The 80th meeting of the Advisory Committee to the Director (ACD), of the National Institutes of Health (NIH) was held on June 8, 2000. Acting NIH Director, Dr. Ruth Kirschstein, welcomed several new members of the committee as well as two visiting members of the NIH Council of Public Representatives (COPR), introduced the Acting Deputy Director, Dr. Yvonne Maddox, and summarized several recent personnel changes at NIH.
Dr. Kirschstein noted that plans to move the Office for Protection from Research Risks (OPRR) from NIH to the Department of Health and Human Services (DHHS) were recently implemented. The Office was renamed the Office for Human Research Protections (OHRP) and Dr. Greg Koski will be its new director. In another development, DHHS established an interdepartmental working group on burdens of illness, including representatives from the Departments of Labor, Commerce, and Defense, that will meet three times per year. She said that a final version of the Guidelines for Human Pluripotent Stem Cell Research is being prepared for publication this summer, following a review by DHHS.
Dr. Kirschstein reported to ACD that, although Congress continues to support plans to double the NIH budget within five years, there was still uncertainty about the pending appropriations bill. Meanwhile, Congress convened several recent hearings on the safety of gene transfer clinical research; NIH and DHHS are holding discussions to recommend several initiatives to strengthen the protection of human subjects in all research, including clinical trials involving gene transfers.
Dr. Wendy Baldwin, Deputy Director for Extramural Research, provided ACD members with additional details about these initiatives, noting a call for new guidelines specifying that investigators develop safety monitoring plans for phase I and II clinical trials to be submitted to IRBs with copies of the plans to also be sent to NIH. Moreover, after October 1, 2000, all clinical investigators must demonstrate that they have been appropriately educated about protecting human subjects. She said that NIH will convene a meeting on August 15–16, 2000, that will focus on institutional review boards (IRBs) and on improving the management of conflict of interest.
Dr. Alexa McCray of the NIH National Library of Medicine summarized recent efforts to create a comprehensive Clinical Trials Database that would make information about on-going trials available to the research community, practicing physicians, and the general public. Between 3,000–4,000 users visit the site each day, accessing some 42,000 pages of information that are regularly updated. The site, which became operational at the end of February, now contains data on some 5,000 trials, and will grow considerably as information about private-sector trials is added to meet the congressional mandate behind the site's creation.
DHHS Secretary Donna Shalala spoke to ACD members and called on them to urge the research community to pay close attention to clinical trials safety issues, noting that the substantial resources being invested in clinical research are at risk following a recent series of incidents. She said the Administration will seek authority for civil penalties against institutions and individuals who do not follow guidelines to protect research subjects. She also noted that Medicare will now begin to pay medical expenses associated with patients who enroll in clinical trials.
Dr. Christine Cassel (The Mount Sinai Medical Center) and Dr. Stuart Orkin (Harvard Medical School) who co-chaired a Working Group on NIH Oversight of Clinical Gene Transfer Research, summarized its provisional recommendations. Dr. Cassel said that the recommended changes to the order of reviews of proposals are meant to ensure that: (1) no patients enrolled in novel gene transfer protocols will be treated without prior review by the Recombinant DNA Advisory Committee (RAC); (2) investigators will inform the RAC regarding the final FDA-approved protocols and IRB-approved consent forms; and (3) investigators will respond to RAC recommendations. If adopted, these changes will not unduly delay the start of the studies under protocol but will heighten awareness of RAC recommendations by IRBs and institutional biosafety committees. She also said that these changes will put more responsibility on institutions for reviewing clinical gene transfer research proposals.
Dr. Orkin said that the members of the Working Group were divided in their opinions about what to recommend regarding adverse event reporting. However, the members agreed to two principles: the first, to maximize protection and safety of human subjects in clinical gene transfer trials and, the second, to derive maximum benefit from the information generated by such trials. He also said that most members of the Working Group agreed that serious adverse events should be reported immediately to the NIH Office of Biotechnology Activities, and that analyzed, rather than raw, data should be provided to the public. FDA cannot disclose such information, therefore, OBA should continue to receive reports of serious adverse events from gene transfer clinical trials. However, further efforts are needed to harmonize OBA and FDA procedures.
Dr. Francis Collins, Director of the National Human Genome Research Institute, presented an update on the Human Genome Project. He said that 90 percent of the human genomic sequence would be completed during the spring of 2000. Dr. David Lipman, Director of the National Center for Biotechnology Information, said that posting draft sequences from the Human Genome Project presents several challenges and that users continue to provide valuable feedback to GenBank about how its displays can be made more helpful. Recent tests of the system indicate that relatively unrefined draft DNA sequences can prove remarkably useful to biologists who are interested in finding particular proteins, and a number of new analytic tools are being developed to further improve these and other capacities of the system. Dr. Lipman also said that the PubMed Central Advisory Committee met for the first time in April 2000, and that the concept is being transformed into a working system.
Dr. Maddox summarized the recent efforts of the NIH Working Group on Health Disparities to develop an NIH-wide strategic plan for research and other activities aimed at reducing such disparities. The draft strategic plan defines activities related to health disparities broadly to include clinical and basic research, research training, and resource development efforts. Health disparities research will focus on differences in the incidence, mortality, and burden of disease that exist among specific U.S. populations, including racial and ethnic groups, such as African Americans, Asians, Pacific Islanders, Hispanics, Native Americans and Native Alaskans. Moreover, socioeconomic status is included as an important index of health disparities. Geographic differences and gender differences also can lead to differences in health status, and they, too, will be taken into account. Several members of Congress have introduced bills to establish a new entity at NIH for dealing with health disparities research, and NIH and DHHS officials are also developing plans to establish such an entity.
Dr. Stephen Straus, Director of the National Center for Complementary and Alternative Medicine, described priorities outlined in the Center's draft strategic plan. The Center plans to study five areas of alternative practices with the same rigor and standards that must be met by all NIH programs, and to provide guidance on these issues to the public. Moreover, it will support basic and applied research, training, and other programs to investigate and validate alternative and complementary medical practices, with the authority to issue grants and contracts. Its budget of $70 million represents a substantial increase over that of several years earlier.
Dr. Richard Klausner, Director of the National Cancer Institute, described the activities of a working group that is implementing recommendations embodied in a report to ACD on bioinformatics-related programs. For example, the group recommends that NIH offer planning grants of up to $500,000 per year, lasting for up to three years that will enable institutions to create programs that could qualify for becoming centers of excellence. NIH also should use "Phased Innovation Awards" to provide individual investigators with resources to develop new bioinformatics technology. To coordinate these efforts, a Biomedical Information Science and Technology Initiative consortium has been formed, with representatives from each of the Institutes and Centers; it will be administered by the Office of Extramural Research.
Dr. Kirschstein said that these and other new activities are increasing the demand on the management at NIH. Dr. Eric Lander, from the Whitehead Institute, suggested that an entity, such as the National Academy of Sciences, study whether the NIH administrative staff should be expanded to allow a more orderly approach for dealing with budget increases and rapidly expanding research-related activities.
Dr. Ruth Kirschstein, Acting Director of the National Institutes of Health (NIH), began the 80th meeting of the Advisory Committee to the Director (ACD) by welcoming new ACD member Dr. Thomas Cech, who is President of the Howard Hughes Medical Institute, and introducing Dr. Yvonne Maddox, who recently was appointed as the NIH Acting Deputy Director. Dr. Maddox also serves as Deputy Director of the National Institute of Child Health and Human Development. Dr. Kirschstein thanked ACD members Dr. Elaine Fuchs, Dr. T.K. Li, Dr. Jane Menken, and Dr. Philip Needleman, whose terms on the committee are ending. Dr. Kirschstein also welcomed two members of the NIH Council of Public Representatives (COPR), Ms. Rosemary Quigley of the University of Michigan, and Mr. Robert Roehr, a journalist based in Washington, D.C.
Dr. Kirschstein reviewed several matters concerning personnel at NIH, noting that Dr. Neal Nathanson, Director of the Office of AIDS Research, is leaving NIH on September 1; Dr. Harold Slavkin, Director of the National Institute of Dental and Craniofacial Research, is leaving on July 1; and that Dr. Norman Anderson left on March 31. Dr. Anderson served as Associate Director for Behavioral and Social Sciences Research. Searches are underway to fill all three positions. She noted that Dr. Peter Kaufman is serving as the Acting Associate Director for Behavioral and Social Sciences Research. Dr. Kirschstein said that two scientists from the NIH Intramural Program, Dr. Leslie Ungerleider of the National Institute of Mental Health and Dr. Reed Wickner of the National Institute of Diabetes, Digestive, and Kidney Diseases, were recently elected as members of the National Academy of Sciences (NAS). She also said that Dr. Maria Freire, Director of the NIH Office of Technology Transfer, received the prestigious Fleming Award from the Department of Health and Human Services (DHHS).
Dr. Kirschstein noted that ACD-recommended plan to move the Office for Protection from Research Risks (OPRR) from NIH to DHHS was implemented. It then was renamed the Office for Human Research Protections (OHRP), and Dr. Greg Koski was named its new director in early June. Recommendations in an ACD-endorsed report for revamping the NIH Office of Medical Applications were recently adopted, and Dr. Barry Kramer from the National Cancer Institute was appointed the new director of that office.
