The 75th meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on December 4, 1997. NIH Director, Dr. Harold Varmus, began by introducing two new members of the Committee and by discussing personnel changes at NIH. He also reviewed several budgetary matters, noting that President Clinton recently signed the Labor, Health and Human Services, and Education Appropriations bill, which specifies an increase of $907 million, or 7.1 percent, over the fiscal year (FY) 1997 NIH budget to a total of $13.648 billion for FY 1998. During the four years that Dr. Varmus has served as NIH director, the NIH budget has grown substantially and prospects for continued growth are bright.
Dr. Varmus said that there are a number of recent Congressional activities that will have an impact on NIH programs and budgets. These activities include: drafting a reauthorization bill for NIH; $30 million earmarked for research on type 1 diabetes (Balanced Budget Act); $15 million for high quality medical research (Supplemental Emergency Act of 1997); and an unspecified amount for research on breast cancer (Stamp Out Breast Cancer Act). In addition, legislation to reform the Food and Drug Administration (FDA) requires NIH to join with FDA and other agencies to establish a database and information service on research, treatment, detection, and prevention activities, as well as a database on clinical trials.
Dr. Elvera Ehrenfeld, Director of the Center for Scientific Review (CSR), identified several important issues related to the review of research proposals that are raising concerns among biomedical researchers. In general, they consistently identified two broad areas of concern: (1) process-related issues affecting the efficiency of grant application reviews, and (2) the organization of grant review study sections and its impact on the fairness of research grant reviews.
Dr. Ehrenfeld and Dr. Wendy Baldwin, Deputy Director for Extramural Research, are implementing a series of changes to the grant application review process to address the first set of concerns. Dr. Ehrenfeld is convening a panel of diverse experts to recommend ways of addressing the second set of concerns. CSR is implementing changes in review procedures and study sections in specific research areas, such as neuroscience where 21 new study sections will be conducting reviews of neuroscience research proposals by June 1998.
Dr. David Nathan of the Dana-Farber Cancer Institute summarized the findings and recommendations of the NIH Director's Panel on Clinical Research. Despite a widespread perception among young investigators of poor career opportunities in clinical research, NIH data indicate the grant success rate for Ph.D.s and M.D.s is about the same and that funding support to M.D.s for clinical research is steady and reasonable. The Panel made several recommendations, including that NIH continue to closely monitor the balance of resources in this field and that training programs be designed to enhance the attractiveness of clinical research careers for medical students, with an emphasis on careful mentoring.
Dr. Baldwin described three separate developments affecting NIH grants and training programs. She first outlined the plans and reasoning behind the decision to eliminate the R29 category of grants for first-time applications from young investigators; during this transition, they will receive special consideration when applying for R01 support. She then summarized draft guidelines outlining how NIH will strengthen the training of clinical investigators, primarily through the K30 clinical research curriculum award for institutions to develop two-year didactic training programs. Finally, she described the modular grants concept, which will support research projects budgeted between $50,000 and $150,000 per year, at fixed dollar increments of $25,000.
Ms. Rebecca Eisenberg of the University of Michigan Law School is chairing a working group that is examining potential problems that NIH-funded investigators may encounter in obtaining access to research tools. A general concern of university-based technology licensing officials is that faculty members are asked to concede ownership or licensing rights to future discoveries following their uses of someone else's research tools, according to an initial survey. An early specific consideration of the working group is concern over potential restricted uses of single nucleotide polymorphisms (SNPs), a research tool of importance for human genetics studies.
Dr. Lana Skirboll, Associate Director for Science Policy, described current NIH efforts to implement the Government Performance and Results Act (GPRA) of 1993. Those efforts focus on developing a performance plan, report, and assessment, based on both qualitative and quantitative NIH-wide performance indicators. Important challenges are to assemble this material into a performance report in 1998 and to develop a plan to assess performance in the future. Part of this assessment involves outside review, which will likely be conducted by a panel that includes ACD members.
