funded clinical trials involving drugs being developed to treat life-threatening diseases.
This central database, for which a new search engine is being developed, is to include descriptive information of experimental drugs being tested, eligibility criteria for participating in specific trials, sites where such trials are being conducted, and contact points for learning more about them. The 1997 statute also asks NIH officials to determine whether comparable information about medical devices may be included in this centralized, publicly accessible database.
Dr. McCray said that NIH officials began planning to meet this mandate in February 1998, established a steering committee during the following month, and several months later named NLM, which already maintains several large-scale institute-based clinical trials databases, as the home within NIH of this new database. NIH officials continue to meet on a monthly basis and to deal with specific challenges that are part of this overall undertaking, such as developing uniform nomenclature for information assembled into the database. She noted that NLM also recently developed an electronic service, called MEDLINEplus, that provides health information to the public through a network of regional medical and public libraries.
Plans call for this new clinical trials database to be developed in several phases, with the initial phase centered on NIH-specific databases, according to Dr. McCray. This phase calls for providing, by the end of 1999, a database that includes pertinent information about all NIH intramural and extramural clinical trials. The next phase, slated to begin in 2000, will involve other Federal agencies and the private sector. Discussions are already under way with private sector organizations, such as the Pharmaceutical Research and Manufacturers of America, on how to accomplish these goals.
Dr. Varmus said that the goal of developing this comprehensive clinical trials database goes beyond meeting the requirements outlined in the 1997 statute. Making such information available to patients will likely also have an impact on future clinical trials and should help in recruiting participants.
In response to a question from Mr. Bradley Margus about how information about the clinical trials database will be gathered and disseminated, Dr. McCray said that several means are already being used to develop this information, with contacts with clinical trials sponsors being a chief means for doing so. The FDA will be a valuable source of information about corporate-sponsored clinical trials in the private sector.
Clinical Biomarkers and Surrogate Endpoints in Clinical Trials Database
In introducing Dr. Skirboll, Dr. Varmus reminded members of ACD that the NIH Clinical Trials Panel had recommended that NIH enrich its interactions with the private sector. Interests in common extend to improving clinical trials, which includes training of specialists who conduct them, making better use of genetic information, and working more effectively with regulatory agencies. Dr. Varmus said that recent discussions with representatives of the pharmaceutical industry are leading to an expanding series of meetings and workshops between NIH and industry on a number of topics related to clinical trials.
Dr. Lana Skirboll, Associate Director for Science Policy, said that biomedical research leading to the development of many new experimental drugs could create a bottleneck when it comes time to evaluate those products. There simply are not enough resources to test all candidate products through comprehensive clinical trials. Hence, surrogate markers and endpoints will be very useful for improving the efficiency of preliminary evaluations.
Dr. Skirboll said that an initial component of ongoing discussions, which involve NIH, FDA, and industry, has entailed defining terms more precisely because there has been little agreement over how to use them. She said that NIH and its collaborators expect to publish a report in the New England Journal of Medicine in 1999 that is intended overcome those definition problems.
Another important goal for NIH is to encourage young researchers to become involved in innovative clinical trials, according to Dr. Skirboll. NIH officials also recently met to consider ways of attracting statisticians to learn more about biomedical problems and to develop innovative ways of applying mathematics to address clinical trial design challenges. She said that NIH also needs to create a variety of clinical research resources, including those that make better use of epidemiology, surrogate endpoints, and biomarker research.
Dr. Skirboll said that several new collaborative efforts are under way. One is from the National Institute of Neurological Disorders and Stroke (NINDS), which will sponsor a meeting to evaluate imaging and immunologic markers as surrogates in multiple sclerosis. A second involves the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) to develop biomarkers for bone turnover in joint disease. A third involves a large, broad-based international meeting on biomarkers and surrogate endpoints that is scheduled for April 15–16, 1999.
Dr. John Niblack, a Vice President of Pfizer Inc., said that the pharmaceutical industry needs new quantitative means to diagnose, evaluate, and monitor chronic diseases. By providing means for evaluating prospective drugs under development, such tools help to stimulate innovation within the industry. For instance, surrogate marker-based diagnostic assays for the human immunodeficiency virus (HIV), which measure viral loads in patients, have stimulated the development of combination antiviral therapies. He outlined six major areas in which Pfizer researchers would benefit if such new tools were developed and made available.
There are three steps to developing and implementing such innovative technologies, according to Dr. Niblack. The first involves creating new technologies, the second involves putting them to practical uses, and the third entails validating them.
Dr. Janet Woodcock, Director of the FDA Center for Drug Evaluation and Research, said that the scientific underpinnings of drug development are central to drug regulation. Although much of drug development entails empirical investigations, having access to good biomarkers helps investigators to go beyond the limitations that a purely empirical approach imposes. Biomarkers are very helpful in decision making during clinical trials, particularly when pivotal clinical outcomes would take many years to develop or could be obscured amid many other clinical signs and symptoms.
Biomarkers are used by regulatory officials to help design clinical trials, according to Dr. Woodcock. They also are helpful in addressing safety and ethical questions about such trials. Moreover, in cases where surrogate endpoints have been validated, regulatory officials may rely on biomarkers when deciding whether to approve particular candidate products. Thus, she said, FDA has an important stake in the development of surrogate endpoints.
Dr. Eric Kandel asked whether a reference to uses of placebos in clinical trials of pscyopharmacological agents included psychotherapy as potentially interacting with drugs. In response, Dr. Niblack noted that the placebo effect is very high in clinical trials involving depressed patients.
Dr. Victor Dzau said that identifying surrogate markers is a very important because not having them can prove a bottleneck in virtually any area of research. Dr. Skirboll pointed out that a surrogate cannot substitute for a clinical endpoint until it has been validated. Dr. Niblack said that a wide effort from the scientific community is typically needed to validate surrogate endpoints.
Dr. Dzau also pointed out that statisticians, like specialists in bioinformatics, can have a difficult time finding career track positions in university environments.
Dr. Varmus said that Dr. Skirboll will report on the April 1999 surrogate markers workshop during the June 1999 meeting of ACD. The agenda for that meeting will also include a discussion of special careers in science (such as in bioinformatics) and a revised proposal on the graduate program at NIH from Dr. Gottesman.
SUMMARY AND CONCLUSIONS
The Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) met on December 3, 1998, to consider several research initiatives that are part of the NIH response to accelerated budgetary growth in genome-related studies, reforms being implemented in the Intramural Program as well as a proposal to develop a graduate training program at NIH, the recommendations in a report from the Institute of Medicine on priority setting and improving communication with the public, and also the development of a clinical trials database and other programs to enhance clinical research studies.
The ACD acknowledged and commented on these programs and reports, and recommended that several of the recommendations outlined in reports that it considered be implemented while others be reconsidered.
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
FY — Fiscal Year
GPRA — Government Performance and Results Act
HIV — Human Immunodeficiency Virus
HGDP — Human Genome Diversity Project
IOM — Institute of Medicine
IP — Intramural Program
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
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
OTT — Office of Technology Transfer
PITAC — President's Information Technology Advisory Committee