Dr. Kirschstein said that both the Senate and House of Representatives Appropriations Committees finished marking up the NIH appropriations bill for fiscal year (FY) 2001. As part of the hearings to review the NIH budget proposals, members of Congress asked many detailed questions about plans for spending recent budget increases, and appeared to endorse the responses given by NIH Institute and Centers directors. Congress continues to support plans to double the NIH budget within five years, beginning with the FY 1999 appropriation. However, because of various constraints, the House version of the FY 2001 appropriations bill conforms to the President's budget request increase of $1 billion for NIH, whereas the Senate version calls for a $2.7 billion increase for NIH. Meanwhile, the mandated delay in spending $3 billion until the final day of the FY 2000 remains in effect, although pending legislation seeks to repeal that provision. NIH is beginning to plan for the FY 2002 budget, with a budget retreat scheduled for June 16 involving senior staff as well as several members of COPR and ACD. Senior NIH staff members will participate in an off-campus leadership forum early in September.
As a follow-up to recommendations from a 1999 workshop on the Measurement of the Burden of Illness, DHHS established an interdepartmental working group (including representatives from the Departments of Labor, Commerce, and Defense) that will meet three times per year. The first report related to NIH under the Government Performance and Results Act (GPRA) was submitted to Congress as part of the FY 2001 budget justification and is also posted on the NIH Web site. Dr. Kirschstein said that several ACD members will be asked to participate in the next annual GPRA review.
Dr. Kirschstein said that a final version of the Guidelines for Human Pluripotent Stem Cell Research is being prepared for publication this summer, following a review of several thousand comments received from December 1999 (the date of publication) through February 2000. The revised guidelines will undergo review by DHHS before being published in the Federal Register.
In response to a recommendation from former NIH Director Harold Varmus, the Working Group on Extramural Construction was established and is chaired by ACD member William Brody. Membership of the Working Group includes: Peter Kohler of Oregon Health Sciences University; Fitzgerald Bramwell of the University of Kentucky; Julie Norris of Massachusetts Institute of Technology; David O'Brien of Stanford University; Earl Richardson of Morgan State University; and Gary Tulesnik of KPMG Consulting. The group is expected to meet and report to ACD in December 2000.
Dr. Kirschstein said that a report from Dr. Ellie Ehrenfeld, Director of the Center for Scientific Review (CSR), outlining Phase I changes for reviewing grant proposals was accepted by the CSR Advisory Council. Dr. Ehrenfeld is now convening teams to develop new study sections under integrated review groups, representing phase II of that reform process.
The NIH Academy program for training post-baccalaureate students in research is now established. Participants will focus in part on research to understand and eliminate health disparities.
Dr. Kirschstein has been participating in meetings involving heads of international research organizations, organized primarily by Dr. George Radda of the Medical Research Council in the United Kingdom. On January 31, Dr. Kirschstein participated by telephone, rather than in person, due to impending congressional hearings. The next meeting will be hosted by NIH at the end of July and will include representatives from Germany, the Netherlands, Switzerland, France, Britain, Japan, Canada, and the Wellcome Trust, as well as Dr. Rita Colwell, who directs the National Science Foundation (NSF).
Members of Congress continue to express concern about gene transfer and gene therapy clinical studies, according to Dr. Kirschstein. For instance, Senator Bill Frist (R-TN) called several NIH staff members to testify before the Subcommittee on Public Health, including Dr. Amy Patterson, who directs the Office of Biotechnology Activities (OBA), and Dr. Lana Skirboll, who is the NIH Associate Director for Science Policy. Dr. Kirschstein reminded ACD members that OBA also has two other major responsibilities: (1) administering the Secretary's Advisory Committee on Genetic Testing, which is chaired by Dr. David Satcher, the Assistant Secretary for Health and Surgeon General; and (2) administering the Secretary's Advisory Committee on Xenotransplantation, which will hold its first meeting during the summer of 2000.
DHHS is holding a series of discussions with NIH and FDA about clinical trials that are supported by the Federal Government, following a request from President Clinton to strengthen the protection of human subjects in all such trials, according to Dr. Kirschstein. NIH leadership, together with Dr. Jane Henney, Commissioner of the Food and Drug Administration (FDA), identified several initiatives for this purpose, including: (1) an aggressive effort to train clinical investigators, Institutional Review Board (IRB) members, and others; (2) issuance of more specific guidance on informed consent; (3) improvements in monitoring of Phase I and II clinical trials; and (4) further guidance on conflict of interest for individuals and for institutions. In addition, NIH is clarifying its guidelines for investigators who work within the NIH Clinical Center.
PRESENTATION BY DR. BALDWIN, DEPUTY DIRECTOR FOR EXTRAMURAL RESEARCH
Dr. Kirschstein invited Dr. Wendy Baldwin, Deputy Director for Extramural Research, to describe several initiatives on protecting subjects in clinical research that are intended for NIH grantees. Dr. Baldwin said that new guidelines amplify the current requirement that there be data safety monitoring plans for phase I and II clinical trials by requiring that copies of these plans should be sent to NIH. The guidelines allow investigators considerable latitude to tailor monitoring plans to suit the degree of risk associated with a particular project. Another new policy component is that, after October 1, 2000, all clinical investigators need to demonstrate that they have been appropriately educated about protecting human subjects. Eventually, institutions will need to provide assurances certifying institution-wide education of clinical investigators as part of new requirements from the Office of Research Integrity.
In addition to these new policies addressed to individual investigators, NIH is reissuing its long-standing policy on conflict of interest, according to Dr. Baldwin. It states that institutions receiving NIH support must have written statements describing their financial conflict of interest policies. NIH also is reminding institutions that IRBs may make use of conflict of interest information available to them when they implement policies at their respective institutions. She also said that HHS will convene a meeting on August 15-16, 2000, that will focus on IRBs and conflict of interest.
Dr. Baldwin said that her office is planning proactive compliance site visits to 10 institutions that receive NIH support during FY 2000. Her office already conducted three such visits — to Johns Hopkins University, the University of California, San Francisco, and the University of Texas Medical Center in Dallas. These visits enable NIH officials to see how compliance policies are being implemented, including conflict of interest policies, adverse event reporting as part of clinical gene transfer protocols, and intervention reporting. Dr. Baldwin said that efforts are being made to reduce the anxiety levels that such visits tend to elicit, with one of the main messages being that these visits are intended in a cooperative rather than an adversarial spirit.
Dr. William Brody from Johns Hopkins University said that, despite fears about the site visit to his institution, the experience proved positive. He said that his university is trying to improve its research auditing procedures and overall compliance with policies for protecting human subjects. He said that it would be helpful for his and other universities to develop a set of best practices, including for how to use audit functions to better assure compliance. In response, Dr. Baldwin said that the series of site visits will help NIH to develop some best practices guidelines documents. She also said that NIH would like to serve as a clearinghouse and consultant for grantee institutions on these issues.
In response to Dr. Thomas Cech of the Howard Hughes Medical Institute, who suggested that NIH convene a meeting for IRB representatives who could share information about these compliance issues, Dr. Baldwin said that such a meeting would be a useful undertaking that would be complementary to the series of planned site visits. She also pointed out that NIH staff attends various professional meetings, where they confer with IRB members and other institutional officials about many of these compliance-related issues.
In response to Dr. Victor Dzau of Brigham and Women's Hospital, Dr. Baldwin explained that these activities did not come under the jurisdiction of the recently discontinued OPRR at NIH and do not fall under the new OHRP that will be headed by Dr. Greg Koski. The OHRP will oversee IRBs. The educational requirement is focused on investigators, rather than IRB members, because of the NIH responsibilities to ensure the qualifications of investigators doing NIH-funded research.
In response to a question from Dr. Elaine Fuchs of the University of Chicago about the importance of clarifying written informed consent documents, Dr. Kirschstein said that a great deal of attention will focus on this issue during the next several months. She said that informed consent and patient protection represent a responsibility shared among federal agencies such as NIH, institutions, and the investigators conducting the clinical studies. Dr. Baldwin said that NIH has a research initiative focusing on the process of informed consent to better understand the behavioral interactions that come into play during this process and to improve the communication skills needed to make it more effective. In response to a request for clarification from Dr. Fuchs, Dr. Kirschstein said that the lines of responsibility for NIH-supported institutions and investigators are unambiguous because NIH funds go to institutions in the name of investigators, and the two need to work as a team.
In response to a question from Dr. Yank Coble, Jr., from Jacksonville, Florida, about a recent Institute of Medicine report on medical errors, Dr. Baldwin said that the report focused on errors in medical care rather than in clinical research. However, the concerns overlap with many on-going activities, including those of the National Bioethics Advisory Commission. In response to a related question from Dr. Eric Lander of the Massachusetts Institute of Technology about research on reducing errors in medical practice, Dr. Kirschstein said that those concerns are a focus of the Agency for Healthcare Policy and Research.
Dr. Michael Gottesman, Deputy Director for Intramural Research, said that the NIH Intramural Program also monitors clinical research and is developing new guidelines for its investigators. He said that he could provide a fuller report at a future meeting.
Dr. Dzau said that the infrastructure of IRBs needs to be better supported and is in need of reform. Dr. Kirschstein said that concern over the growing costs associated with IRBs is widespread throughout DHHS. Dr. Baldwin said that two new measures will begin to address some of these issues. One is the "just-in-time" initiative in which proposals may be submitted to NIH for scientific review before being fully reviewed by IRBs, thus avoiding an unnecessary IRB review for those proposals that are not approved for funding. This effort is part of a broader program to reduce regulatory burdens on researchers.