Mr. Jack Mahoney, former Deputy Director for Administration, NIH, described a recent review of NIH administrative structure and practices that was conducted by Arthur Andersen Consulting, with assistance from NIH senior managers. The Arthur Andersen report concludes that NIH research management and support practices are functioning properly, the decentralized administrative structure is sound, the public and legislative affairs staffing levels are appropriate, and, in some categories such as the extramural grants program, NIH operates as well as, or better than, other governmental organizations. The report made 80 specific recommendations, which NIH senior managers are implementing on a priority basis.
Dr. Harold Varmus, Director, National Institutes of Health (NIH), began the 75th meeting of the Advisory Committee to the Director (ACD) by introducing two new members of the Committee; Dr. Yank Coble, a physician and faculty member of the University of Florida, and Dr. Shirley Tilghman, a Howard Hughes Medical Institute investigator and professor of biology at Princeton University. He invited all the Committee members to provide suggestions for future agenda items, and reminded them that they may be called upon to serve NIH in other advisory capacities during the terms of their ACD memberships.
Dr. Varmus reviewed several recent personnel changes at NIH, including: the retirement in September of Dr. James Snow, Director, National Institute on Deafness and Other Communication Disorders; the departure in December of Dr. Zach Hall, Director, National Institute of Neurological Disorders and Stroke; and the departure in November of Dr. William Paul from the position of Director, Office of AIDS Research. Searches are under way to fill these positions, as well as the following positions: Associate NIH Director for International Research, a position that also entails directorship of the Fogarty International Center; Chief Information Officer for NIH; and Director of the AIDS Vaccine Research Laboratory.
Dr. Varmus reviewed several budgetary matters affecting NIH. On November 13, 1997, President Clinton signed the Labor, Health and Human Services, and Education appropriations bill, which specifies an increase of $907 million, or 7.1 percent, over the FY 1997 NIH budget to a total of $13.648 billion for FY 1998. In addition, the appropriations bill provides $90 million for the NIH Clinical Research Center, and $17 million to help construct a facility for the AIDS Vaccine Research Center. The legislation authorizes research on Parkinson's disease, maintains a ban on Federal support for human embryo research, and continues a ban on needle exchange programs until the Secretary of the Department of Health and Human Services (HHS) makes a determination on this issue sometime after March 31, 1998.
Dr. Varmus said that other Federal legislation also affects the NIH budget, including the Balanced Budget Act, which earmarks $30 million for research on type 1 diabetes; the Supplemental Emergency Act of 1997, which provides $15 million for high quality medical research; and the Stamp Out Breast Cancer Act, which provides an unspecified amount for research on breast cancer.
Dr. Varmus said that, although the FY 1999 budget for NIH is under active development, details about it will not be made public until February 1998. Nonetheless, dramatic changes have taken shape during the four years that he has been serving as NIH director, with an overall positive effect on NIH budget prospects. For instance, when the NIH budget was threatened by serious cuts in 1993, Dr. Varmus argued for the scientific community to adapt to "life in the steady state." The following three years, however, brought a period of low overall inflation and NIH budgets grew annually by six to seven percent–in effect, providing a more powerful increase to research budgets and permitting NIH to plan scientific initiatives and institute positive changes in grant policies.
Since Congress passed the Balanced Budget Act, the prospects for further increases in the NIH budget are even more favorable, according to Dr. Varmus. Although there is widespread interest in doubling the NIH budget within the next five to ten years, it is important to remember that the budget is determined on an annual basis, and the importance of the role of inflation.
Dr. Varmus said that, however the NIH budget increases, planning efforts to use new funds should not devolve into a debate of conducting research on one disease versus another. Instead, such discussions should focus on general mechanisms for supporting science, including appropriate use of funds for training, construction, shared resources, equipment, and different types of grants.
Dr. Varmus reviewed several other legislative matters affecting NIH. Because the 1993 authorizing legislation has expired, NIH now operates under older Public Health Service legal authority. To remedy this situation, the Senate is moving toward drafting a reauthorization bill. Recently, Senator Bill Frist (R-TN), Chairman of the Subcommittee on Public Health and Safety, has convened three hearings on NIH-related matters: research priority setting, coordination of research activities, and clinical research and alternative medicine.
Recent legislation reforming the Food and Drug Administration (FDA) included the directive to NIH, FDA, and the Centers for Disease Control and Prevention (CDC) to establish a database and information service on research, treatment, detection, and prevention activities of the three agencies, as well as a database on clinical trials. Dr. Varmus said that this requirement poses a considerable challenge that is part of a larger undertaking to make scientific information more readily available to the public.
In June, Dr. Varmus appeared before the House of Representatives Subcommittee on Oversight and Investigations, which is chaired by Representative Joe Barton (R-TX), to discuss a violation, which involved misappropriation of NIH equipment in the Intramural Program, of the ban on human embryo research. Dr. Varmus said that the members of the Subcommittee have taken a considered approach to this difficult problem but have scheduled no further hearings on this topic.
Dr. Varmus reviewed the progress on several issues considered at earlier meetings of the Committee. For example, a malaria research initiative was discussed during the 74th ACD meeting in June 1997. Subsequently, in July, Dr. Varmus, Dr. Anthony Fauci, Director, National Institute of Allergy and Infectious Diseases (NIAID), and several colleagues attended a meeting in the Hague, the Netherlands, to consider how separate agencies might collaborate while reviewing and funding malaria research proposals. Although these matters were not resolved, the meeting helped lead the Tropical Disease Research Organization (TDR) within the World Health Organization (WHO) to assemble a $3 million program to fund malaria research in Africa. Funding for this program is being provided in part by NIH, the World Bank, TDR, and several other organizations.
In November, the Wellcome Trust held a meeting in London to consider the progress of the general collaborative research program on malaria. It was decided that, for the present time, funding would continue to be made largely by independent institutions, with the exception of the one program led by the TDR. The Wellcome Trust will serve as the broker and secretariat for future malaria-related research activities. Meanwhile, repositories for reagents that are valuable for malaria research are being set up under the auspices of NIAID, and electronic mail and Internet connections are being established in Mali, Kenya, and at least one francophone company.
Dr. Varmus outlined several developments related to AIDS vaccine research, which also was discussed during the 74th meeting of the Committee. In response to a recommendation from the AIDS Vaccine Advisory Committee, chaired by Dr. David Baltimore, NIAID established a program for vaccine innovation grants. Within seven months, this program has awarded 58 grants, half to investigators who are new to this field. The advisory committee also has held several workshops, including one in Madrid to stimulate greater involvement of researchers in Europe. At the same time, the AIDS Vaccine Research Center is holding meetings every two weeks, involving as many as 80 investigators. NIH also held a meeting with representatives from industry to discuss the vaccine program and collaboration opportunities.
Dr. Varmus summarized additional developments affecting other issues from past meetings, including research priority setting and several efforts affecting new investigators. A booklet describing priority setting at NIH has been published. In addition, in the NIH appropriations bill, passed by Congress, included $300,000 for a study by the Institute of Medicine on how NIH sets research priorities.
Several new programs within the NIH Intramural Program are geared to the training of young investigators. One, involving students in the clinical research program at NIH, was instituted following recommendations from the Clinical Research Panel, which was chaired by Dr. David Nathan. This training program could serve as a model to be used by academic medical centers. Related to this program, NIH is looking for a director for the Intramural Education Office to develop a graduate program at NIH.
Dr. Varmus described several events involving high-level officials participating in NIH-related activities. In June, President Clinton received recommendations on human cloning from the National Bioethics Advisory Committee, as part of a White House ceremony. In November, the presentation of the Presidential Early Career Awards included 11 NIH-supported scientists, one from the Intramural Program and the others from the Extramural Program.