In addition, NIH is considering revising current guidelines for recovering research costs as one way to support IRBs. There are some activities that are project costs which make the work of the IRB go more smoothly, but do not add to the costs of running an IRB. For example, data safety monitoring provides valuable information for IRBs but is appropriately supported from project grants, according to Dr. Baldwin. NIH is discussing with the Federal Demonstration Partnership approaches to developing IRB cost data that could be used to inform policy decisions about the system. Some institutions receiving NIH funds have reached the 26 percent cap on the administrative portion of indirect costs, while others have not. This is important since it is the pool of funds available to support IRB activities. NIH would like to develop a more comprehensive picture of how IRB activities are supported within institutions.
Dr. Dzau noted that some institutions compensate faculty members for their service on IRBs. Dr. Donald Wilson of the University of Maryland School of Medicine in Baltimore said that several years ago OPRR auditors recommended compensating faculty for IRB service, but that this practice would pose serious problems on campuses where faculty members are expected to serve on a variety of committees without additional compensation. Dr. Baldwin agreed that such service is usually viewed as being part of one's civic duties within the university community.
Dr. Lander said that if the main purpose of IRBs is to protect patients, perhaps IRB activities should be fulfilled by professionals whose services are paid for to defray the costs, for instance, of evaluating new drugs. Dr. Baldwin noted that we would like to develop more information about the effectiveness and efficiency of different IRB practices. This would help us develop a sense of which practices work well and will also help in identifying inefficiencies and where administrative improvements are needed within the system.
Dr. Jane Menken, of the University of Colorado at Boulder, asked whether some proportion of IRB costs stems from research that is not supported by NIH. In response, Dr. Baldwin said that the proportion varies and that OHRP has broad jurisdiction over all such research involving human subjects. In most institutions that have a multiple project assurance, all research is covered by the Federal guidelines. However, there are different strategies for supporting the costs of running the IRB system. In some cases, the pharmaceutical companies are paying a flat rate for such review. She also said that it makes sense to address questions about the 26 percent cap broadly in terms of a range of compliance issues, and not merely to restrict the discussion to IRBs.
Dr. Kirschstein said that NIH administrators will identify which of these issues require further study and will form a group to look into them.
Mr. Phillip Williams, formerly of the Times Mirror Company, said that it will be useful for NIH to air these issues with other stakeholders and the public, including through the use of electronic media. In response, Dr. Kirschstein agreed and said that COPR is devoting considerable attention to public outreach issues.
In response to a question from Dr. Fuchs about pending revisions in the stem cell research guidelines, Dr. Kirschstein said that Dr. Lana Skirboll in the Office of Science Policy and her staff are planning to publish final guidelines in the Federal Register. Dr. Skirboll said that, although thousands of comments are being reviewed, the principles set forth in the earlier draft guidelines remain intact. A new board to review research proposals, regarding compliance with the guidelines, is being established, and it will begin working as soon as the final version of the guidelines is published.
In introducing Dr. Alexa McCray of the NIH National Library of Medicine (NLM), Dr. Kirschstein said that FDA reform legislation mandates NIH to establish a comprehensive Clinical Trials Database.
Dr. McCray said that, since the publicly accessible electronic database was launched on February 29, 2000, the Web site — "ClinicalTrials.gov" — has been visited about 6.6 million times. Each day, with Tuesday usually being the heaviest each week, between 3000- 4,000 users visit the site, accessing some 42,000 pages of information.
To give ACD members a sense of how a typical user navigates this system, Dr. McCray conducted several demonstration searches, including one that turned up 29 clinical studies on heart disease, each of which then can lead users to find additional helpful information about the trials, including their status sponsors, locations, and also type, design, and eligibility criteria for enrolling in the trial. The system also is networked with related topics in the NLM MEDLINE system. The system also makes it easy for someone to contact investigators running a particular trial by email.
Dr. McCray also conducted a somewhat more complex demonstration search by querying the system with the phrase, "multiple myeloma and bone marrow transplantation." This search turned up 23 studies with open enrollments as well as information indicating that different institutes within NIH are sponsoring various studies within this group. This feature is part of the "one-stop shopping" that is designed into the system, enabling users to learn a great deal about clinical trials for a particular disease without first knowing which of several institutes might be sponsoring research on that topic. Along similar lines, the system is designed to help users even if they misspell key words. It also permits focused searches where the user may specify not only the name of a disease but also a specific experimental treatment and whether the trials of interest involve adults or children. It also is possible to browse the system by other means, including by sponsor, by letter of the alphabet, or by specific conditions, such as obesity. (Dr. McCray interrupted her description of the system for a presentation by Secretary of the Department of Health and Human Services Donna Shalala.)
Dr. McCray said information for about 5,000 clinical trials is now in the system during this first phase of operations. The second phase will be more difficult as it entails obtaining comparable information from other federal agencies and from the private sector. NLM is collaborating closely with officials at FDA to implement this second phase.
Dr. Christine Cassel of Mount Sinai Medical Center in New York praised the system for its value in providing practicing physicians and the public with greater access to information about clinical trials.
In response to a question from Dr. William Brody from Johns Hopkins University about whether the system is designed primarily for physicians, Dr. McCray said that patients and family members also are using the system extensively, particularly because it is designed for easy access. In response to his follow-up question, she said that the system is updated nightly.
In response to Dr. Shirley Tilghman from Princeton University, Dr. McCray said that NIH is working closely with FDA to collect information for the system on clinical trials in the private sector.
Dr. Yank Coble, Jr., from Jacksonville, Florida, said very few of the 100,000 Web sites on health issues are as helpful as is this system to patients. He asked whether it cross-links to other systems, particularly the National Guidelines Clearinghouse. Dr. McCray said that it does not, but that the suggestion is a good one.
In response to Ms. Rebecca Eisenberg of the University of Michigan, who calls the system amazing, Dr. McCray said that many other health organizations, patient advocacy groups, and a local television (NBC affiliate) health program are among the many groups linking with the NLM site.
REMARKS FROM THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Dr. Donna Shalala, Secretary of the Department of Health and Human Services (DHHS) first thanked Dr. Kirschstein for her willingness to take over leadership of NIH. Secretary Shalala reminded ACD members of the rapid growth of the NIH budget in recent years and said that the current appropriation bill for NIH will probably not be settled until this fall at the very end of the fiscal year.
Secretary Shalala said that the appointment of Dr. Greg Koski to head the relocated (and renamed) Office for Human Research Protection (OHRP) represents an important step toward meeting the serious challenge of protecting human subjects in clinical trials. However, she also called on the research community to pay close attention to these issues, noting that the substantial resources being invested in clinical research are at risk from a recent series of incidents, which some members of Congress and the public view as part of a pattern. Matters are serious enough to warrant new legislation that will permit civil monetary penalties, an enforcement tool that fall between token reprimands and shutting programs down, according to Secretary Shalala. She plans to reduce requirements on IRBs but also to add new responsibilities to them to find the proper balance. She said that, although IRBs require adequate resources, university administrators need to make sure that IRBs are meeting their responsibilities.
Secretary Shalala said that Medicare will now begin to pay medical expenses associated with patients who enroll in clinical trials. This Medicare policy change will greatly increase the numbers of people, particularly among the elderly, available to participate in clinical trials. DHHS officials estimate that this change will cost about $350 million per year.
Secretary Shalala said that she plans to leave DHHS in very good shape in January 2001 when the next administration takes over. For example, a search is under way for someone to head the new office with oversight for scientific fraud. In addition, her staff will take steps to make databases accurate and to ensure that other such investments are appropriate. Moreover, NIH is moving to address the research challenges of health disparities among minorities. Elsewhere, DHHS is taking steps to improve quality healthcare throughout the system. She vowed that, by the time she leaves office next January, NIH would be in the best shape it has ever been.
In response to a question from Mr. Arthur Ullian, Chairman of the Task Force on Science, Health Care, and the Economy, Secretary Shalala said that DHHS officials have identified offsets within Medicare to deal with the cap on spending when funds are allocated to support patients on clinical trials. She also pointed out that some Institute Directors argue that there are no additional costs for patients enrolled in clinical trials over those receiving standard medical care. She said that the Medicare budget is in good shape.
Dr. Christine Cassel of Mount Sinai Medical Center in New York said that enrolling elderly Medicare patients in clinical trials may cost less than does ordinary care and this program will be very different from experimental treatment as insurance companies define it. She added that determining those actual cost differences will be a challenge for NIH. Dr. Richard Klausner, Director of the National Cancer Institute, said that he is organizing a series of collaborative studies with the Department of Defense to determine the differences in cost between standard medical care and those associated with clinical trials. He noted that, although data from cancer trials indicate that those costs are the same, subtle questions about trial-associated costs versus costs associated with adverse events from experimental treatments need to be addressed.
In response to a question from Dr. William Brody from Johns Hopkins University about financial distress at academic teaching hospitals, Secretary Shalala said that there is great diversity among those institutions, adding to the difficulty of seeking remedies for their problems. She said that, because Medicare no longer overpays academic health centers, they have no convenient means for covering additional costs that are not being borne by health maintenance organizations and other payers in the private sector. Although there may be an appropriate federal role in making up this difference, to do so through Medicare is sloppy, according to Secretary Shalala. She said that the system for taking care of indigent patients who are not covered by health insurance also is sloppy. Trying to use Medicare to address these problems, particularly during a period when the elderly population is expected to double, is problematic. The problems are further compounded by major differences, some of them regional and others urban versus rural, among the academic teaching institutions that are seeking redress as well as in the contentious politics surrounding these issues. Secretary Shalala said that she hopes to do something about these issues before leaving office.