Vice President Gore also participated in several events, including the opening of "Pub Med," which provides free electronic access to information held at the National Library of Medicine, and the opening of the Cancer Genome Anatomy Project Website, a more specialized series of electronic databases organized under the auspices of the National Cancer Institute (NCI). The Vice President, former Senator Mark Hatfield, HHS Secretary Donna Shalala, Senator Arlen Specter (R-PA), Representative John Porter (R-IL), and two cystic fibrosis patients who are enrolled in experimental protocols at the Clinical Center, participated in the groundbreaking ceremony for the Mark O. Hatfield Clinical Research Center now under construction at NIH.
Dr. Varmus summarized continuing efforts to conduct reviews of Institute and Center Directors on a five-year basis, stating five such reviews have been completed and four others under way. These reviews, several of which involved members of the Committee, are providing directors with valuable feedback. In addition, independent reviews of components of the Intramural Program are continuing to provide information that has led to valuable improvements. Reviews of the overall Intramural Program, the intramural programs of NCI, the National Institute of Mental Health (NIMH), and of the National Institute on Drug Abuse (NIDA) are completed; reviews of programs within five additional Institutes are under way.
Recommendations from reports reviewing the NIH Recombinant DNA Advisory Committee (RAC) have been implemented, reducing the size of RAC from 25 to 15 members, and moving all approvals of gene therapy clinical trials to FDA. RAC members continue to discuss new approaches and techniques for gene therapy. The committee, in conjunction with the Office of Recombinant DNA Activities, is organizing forums on new technologies, one of which was held in December 1997, and gene therapy policy conferences, held in September 1997, with another scheduled for March 1998.
Dr. Varmus summarized several developments affecting the NIH program to study alternative medicine. The appropriations bill substantially increases funding for this program from $13 million in FY 1997 to $20 million in FY 1998. The NIH Office for Alternative Medicine (OAM) is organizing efforts within individual institutes to apply scientific validation study methods to widely followed alternative medicine practices, such as the use of St. John's wort extracts to treat depression and acupuncture to treat osteoarthritis; studies of other such products or procedures from alternative medicine are being planned. In addition, Dr. William Harlan, who directs the Office for Disease Prevention, of which the OAM is a part, is helping Dr. Varmus to organize a multiagency group, including representatives from FDA, CDC, the Agency for Health Care Policy and Research, and several institutes at NIH, to provide oversight and recommendations on alternative medicine research priorities.
Dr. Varmus noted that Anne Alexander has been appointed the director of the National Foundation for Biomedical Research, whose board is chaired by Dr. Charles Sanders, formerly the director of Glaxo. The Foundation is involved in several activities, such as the new clinical research training program at NIH. Congress earmarked $500,000 in start-up funds for the Foundation in the appropriations bill.
Dr. Varmus said that NIH is involved in discussions with representatives of the biotechnology and pharmaceutical industries, as well as of several Federal agencies concerning how to improve the development and testing of new drugs. Specific issues of interest include the use of surrogate markers to accelerate drug evaluations; the training of clinical researchers, especially of clinical pharmacologists; and means to work more effectively with the managed care industry while evaluating drugs.
In September 1997, the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop to consider opportunities in diabetes research. The workshop was convened in part because Congress has allocated substantial new funding for diabetes research, primarily through the Balanced Budget Act. A panel with representatives from advocacy groups, the research community, and the eight to ten institutes involved in this research, will oversee these new plans for research.
Several ethics-related issues, which may become a topic for ACD consideration, are under discussion at NIH. For instance, officials from NIMH and several other institutes held a workshop in December 1997 to consider informed consent issues, particularly as they apply to the participation of individuals with mental impairment in clinical trials. The Genetics Testing Task Force recently completed a report on ethical issues involved in such testing. A new trans-NIH bioethics committee is considering both these issues. In addition, Dr. Ezekiel Emanuel, who is the Director of the Bioethics Office at the Clinical Center, is heading a new teaching program in bioethics.