In response to a question from Mr. Phillip Williams, formerly of the Times Mirror Company, Secretary Shalala said that adequate information is available for analyzing the needs of academic health centers. For instance, sometimes the issues revolve around the nature of the market that particular centers serve, other times they reflect the very different structures that teaching institutions have developed to serve their local needs. However, in terms of the Federal Government's role, the difficulty centers on how and where to intervene in ways that will prove politically acceptable, according to Secretary Shalala. Although another study may not be needed, a blue-ribbon panel that could develop a shrewd strategic plan might find a way to some workable solutions. For instance, it might recommend doubling the Medicare reimbursement rate as one way of broadly addressing the issue.
Secretary Shalala said that, in the meantime, the administration will try to help teaching hospitals because they represent a public good and they are inextricably bound up in the current expansion of clinical research, during a period of rapid progress in biomedical research. These institutions also are important, not only for delivering health care and for their coninuing involvement in research, but because of their overall impact on the economy.
Mr. Ullian said that even short-term adjustments in the Medicare system can have a big impact on the flow of research and new products from the biotechnology industry. Decisions by Medicare about reimbursing for specific products can determine whether there will be a viable market for them. Secretary Shalala said that Medicare is such a big player that private insurers often lag in terms of making reimbursement decisions. Moreover, the Medicare decision-making process has been made more transparent during a period when many more products are being directly marketed. In addition, FDA has done a great deal to streamline reviews of therapeutic products, which benefits the pharmaceutical and biotechnology industries. With so many new products, questions of reimbursement and maintenance of quality care loom. Secretary Shalala said that, in the face of so many factors, Medicare should not be paying sticker price for every new product. As a trustee of the system, she is charged with maintaining high quality at an affordable price #151; a difficult balancing act.
In response to Ms. Rebecca Eisenberg of the University of Michigan, Secretary Shalala said that Medicare is improving in terms of its ability to decide what services to cover. Medicaid is different because coverage decisions are made at the state level. Although the Federal Government should share in paying for drugs, the program should receive discounts, particularly when it is a major purchaser creating the market for those drugs. Meanwhile, pharmaceutical companies agree to price controls outside the United States, with the understanding that some groups within the U.S. will continue to pay full price.
Secretary Shalala said that the Federal Government would like to negotiate a fair price for drugs, but this effort is complicated by the seamless nature of the current system that accepts improvements in health care in exchange for bearing many of the costs for research that leads to new drugs. She said that an important question is how much of the development costs — which may extend to marketing and advertising costs — associated with those new drugs should also be borne. It will be critical as part of health care to cover at least some of the costs of drugs, perhaps 50 percent, for senior citizens. However, to do this will require working with the pharmaceutical industry a reasonable pricing scheme to provide pharmaceutical benefits for everyone in Medicare. Secretary Shalala said that not only senior citizens but also younger people are becoming vocal about this issue, and they are beginning to label pharmaceutical companies in much the same way that some critics have labeled tobacco companies — a treatment that makes her uncomfortable.
Dr. Kirschstein thanked Secretary Shalala for her seven and a half years of service, and ACD members gave her a standing ovation.
Dr. Kirschstein later said that decisions for Medicare to cover routine care costs for patients enrolled in clinical trials were made over several days just before the ACD meeting and, thus, many details will need to be worked out, including a precise definition of a clinical trial. Dr. Robert Wittes, Director of the Cancer Chemotherapy Program at NCI, will head a committee with responsibility for implementing this new NIH program, which is expected to expand and change.
REPORT FROM THE WORKING GROUP ON NIH OVERSIGHT OF CLINICAL GENE TRANSFER RESEARCH
Dr. Kirschstein reminded ACD members of continuing discussions about the safety and oversight of gene transfer and gene therapy research, particularly following the death, in September 1999, of a young man enrolled in such a clinical trial. Former NIH Director Harold Varmus established a Working Group of the ACD, co-chaired by Dr. Christine Cassel of The Mount Sinai School of Medicine in New York, and by Dr. Stuart Orkin of Harvard Medical School in Boston, who had served as the co-chair for an earlier review by NIH of such research. Other members of this Working Group include ACD member Dr. Victor Dzau of Brigham and Women's Hospital in Boston as well as several members of the NIH COPR.
The members of the Working Group were asked to respond to four questions:
Is the current framework for oversight and public discussion of clinical gene transfer appropriate, especially with regard to the respective roles of RAC and the NIH guidelines?
Are current NIH mechanisms adequate for coordination of the oversight of clinical gene transfer with FDA, OPRR (now OHRP after its move to DHHS), IRBs, and IBCs?
Are additional NIH measures needed to minimize risk associated with clinical gene transfer research?
What should the NIH role be with regard to reporting, analysis, and public discussion of serious adverse events?
Dr. Cassel said that the members of the Working Group met four times, including once in conjunction with the Recombinant DNA Advisory Committee (RAC), which was established in 1975. She said that members of the Working Group agreed that gene transfer research is an exciting field with great promise and thus they saw their mission as improving public confidence in the safety and oversight of this research.
Dr. Cassel said that the Working Group formulated four principles for gene transfer research:
it should meet the highest ethical and scientific standards;
human subjects in gene transfer clinical trials should receive maximum possible protection by investigators, institutions, and oversight agencies;
human subjects in such trials should be provided fully with informed consent information and also with up-to-date synopses of potential benefits and risks from on-going gene transfer research; and
all risks and adverse events in clinical gene transfer trials should be monitored, interpreted, and communicated in a timely fashion to current and prospective subjects for such trials, the general public, investigators, IRBs, and research sponsors.
Dr. Cassel pointed out that NIH and FDA share oversight responsibilities for gene transfer research, although each institution plays different and complementary roles. The NIH RAC, which is under the administration of the NIH Office of Biotechnology Activities (OBA), exercises those responsibilities for NIH, using the NIH Guidelines for Research Involving Recombinant DNA Molecules as its governing document. Typically, investigators planning gene transfer clinical research first seek approval from their respective institutional review boards (IRBs) and institutional biosafety committees (IBCs). Once those bodies approve a proposal, it then is submitted to OBA for preliminary review by RAC and, if it is one of the 10 percent such proposals now considered novel, for a full review by RAC during one of its quarterly meetings. Proposals that are forwarded to OBA also need to be reviewed by officials at FDA, and human subjects cannot be enrolled until FDA issues an IND (investigational new drug) approval.
Because RAC consideration of a novel gene transfer proposal no longer is a prerequisite for IRB, IBC, or FDA approval, and because RAC meetings occur only quarterly, RAC deliberations may now occur after subjects already are enrolled and participating in gene transfer clinical trials, according to Dr. Cassel. This change was instituted several years ago, following recommended changes in RAC called for by former NIH Director Harold Varmus.
The Working Group is not seeking to return to former practices for RAC, namely formal recommendations to the NIH Director whether proposals be approved or deferred, according to Dr. Cassel. Instead, the Working Group recommends that such proposals be submitted to OBA, and potentially RAC (if the proposals are deemed novel), before they are reviewed by IBCs and possibly also by IRBs. For the 90 percent of proposals that are deemed non-novel, this change in procedure would greatly expedite overall review. Importantly for novel proposals, the review and analysis from RAC will feed back into the overall multi-layer review, meaning the IBC approval will depend on RAC deliberations, and the investigators also will be subject to those concerns before the clinical testing phase begins. Nonetheless, this proposed change still will not entail obtaining RAC-NIH approval, as investigators are being asked, not required, to respond to concerns that RAC may raise.
Dr. Cassel said that, in sum, these recommended changes would ensure that: (1) no patients are treated on novel gene transfer protocols without prior RAC review; (2) investigators will inform RAC regarding FDA-approved protocols and IRB-approved consent forms; and (3) investigators respond to RAC recommendations. If adopted, these changes will not unduly delay protocols but will heighten awareness of RAC recommendations by IRBs and IBCs. She also said that these changes will put more responsibility on institutions for reviewing clinical gene transfer research proposals, and that they will likely benefit from efforts from NIH and DHHS to provide them with more resources.
Dr. Orkin said that the members of the Working Group were divided in their opinions about what to recommend regarding adverse event reporting. However, the members agreed to two principles, the first to maximize protection and safety of human subjects in clinical gene transfer trials and, second, to derive maximum benefit from the information generated by such trials by making that information available to investigators, participants and the general public.
Dr. Orkin said that part of FDA's responsibility is to decide whether an adverse event warrants halting a clinical trial, whereas an important role for NIH is to provide information to the public, subjects, and investigators about those events. However, another NIH responsibility is to help ensure the privacy of individuals who participate in such trials. The Working Group members sought to develop a uniform and streamlined reporting and analytical system for identifying serious adverse events that occur during such trials as well as any trends across trials. However, differences between NIH and FDA regulations make fulfillment of these goals problematic.
The members of the Working Group considered several options, including that only FDA but not OBA and RAC receive reports of adverse events, that OBA and RAC receive reports only of life-threatening events, or that all serious adverse events continue to be reported to OBA and RAC, according to Dr. Orkin. He said that they also considered whether the frequency of such reporting be changed, either to one summary submitted annually or immediately following individual events. The question also arose as to how such information should be transmitted to the public—as raw data or in a summarized, analyzed format. He said that most members of the Working Group agreed that serious adverse events should be reported immediately to OBA, and that analyzed rather than raw data should be provided to the public.
Dr. Orkin said that differences in procedures and in regulations between FDA and NIH further complicated the Working Group's efforts to suggest how to harmonize reporting procedures for serious adverse events associated with gene transfer clinical research. For instance, FDA typically confers with sponsors, whereas NIH confers with investigators. FDA rules specify that sponsors report unexpected fatal or life-threatening events within seven days, whereas NIH specifies immediate reporting of such events. FDA also is not permitted to disclose information to the public, unless a sponsor authorizes that disclosure, whereas most information submitted to NIH is available to the public.
The consensus of the Working Group is that, because FDA cannot disclose such information, OBA should continue to receive reports of serious adverse events from gene transfer clinical trials, according to Dr. Orkin. Moreover, reporting to OBA and FDA should be harmonized, with the simplest way of doing so for duplicate reports to be sent simultaneously to OBA and FDA. Finally, he said that, instead of receiving raw data about serious adverse events, the public should receive interpreted information in context. A standing committee, possibly a RAC subcommittee, should be established to review reports of adverse events and analyze that information for any trends.
In response to Dr. Shirley Tilghman from Princeton University, Dr. Orkin said that the guidelines specify that NIH receive information about adverse events on clinical gene transfer trials but that the guidelines do not indicate how that information is used. FDA has regulatory authority that enables it, for example, to halt clinical trials, whereas NIH has no such authority. Instead, RAC in its periodic meetings or NIH through specially convened meetings may review such information in search of trends. However, RAC is not constituted to analyze fully such data. Dr. Cassel noted that information about serious adverse events is submitted not to RAC, but to OBA. Moreover, IRBs are mandated to analyze such data for trends. However, because IRBs lack resources for such analysis, it is important for OBA to receive those data and to try to identify trends that might be difficult to discern or that might emerge by analyzing data from several separate trials.
In response to Dr. T.K. Li from Indiana University School of Medicine, Dr. Orkin said that FDA and NIH define serious adverse events somewhat differently, but the Working Group did not try to suggest ways of harmonizing those definitions.
In response to Dr. Kirschstein, Dr. Orkin said that FDA, NIH, and IRBs (rather than OPRR) are contacted at somewhat different times when investigators report serious adverse events. Dr. Michael Gottesman, Deputy Director for Intramural Research, pointed out that OPRR (now OHRP) also has specified reporting requirements for adverse events, and that these requirements add more complexity, and possibly more confusion, with which investigators need to deal.
In response to a question about how many human subjects are involved in gene transfer research, Dr. Pearl O'Rourke, of the Office of Science Policy, NIH, said that about 4,000 have enrolled during 10 years across all such clinical trials.
Dr. Elaine Fuchs of the University of Chicago said that the timing of adverse reporting to FDA and NIH is a critical issue, one that risks delay but also could jeopardize patient confidentiality. In response, Dr. Orkin said that law specifies that FDA maintain certain seven- and 15-day reporting requirements for different categories of adverse events, making it difficult to change, but that harmonization would be sensible. He also said that the reporting of life-threatening or fatal events should be immediate. Dr. Cassel said that FDA is trying to change some of its requirements with respect to timing and to disclosing information that now must be kept confidential by law because it is considered proprietary. She said that establishing an interagency group with members from FDA for dealing with serious adverse event reports might be a valuable, perhaps only an interim step.
In response to Dr. Yank Coble from Jacksonville, Florida, who asked whether the Working Group considered JCAHO's sentinel event requirements or state-level requirements, Dr. Kirschstein said that it did not. In response to Dr. Fuchs, Dr. Cassel said that the Working Group did consider confidentiality issues, which is why it recommended against disclosing raw data about serious adverse events.
In response to Dr. Tilghman's question about disseminating information about serious adverse events to investigators conducting other clinical trials whose patients may also be affected, Dr. Orkin said that FDA has authority for intervening with other ongoing clinical trials in addition to the one where the adverse event occurred. In addition, in the case of the death associated with use of an adenovirus-based vector, OBA convened a workshop to examine safety issues related to the use of such vectors. Dr. O'Rourke said that not only did FDA suspend the clinical trial at the University of Pennsylvania where the death occurred, but also did so with three other clinical trials in which a similar vector was being administered by similar means to participants. Meanwhile, OBA quickly considered notifying about 70 investigators who were using adenovirus-based vectors whether they should halt trials but this option was determined to be inappropriate. She also pointed to additional reasons why harmonizing FDA and NIH reporting requirements is difficult.
Dr. Victor Dzau from Brigham and Women's Hospital said that good research practice is the real goal, but that isolating a single field such as gene transfer research for such scrutiny can be problematic. Nonetheless, events warrant a special review process to protect the public. He also asked whether the Working Group's report should be considered interim or whether the ACD should endorse it. He said that there is consensus among Working Group members concerning the first part of their report. In response, Dr. Kirschstein said that ACD members should reflect on the proposals and report back to her individually because this matter cannot be postponed to the next ACD meeting in December. Alternatively, because of the urgency of the matter, it might be necessary to hold a conference by telephone to resolve differences. She said that, after the RAC-based approval process stopped, no reasonable process was put in its place, leaving a void. Hence, something is needed immediately to fill that void.
Dr. Lana Skirboll, who is Associate Director for Science Policy, pointed out that a RAC Working Group is reviewing serious adverse event reporting discrepancies between NIH and FDA, and its recommendations could help in revising the process for handling adverse event reports. In response, Dr. Kirschstein said that the ACD Working Group needs to determine whether it can reach consensus on this issue. Moreover, another group will need to examine this issue more broadly, as it applies to all clinical trials, and this effort will require having an agreed-on definition of serious adverse event.
Dr. T. K. Li pointed out that sponsors of clinical trials often define reportable events, but that different criteria may be required for gene transfer trials. Dr. Cassel said that, although report timing requirements differ, NIH uses the same definition as FDA for serious adverse events. However, defining differences in severity of events becomes useful when looking at data for trends.
Dr. Kirschstein said that serious adverse events during a hepatitis drug trial at the NIH Clinical Center seven years ago brought some new insights. Thus, clinical trials involving gene transfer or other novel technologies may require oversight that is beyond the usual. For instance, in addition to review of gene transfer research by the RAC, NIH is establishing a new Committee on Xenotransplantation. She also said that, in addition to the many layers of oversight already discussed, the individual Institutes have a responsibility to monitor the safety of clinical research that they support.
Dr. Kirschstein asked the ACD members to separate the two sets of issues presented, and to respond to the Working Group recommendations on procedural changes outlined by Dr. Cassel within one week. She said that it is important to complete that task and put responsibility into an organization with which NIH can deal.
Dr. Cassel noted that the Working Group final report also deals with three other issues, namely, conflict of interest, a gene transfer database, and infrastructure resource needs. Dr. Orkin said that the Working Group members will probably not reach consensus on the issue of reporting adverse events and, instead, will likely submit majority and minority reports.
Dr. Kirschstein introduced Dr. Francis Collins, Director of the National Human Genome Research Institute (NHGRI), to present an update on the Human Genome Project.
Dr. Collins likened the Human Genome Project to the Lewis and Clark Expedition. He said that the emphasis of the project has shifted from the development of genetic and physical maps to an intensive effort to determine the sequence of the genomic DNA. The sequencing phase of the overall human genome effort began as a pilot project in 1996, and over the following three years about 10 percent of the genome sequencing was completed. However, in March 1999, investigators at the 5 major international centers involved in the public project agreed to accelerate this phase dramatically, with the goal of completing a working draft of 90 percent of the human genomic sequence by the spring of 2000.
This goal is now within reach in large part because of the concerted efforts of the five largest groups involved, namely the Whitehead Institute, Washington University, and Baylor University, supported by NIH; the Joint Genome Institute, supported by the Department of Energy; and the Sanger Centre in the United Kingdom, supported by the Wellcome Trust. As of June 6, 2000, they have completed 20 percent of the genomic sequence and assembled another 2.9 billion base pairs as working draft sequence, which because of estimated redundancies represents about 68 percent of the genome — altogether those components amount to close to 89 percent. These groups have cooperated closely and conferred regularly by telephone, making their data available every 24 hours. He noted that ACD members Dr. Eric Lander of the Whitehead Institute and Dr. Shirley Tilghman have both played important roles in this effort.
The strategy of the public project is to build and use a library of human DNA segments contained in bacterial artificial chromosomes (BAC) whose map positions can be readily determined, and then to assemble those sequences BAC by BAC. Dr. Bob Waterston and his collaborators at Washington University were responsible for assembling BACs into contiguous segments containing, on average, two million base pairs.
Dr. Collins said that, despite some of the draft sequence not yet meeting consensus standards, the sequence of the human genome can be considered largely in hand, with much of the available draft sequence already helping investigators working on specific projects outside the genome effort. Nonetheless, there is a firm commitment to finish the task and to refine the draft sequence data to meet standards exemplified by chromosomes 21, whose sequence was published in December 1999, and 22, whose sequence was published in May 2000. That information is being used to identify and study genes involved in an array of human diseases.