Dr. Varmus noted several highlights from NIH-sponsored research programs, including completion of the sequence of the Escherichia coli genome; isolation of genes encoding telomerases; identification of a gene responsible for a familial form of Parkinson's disease, which encodes a protein that is also implicated in Alzheimer's disease; isolation of the gene responsible for Niemann-Pick type C disease, which is involved in cholesterol metabolism; evidence that diuretics markedly reduce the incidence of congestive heart failure among elderly individuals with hypertension; the isolation of an infectious clone of the hepatitis C virus; development of a new mouse model for sickle cell disease; and discovery that mutations in an ABC gene may be responsible for a sizable fraction of cases involving age-dependent macular degeneration. In addition, two vaccines have made marked progress: an oral vaccine to protect against rotavirus infections and an aerosol vaccine to protect against the influenza virus.
Dr. Varmus also mentioned several up-coming meetings of interest, including a Department of Health and Human Services workshop on xenotransplantation policy in January 1998, back-to-back meetings on the mouse genome and mouse genetics, and a workshop on the design of clinical trials information systems in February 1998.
Dr. Philip Needleman said that the expanding AIDS vaccine research efforts are especially important because of reports that the new class of antiviral drugs known as protease inhibitors, which are used for treating individuals infected with the human immunodeficiency virus (HIV), are sometimes failing clinically because of viral resistance.
In responding to a question from Dr. Jane Henney about the allocation of new resources for diabetes research, Dr. Varmus said that NIDDK is administering those resources and that other agencies, including CDC and the Indian Health Service, will also be using some of these resources. He agreed that IOM, which will be analyzing, in general, how NIH sets research priorities, also should look at this specific case as part of that broader study. More information about plans for the IOM study, the terms of which are being negotiated, will be provided at the next ACD meeting. In addition, Dr. Varmus said that basic biology research and prevention studies in diabetes are part of a continuum.
Dr. Marc Kirschner asked how recent increases in NIH budgets affected priority setting. Specifically, do greater resources lead to the funding of a greater number of grants from year to year, or is there a broader impact on larger programs? Dr. Varmus said that NIH has received substantial increases in funding above inflation during recent years, and these additional resources have been used for both purposes. Thus, for example, the success rate for grant proposals has risen from about 20 percent to nearly 30 percent, and the number of new grants from about 6,000 to nearly 7,800.
Meanwhile, the number of research initiatives has also been expanding, with priorities based on recommendations from institute and center directors. They typically rely on program announcements to encourage investigators to submit competitive grant proposals in new areas of research emphasis. In addition, more directed programs, such as the Cancer Genome Anatomy Project, have been developed following advice from the wider research community. In addition to spending new resources directly on research, it also is important to consider other needs, such as training, shared resources, facilities, and research instruments.
Responding to a question from Dr. Coble about legislative proposals regarding the privacy of clinical records, Dr. Varmus said that this issue might be considered at a future ACD meeting. Dr. Wendy Baldwin pointed to two NIH initiatives in bioethics, one to develop and support a short-term training program in this field, and the other to support individuals seeking to specialize in this area.
Responding to a question from Dr. Elaine Fuchs about shortages of resources for training foreign students and supporting postdoctoral researchers from abroad, Dr. Varmus pointed out that research grants may be used as a source for salary support for such individuals. He also suggested that this issue might be taken up at a future ACD meeting.
REPORT ON THE CENTER FOR SCIENTIFIC REVIEW
Dr. Elvera Ehrenfeld, who has served as Director of the Center for Scientific Review (CSR, formerly the Division of Research Grants [DRG]) since early 1997, said that she spent the first months in her new position focusing on outreach activities to learn what grant-related issues are of concern to the broader community of biomedical researchers. Two broad areas of concern were consistently identified: (1) process-related issues affecting the efficiency of grant application reviews, and (2) the organization of grant review study sections and its impact on the fairness of research grant reviews. She also said that members of several specific groups, particularly researchers working in clinical medicine, the behavioral sciences, and instrumentation development and bioengineering, reported that their specialty areas are not receiving fair treatment during proposal reviews.