The Human Genome Project several years ago laid out eight major goals, and they include continuing to improve sequencing technologies, studying human variations (particularly those that correlate with specific diseases), and analyzing other organisms such as the mouse. Even as human DNA sequencing efforts are reaching a critical milestone, plans for scaling up mouse genomic sequencing are accelerating, according to Dr. Collins. Moreover, an electronic review procedure has been implemented that enables researchers to seek priority sequencing for particular BACs of high biological interest. In addition to the mouse genome, plans to sequence genomes of other species, such as the rat and the zebrafish, are also accelerating. For instance, the Council of the National Heart, Lung, and Blood Institute recently approved funding for an intensive effort to sequence the rat genome.
Dr. Collins said that investing in bioinformatics is now more important than ever to maximize the usefulness of the genomic data being generated. He then introduced Dr. David Lipman, Director of the National Center for Biotechnology Information (NCBI).
Dr. David Lipman said that human genome sequence data continue to accumulate in GenBank at an accelerating rate. A short survey of users of this database indicates that more than 65 percent of them identify gene product — protein — analysis as the primary reason that they visit the site. The second reason is an interest in known genes and associated structural features such as introns or regulatory sequences. For example, when the annotated fruit fly (Drosophila melanogaster) genomic sequence was posted on the Web site, users quickly began looking for information about particular messenger RNA sequences. Thus, it is important to tailor the GenBank system to make such information readily accessible to users.
Dr. Lipman said that posting draft sequences from the Human Genome Project presents certain challenges. For instance, the data are being compiled BAC (bacterial artificial chromosome) by BAC, but each one of these draft units contains gaps as well as fragments whose relative order has not been determined. The strategy for dealing with the challenge of displaying these draft sequences is to display a map of the BACs, as well as overlaps between pairs of them. Additional efforts entail using raw and redundant data to improve these assemblages to refine the ordering of the fragments. In addition, some display screens available to users enable them to see maps of several different displays at once, including STSs and SNPs. Users continue to provide feedback to GenBank about how those displays can be made less confusing and more helpful to biologists who query them.
Dr. Lipman said that users interested in protein structure and function can interrogate components within genomic sequences to study specific types of protein domains within sets of proteins. For instance, previously unrecognized domain patterns are being identified, suggesting new classes of proteins with potentially novel functions. Models for conducting such searches and analyses are being refined.
Also, in collaboration with Dr. Eric Lander at the Whitehead Institute, Dr. Lipman compared two separate approaches to probing genomic databases at different states of refinement for sets of likely encoded proteins. One approach entails "translating" by computer sequence data into all possible proteins that those sequences could generate. The other entails using a program called GenScan that makes similar predictions about encoded proteins without an intervening "translation" step. This latter approach yielded higher numbers of proteins, and it did not matter whether the sequences being scanned were raw drafts or highly refined, finished material. Ordering the fragments does little to improve these yields. Together, these test results indicate that relatively unrefined draft DNA sequences can prove remarkably useful to biologists who are interested in finding particular proteins, according to Dr. Lipman.
Dr. Lipman said that the GenScan-based initial searches can be further refined by using the sizable expressed sequence tag (EST) database. Individual ESTs within the database were compared to data within the genomic sequence. When one EST matches to sites on adjacent fragments of the genomic sequence, it suggests in some cases that an intron region within that gene is being identified along with the splice junction. In a further test of this analytic strategy, it successfully identified 70 percent of known introns within a group of 621 genes. Use of the EST database not only may help in identifying genes and introns, but also in ordering fragments among BACs, according to Dr. Lipman. He also described other approaches for using GenScan and EST data to look for intron-exon structures of specific genes within the genomic sequence databases.
Dr. Lipman presented an analysis by Dr. Eugene Koonin showing the value of the draft genome sequence. By scanning for a specific domain, called BRCT, he identified what appears to be a novel protein containing it within only the human and Drosophila databases — one that had not been identified by analysis of ESTs because, in this case, they were too fragmentary.
GenBank also is developing new tools, starting with programs called PFAM and SMART, to look at particular encoded protein structures and to search for potential specific functions, according to Dr. Lipman. For instance, one such tool scans the genome for particular enzyme domains, such as a kinase domain, and then can display and align those domains from well-studied kinases with three-dimensional graphics.
Dr. Lipman then switched topics to discuss PubMed Central. First, he named the members of the PubMed Central Advisory Committee, which met for the first time in April 2000. He said that they support the basic concept but are deferring discussion of using the system to distribute preprints of articles because of several pilot experiments for this idea under way elsewhere. An e-mail poll is being planned to determine what other journals might be included in the system and the basis for making such decisions.
In response to a question from Dr. Shirley Tilghman from Princeton University about access to these GenBank analytical systems, Dr. Lipman said that many of the results of these tentative analyses, including ESTs, predicted proteins, and alternative splice sites, will be displayed as maps and thus are accessible to outside users. However, users will need to do follow-up analysis on their own, although GenBank plans to continue refining what its system can present to users.
Dr. Larry Smarr of the University of Illinois said that these growing datasets and analytic tools present challenging opportunities to develop more sophisticated bioinformatics algorithms. He also asked whether the National Center for Biotechnology Information (NCBI) could serve as a clearinghouse. Dr. Lipman agreed and said that considerable developmental work already is under way. He also said that the NIH Biomedical Information Science and Technology Initiative (BISTI) will contribute to these overall efforts. How electronic data are encoded also matters, and different developers seem not to accept the ASN.1 system preferred by NLM.
Dr. Francis Collins said that NHGRI is very enthusiastic about BISTI and is encouraging the Centers of Excellence in Genomic Science to emphasize computational biology and to encourage the development of new analytic tools. Dr. Kirschstein said that Dr. Marvin Cassman, Director of the National Institute of General Medical Sciences also is supporting the development of such tools.
In response to Ms. Rebecca Eisenberg of the University of Michigan, Dr. Lipman said that 175,000 different users access the NCBI site every day, with about 40,000 looking at gene sequence information. In addition, each day brings hundreds of e-mails and telephone inquiries. Some users have very simple requests, others have very specific suggestions to make about improving the system and its tools. He said that company scientists tend to come forward with requests that, in general, indicate they are about six months ahead of their academic counterparts. Moreover, on occasion, individual researchers who specialize in a particular area will come forward with information about specific gene families and will help to improve the annotations within the GenBank database. He pointed out that Dr. Kirschstein and Dr. Collins have helped to expand the GenBank curator staff, who are helping to realize such improvements within the databases.
In response to Dr. Tilghman, who said that acquisition of sequences from the mouse genomic program will further complicate data handling challenges at GenBank, Dr. Lipman said that a special repository for that data will be needed. He also said that a group at NCBI already is comparing mouse and human gene sequences and that other comparisons across species will come to be very important.
Dr. Eric Lander said that Dr. Lipman and other staff members of NCBI deserve special praise for developing this system in addition to their other duties. Dr. Kirschstein joined in this praise and extended it to include Donald Lindberg, the Director of the National Library of Medicine.
In response to a question from Dr. Smarr about PubMed Central, Dr. Lipman said that some of the initial controversy has settled down and that some organizations that rejected the idea now are asking about helping to develop the new system.
REPORT FROM THE WORKING GROUP ON HEALTH DISPARITIES
Before introducing Dr. Yvonne Maddox, Dr. Kirschstein made note of two special events. In May, the NIH Office of Research on Minority Health marked its 10th anniversary with a three-day meeting on health disparities, and many luminaries attended, including DHHS Secretary Shalala, Under Secretary Kevin Thurm, and Surgeon General David Satcher. This fall, the Office of Research on Women's Health will mark its 10th anniversary with a symposium that is being planned by Dr. Vivian Pinn and Dr. John Ruffin.
Dr. Kirschstein said that she reestablished the NIH Working Group on Health Disparities early in 2000, making each of the Institute and Center Directors members and appointing Dr. Maddox and Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID) its co-chairs. She also said that Rep. Jesse Jackson Jr. (D-IL) has asked many probing questions about these issues.
Dr. Maddox said that former NIH Director Dr. Harold Varmus established a Working Group in September 1999 to examine health disparities research, which at the time had a budget of $1.4 billion. However, NIH was engaged in such research long before that time. For example, the NIH Office of Research on Minority Health, which is directed by Dr. John Ruffin, was established a decade ago, and the National Institute of General Medical Sciences (NIGMS) also has been involved in such research for more than 30 years, as well as in training minority group members for careers in research. She also said that one early task for the current NIH Working Group was to refine the working definition of health disparities research.
Dr. Maddox said that former DHHS Secretary Margaret Heckler established a task force in 1985 to study health disparities and developed priorities, including cardiovascular diseases and stroke, diabetes, infant mortality, substance abuse, and accidents and violence, that resemble several of those identified more recently. In 1990, then DHHS Secretary Louis Sullivan presented the Healthy People 2000 report, describing a broad set of public health goals that included eliminating health disparities between the minority and majority populations. Subsequently in 1998, President Clinton presented his race initiative, which looks still more broadly at social and legal disparities as well as health disparities between the races.
DHHS Secretary Donna Shalala responded to that presidential initiative by urging that health disparities be eliminated by 2010, according to Dr. Maddox. With Surgeon General David Satcher, Secretary Shalala identified 6 areas on which to focus, namely infant mortality rates, cancer screening and management, cardiovascular disease, diabetes, HIV/AIDS, and immunization.
The NIH Working Group that was formed in September 1999 delivered its first set of recommendations to then-NIH Director Varmus in December, just before he stepped down. The Working Group recommended that NIH develop a strategic plan, an effort that began in January 2000 soon after Acting NIH Director Dr. Kirschstein reestablished the Working Group and broadened its membership to include all Institute and Center Directors. In February the Working Group members agreed to complete separate draft strategic plans by early April. Those plans then were used to develop a NIH-wide strategic plan, whose first draft was completed by May 26, 2000, and is now being revised in response to comments, for use in developing the fiscal year 2002 budget.
Dr. Maddox said that the draft strategic plan defines health disparities-related activities broadly to include clinical and basic research, research training, and resource development efforts. Health disparities research will focus on differences in incidence, mortality, and burden of disease that exist among specific U.S. populations, including racial and ethnic groups, such as African Americans, Asians, Pacific Islander, Hispanics, Native Americans, and Native Alaskans. Moreover, socioeconomic status is included as an important index of health disparities, as are geographic and gender differences.
Dr. Maddox cited several diseases, including HIV/AIDS and asthma, as examples of major health disparities, with African Americans disproportionately affected. For example, African American children are 26 percent more likely to have asthma and are four- to six-times more likely to die from it than are white children. Another focus is on reducing the infant mortality rate, which at 14.2 per 1,000 is particularly high among African Americans and about double the overall rate. The rate for sudden infant death syndrome also is more than twice as high than for whites, and for Native Americans it is about five-times as high.
In response to a question from Dr. William Brody about whether HIV/AIDS is more a subject for other public health agencies, Dr. Maddox said that health disparity-related efforts are not limited to NIH but involve other agencies within DHHS, particularly the Centers for Disease Control and Prevention, which has lead responsibility for HIV/AIDS. Nonetheless, many of these research issues, including behavioral questions related to reducing the risk of becoming infected with HIV, are matters for NIH to study, according to Dr. Maddox. Dr. Fauci added that, early in the epidemic, very few African Americans and Hispanics were enrolled in clinical trials administered under the NIH AIDS network, despite the fact that this population was disproportionately affected by the disease. One result is that, early on, there was no information available as to whether members of these population groups and also whether users of intravenous drugs would respond differently to the antiviral drugs being developed. Dr. Eric Lander of the Whitehead Institute said that genetically determined host factors also affect susceptibility to HIV infections, and these factors are unevenly distributed among ethnic and racial groups.
Dr. Maddox said that the five-year NIH strategic plan not only identifies research priorities but also outlines plans for recruiting and training investigators from minority groups, for community outreach programs, including to recruit more minority group members to participate in clinical trials, for forming stronger partnerships between majority institutions and those serving minority populations, such as the historically black colleges and universities, for recruiting more minority group members to serve on NIH peer-review panels, and for recruiting them to many other full-time positions on the NIH campus. The plan also outlines strategies for evaluating the success of this overall initiative. A final draft of the NIH strategic plan is expected late in June.
Dr. Maddox said that several members of Congress have introduced bills to establish a new entity at NIH for dealing with health disparities research, including Representative Jesse Jackson Jr. (D-IL), Rep. Bennie Thompson (D-MS), and Senator Edward Kennedy (D-MA). Although very similar, the bills differ in terms of whether such an entity should be free-standing or administered within the NIH Office of the Director. DHHS Secretary Shalala and NIH Director Dr. Kirschstein have supported the establishment of a Center for Health Disparities, a step that could be taken at the administrative level without legislation, according to Dr. Maddox. Dr. Kirschstein added that Secretary Shalala and the Deputy Secretary are encouraging NIH to move ahead with establishing such a free-standing center, possibly before the beginning of the next fiscal year.
In response to Dr. Donald Wilson, of the University of Maryland School of Medicine, who called health disparity a very complicated issue, Dr. Maddox said that NIH would be developing sophisticated strategies for multi-layered research on these complex problems. She also pointed out that this complexity takes some components of the overall issue beyond the realm of NIH and into that of other agencies within DHHS.
Dr. Victor Dzau, of Brigham and Women's Hospital, who called this NIH effort a very important mission, said that, as an Asian, he finds the definition of minority group member very confusing. Nonetheless, he said that this initiative provides an important opportunity to study diversity and biomedical differences among different population groups.
In response to Dr. Thomas Cech, of the Howard Hughes Medical Institute, who asked about the scope of responsibilities for the proposed new Center at NIH, Dr. Maddox said that it would be similar to the National Center for Complementary and Alternative Medicine, with grant-making authority and broad research coordinating responsibilities among the various other Institutes and Centers. Dr. Kirschstein said that there has been an extensive debate about the need for the new Center and its precise role. However, she added, because there is considerable work to do and some of it would not be done by existing entities, there is ample justification for the new entity. Dr. Fauci said that, with or without the new center, the other Institutes would have important health disparity research to pursue. Moreover, with creation of a new center, there will be a conscious effort not to shift all such research into it, but to retain appropriate efforts at each of the Institutes and Centers.
Dr. Elaine Fuchs, of the University of Chicago, agreed with Dr. Wilson about the complexity of the overall issue and pointed out that it cuts broadly across DHSS, particularly with respect to recruiting and training members of minority groups. In response to her question about top priorities, Dr. Maddox said that obtaining a better understanding of diseases probably is most important. For instance, although many experts suspect that pre-term birth can be attributed to infections such as bacterial vagenosis, NIH-supported researchers need to develop solid data to determine whether this hypothesis is correct. Dr. Kirschstein said that she, Dr. Ruffin, and others have served on a number of interagency committees, that NIH will continue to cooperate with them, but it is time for NIH to move forward with its own initiative.
Dr. T. K. Li, of Indiana University School of Medicine, said that such research, which is his specialty, requires studying specific population groups and determining how they respond differentially, for instance, to various drugs. For example, Asians tend to respond to drugs for treating mental disorders very differently from other population groups.
Dr. Jane Menken, of the University of Colorado at Boulder, commended NIH for the initiative and said that it will be valuable to determine how much of health disparities is due to biology and how much to socioeconomic differences among population groups.
REPORT FROM THE DIRECTOR, NATIONAL CENTER FOR COMPLEMENTARY AND ALTERNATIVE MEDICINE
Dr. Kirschstein introduced Dr. Stephen Straus, telling ACD members that he was appointed Director of the National Center for Complementary and Alternative Medicine (NCCAM) in October 1999.
Dr. Straus invited ACD members to transmit comments on the draft strategic plan that he was about to summarize for them. He said that, although definitions for this field tend to be vague, the Center's working definition is that complementary and alternative practices are those that are not integral to conventional medicine. He said that they are being used by a remarkably large proportion of the U.S. population, perhaps 40 percent and growing rapidly, and perhaps two-thirds of people throughout the world. It is estimated that this growth in the U.S. was 30 percent during the past decade, with most costs borne by users without reimbursement through health insurance, according to Dr. Straus.
Dr. Straus said that most U.S. use of alternative medicine seems to be to complement conventional medicine. However, many users do not tell their physicians of that use, complicating efforts to understand whether those practices interfere in any way with conventional therapies. A good deal of that use is to improve wellness and relieve symptoms attributable to chronic, degenerative, or fatal illnesses. He said that the five general fields that come under this rubric are entire alternative medical systems, mind-body interventions, biologically-based treatments, manipulative treatments, and energy therapies.
Among the alternative systems are traditional Chinese and traditional Korean medicine, ayurvedic medicine from India, other medicines of indigenous peoples, U.S.-based homeopathy that developed within the past two centuries, and naturopathy that developed in Germany. Among the mind-body interventions considered by the Center are mediation; dance, music, and art therapy; prayer and spirituality; and other approaches to mental healing. Included among the biologically-based therapies are herbal therapies, including use of gingko biloba and St. John's wort; a range of special diets to manage obesity, diabetes, and high cholesterol; orthomolecular therapies; and other specific therapies, such as the use of Laetrile and bee pollen. The manipulative therapies include chiropractic medicine and osteopathic manipulation. Energy therapies delve into some areas with little science base, with a focus on internal and external fields, but they also embrace traditional practices, such as Qi Gong; other examples include Reiki therapy, therapeutic touch, and acupuncture.
Dr. Straus said that user demand has stimulated some acceptance of these practices by the health services industry, and many health maintenance organizations (HMOs) offer particular forms of alternative therapies, such as chiropractic (65 percent, according to a survey by Landmark Health Care) and acupuncture (31 percent). HMOs provide these services to satisfy demand and, because in some states, they are required to do so by statute. Scientific evidence supporting a complementary and alternative medicine approach rarely enters into current HMO decision-making.
Dr. Straus said that scientific investigations of some of these practices may indicate benefits. For instance, a report published in November 1999 in the British Medical Journal summarized a clinical trial comparing St. John's wort, the tricyclic antidepressant imipramine, and placebo. The depression scores indicate that St. John's wort and imipramine provided similar improvement in depression. However, this same herbal product also interferes with the metabolism of indinavir, an antiviral protease inhibitor of HIV, accelerating its hepatic clearance through the P450 system. Other examples of the complex pharmacology of such products include an herb used by women for weight loss, Aristolochia, that can cause irreversible kidney failure; when manufactured slightly differently, this same herb can induce bladder cancer.
Because of these and other serious adverse reactions as well as because of the potential efficacy of alternative practices, it is important for NCCAM to study these practices scientifically with the same rigor and standards as are met throughout NIH, and to provide guidance to the public that NIH serves, according to Dr. Straus. Moreover, Congress enacted legislation in 1998 mandating NCCAM to support basic and applied research, training, and other programs to investigate and validate alternative and complementary medical practices. An earlier effort under the Office of Alternative Medicine was funded at $2 million in 1993. Since then, NCCAM was established with authority to issue grants and contracts, and funding levels have risen to nearly $70 million. There has been a several-fold increase in grant applications this year over last.
Dr. Straus said that NCCAM plans to develop a research infrastructure, training programs, and the means to communicate its findings to the public. The new program also needs to overcome resistance from the medical community to unconventional practices that prove safe and effective, and also similar resistance on the part of alternative practitioners to conventional therapies. The first goal of the Center is to support high quality research through investigator-initiated proposals. Some of this research will be global, and some will be intramural; NIH is conducting a search for someone to direct the NCCAM intramural research program. Among current activities, NCCAM is supporting a series of phase III clinical trials to evaluate various alternative therapies, including acupuncture for arthritis, St. John's wort for depression, Gingko biloba to prevent dementia, and glucosamine and chondroitin sulfate versus a Cox-2 inhibitor or a placebo in a five-arm trial, and of shark cartilage as an adjunctive therapy for treating lung cancer.
The Center also supports smaller-scale research through R21 grants, and will support the training of investigators to conduct basic and clinical studies in this area. NCCAM also is developing a centers program, with 11 centers specializing in areas such as botanicals, drug addiction, and cancer. To conduct major clinical trials, NCCAM requires investigators to receive INDs from FDA, and this requirement entails having standardized products available. Several other areas are of particular interest, including pain management, nutrition and exercise, stress management, and the pharmacology of natural products.
Dr. Elaine Fuchs of the University of Chicago said that the clinical results summarized by Dr. Straus comparing the effectiveness of St. John's wort and imipramine against depression are little different from the placebo. She said that other studies of alternative therapies also provide little evidence of effectiveness, suggesting that the public is guiding the scientists in this research, rather than scientists educating the public. In response, Dr. Straus said that the broad field of treatments for depression has many confounding results, soft end-points, and subjective findings. However, he said that the St. John's wort and imipramine findings are statistically significant, and the placebo effect is an important component of these studies. NIH is convening a workshop on the placebo effect November 19-21, 2000.
Dr. Shirley Tilghman of Princeton University said that, although it is important to conduct scientific tests of alternative medicines, she did not understand why special training is needed in this area. In response, Dr. Straus said that researchers working in this area will need to have the same training as others working in conventional medicine, but they need to work within this context to develop the sensitivity and understanding of the culture with which they will deal. Dr. Kirschstein said that the statute establishing NCCAM also specifies that it train investigators. Dr. Straus added that training good clinical investigators provides a general benefit. Dr. Donald Wilson of the University of Maryland School of Medicine said that the Council of Deans endorses the idea of bringing rigorous scientific standards to the study of alternative and complementary medicine. He noted that medical students often are learning of such treatments and practices from health store clerks or on the Internet, and that it would be better for them to learn these things in better ways.
Dr. Thomas Cech of the Howard Hughes Medical Institute said that it is important to have a strong scientist, namely Dr. Straus, heading NCCAM. He pointed out that individuals who use alternative therapies often insist that they be used not as pure compounds but as mixtures or as unrefined extracts from plants. The type of preparation tested could make a difference in the results of clinical trials. In response, Dr. Straus said that this issue is sensitive and controversial. In general, NCCAM council members advise studying plant extracts instead of purified compounds, pointing out that other Institutes and Centers can conduct conventional studies on highly purified agents, according to Dr. Straus. Moreover, it is a valid scientific question — one that NCCAM will pursue — to determine whether various extracts are more or less effective than the purified products derived from those mixtures. In the short term, plans call for testing products as they are commercially available.
REPORT ON THE STATUS OF THE IMPLEMENTATION OF BISTI
Dr. Kirschstein reminded ACD members that NIH established an Office of Bioimaging and Bioengineering, an outgrowth of the Bioengineering Consortium of Institutes and Centers (BECON). During the June 1999 ACD meeting, Dr. Larry Smarr and Dr. David Botstein of Stanford University presented a report that led to the Biomedical Information Sciences and Technology Initiative (BISTI). An implementation group, co-chaired by NCI Director Dr. Richard Klausner, NHGRI Director Dr. Francis Collins, and NIGMS Director Marvin Cassman developed plans for the BISTI program. Meanwhile, the Institute Directors agreed to rename the Office of Bioimaging and Bioengineering, now calling it the Office of Bioengineering, Bioimaging, and Bioinformatics (OB3 ).
Dr. Klausner said that former Director Varmus asked him and others in October 1999 to form a group to implement recommendations embodied in the report presented to ACD by Dr. Smarr and Dr. Botstein. He said the members of this group, particularly Dr. Carol Dahl, who directs the NCI Office of Technology and Industrial Relations, put considerable effort into meeting the challenges of implementing the Smarr-Botstein recommendations.
The first of its recommendations is to establish national programs of excellence for integrating information sciences with biomedical research. However, identifying which departments at universities are best suited for implementing this recommendation is not so straightforward, according to Dr. Klausner. The implementation group chose to follow a two-track approach by creating several centers and by issuing planning grants of considerable size (up to $500,000 per year and lasting up to three years) that will enable institutions to create programs that could eventually qualify for becoming centers. This trans-NIH mechanism, funded at about $10 million for the planning grants, should allow academic institutions to establish training programs and build infrastructure. Meanwhile, individual Institutes at NIH can separately review applications to fund specialized bioinformatics centers of excellence.
Dr. Klausner said that another recommendation calls for NIH to support activities through investigator-initiated research. The implementing group concluded that traditional R01 would not be the best mechanism but, instead, that the Phased Innovation Award for technology development is better suited to this purpose.
To coordinate these efforts, a BISTI consortium has been formed, with representatives from each of the Institutes and Centers, and it will be administered by the Office of Extramural Research under Dr. Wendy Baldwin, according to Dr. Klausner. This consortium will serve as a continuing forum to share information about on-going developments in an area that is experiencing rapid growth. He said that it will serve another important purpose, namely to help determine how NIH will participate in the wider federal build-up of the information infrastructure, an initiative that is administered under NSF but it involves several other federal agencies and departments.
Dr. Klausner described several examples where NCI is involved in innovative bioinformatics projects and activities. In clinical trials, for instance, NCI is developing a Cancer Informatics Infrastructure with common data elements and a Web-based structure to provide information about clinical trials. NCI also is setting up a Center for Bioinformatics that Dr. Ken Buetow will manage. To begin with, it will be restricted to a limited number of data-rich activities, such as clinical trials and mouse models for human cancer, that will be incorporated into this system.
Eventually, however, the goal is to develop a single portal for containing and providing comprehensive information about cancer research findings, according to Dr. Klausner. In the shorter term, the plan is to develop modules, such as one for the Director's Challenge, a new approach to the molecular classification of cancers, that will contain a range of data sets organized around a particular theme, or core. Another challenge is to make these cores interoperable. However, reaching these goals is not simple, nor will it be cheap. Dr. Klausner said that the effort to build a Web-based National Cancer Clinical Trials System requires $25 million per year but is under funded by a factor of two-three.
Dr. Larry Smarr, of the University of Illinois, said that he was pleased to see this program taking shape under the leadership of the BISTI Consortium. He warned that the system is likely to grow exponentially and that considerably more infrastructure will be needed to meet those growth needs. The challenge is compounded by discontinuities in both hardware and software, and the tendency of clusters of scientists to accept or develop new systems that may not mesh with those being used by others. Thus, he recommended trying to find an infrastructure that is scalable and usable among different centers, rather than having individual centers invest huge amounts in building their own separate infrastructures. He also suggested that the Intramural Program, perhaps the Frederick Cancer Center, could assume this responsibility.
In response, Dr. Klausner said that the Frederick facility is specialized in traditional computational biology and is not well suited to meeting other bioinformatics needs and would be difficult to adapt to them. In fact, efforts are under way to build a system within NCI into which that on-going effort could fit, according to Dr. Klausner. He said a good example of a working bioinformatics system at NIH is NCBI but that it is not designed to serve the needs of a specialized clinical trial system, such as NCI or other Institutes might develop.
Dr. Kirschstein said that a broad array of new activities is increasing the demand on management at NIH and that more people will be required to administer these programs and more resources will be needed to meet this increased overhead demand. In response to Dr. Eric Lander from the Whitehead Institute, she said that, despite considerable growth in the NIH budget, Congress has not permitted the administrative side of NIH to grow commensurately, but that efforts are under way at several levels to explain this problem to members of Congress. Dr. Lander suggested that an entity such as the National Academy of Sciences should study this issue.
The Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) met on June 8, 2000, to consider a series of recent developments to strengthen the protection of human subjects in research, recent successes in the Human Genome Project, plans for implementing an electronic system for clinical trials data and plans for disseminating scientific literature by another electronic system, a comprehensive program for reducing health disparities through research and other activities, plans for studying alternative and complementary medicine, and recent efforts to implement recommended actions involving bioinformatics programs.
The ACD acknowledged and commented on these reports, and ACD members recommended that the National Academy of Sciences study whether the NIH administrative staff should be expanded to allow a more orderly approach for dealing with budget increases and rapidly expanding research-related activities.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Yvonne Maddox, Ph.D. Acting Executive Secretary Advisory Committee to the Director, NIH