Changes to improve the efficiency of grant application review processing are being implemented, largely under the direction of Dr. Baldwin at the Office of Extramural Research but also through CSR, according to Dr. Ehrenfeld. She said that efforts to address the second set of concerns, which focus on fairness of reviews, represent a more formidable challenge.
One important set of questions revolves around whether, in some study sections, reviewers deal with highly competitive proposals and generally are overwhelmed with too many high quality applications, while other study sections review areas of less competitive scientific activity and fewer high quality applications, leading to entitlements. There may be no appropriate study section for newly emerging areas of science. Although established many years ago, most study sections have been variably modified and remodeled over the years.
Dr. Ehrenfeld observed that, although the way scientific research has changed enormously during the past decade, no one has tried to evaluate the entire study section organization or to develop a strategy for wholly revamping it. Indeed, the multidisciplinary nature of current research may necessitate fundamental changes in the way research proposals are reviewed. Faced with the need to broaden the composition of review groups makes the retention of the expertise needed to review rigorously all the proposals that come before such groups a very difficult challenge, according to Dr. Ehrenfeld.
Dr. Ehrenfeld is convening a panel of diverse experts to recommend ways of addressing these issues. The panel is expected to complete its deliberations in about one year. CSR has already implemented changes in review procedures and study sections in specific research areas. For example, because Congress mandated that the NIMH, NIDA, and the National Institute of Alcohol and Alcohol Abuse (NIAAA) research programs be integrated into NIH, CSR has reorganized the system for reviewing all neuroscience-related research grant proposals. By June 1998, 21 new study sections will be conducting these reviews.
Dr. Ehrenfeld said that this reorganizational effort was undertaken in a collegial manner, and included representatives from the extramural community working in close cooperation with representatives of NIMH, NIDA, NIAAA, and several additional institutes, such as the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development, and the National Institute on Aging. Several other Institutes with smaller neuroscience portfolios also chose to participate in the integration effort. The process may serve as a useful model for other efforts to reorganize study sections within CSR. Indeed, similar reorganization efforts, affecting the review of proposals for AIDS research and for research in the behavioral sciences, are under way.
To address the concerns of researchers working in clinical medicine, the behavioral sciences, and bioengineering, who report that their specialty areas are not receiving fair treatment during proposal reviews, Dr. Ehrenfeld will seek help from several consultants within those respective communities. For example, Dr. Michael Simmons, a pediatrician from the University of North Carolina, has worked with her and several institute directors to identify potential problems and gaps in clinical research within their overall research portfolios. She and Dr. Simmons also have met with many representatives of the clinical research community at their institutions and through their professional organizations. Dr. Simmons is expected to deliver his final report and recommendations by the end of 1997.
Dr. Ehrenfeld said that part of this analysis indicates that, in study sections with relatively few clinical research applications to consider, the success rates of those applications also tends to be low. However, for those study sections with many patient-oriented research proposals to review, the success rates of clinical and non-clinical proposals tend to be better balanced. To address this issue, such reviews will be clustered into appropriate biological groups to determine whether such a change will alleviate the current unevenness.
Dr. Ehrenfeld alluded to several other CSR initiatives, including efforts to improve the process for recruiting reviewers and to enhance interactions between the institutes and the review offices.
Dr. Needleman asked whether the decision to establish 21 new neuroscience study sections reflected workload needs or scientific categorizations. Dr. Ehrenfeld said that both of these and other considerations led to establishing 21 study sections, an increase in the aggregate number of study sections that dealt with similar subject matter. Basic decisions were made on scientific and programmatic grounds, with flexibility to accommodate expanding interest in certain research areas and with considerable input from the extramural community.
The 21 study sections are clustered into three broader Initial Review Groups (IRGs), an organizational structure which allows oversight in considering broader scientific questions concerning overall research directions in sub-areas within neuroscience. CSR is establishing IRG oversight groups, which will be comprised of from five to nine reviewers from the extramural community, and will provide advice regarding the distribution of proposals within the IRG in choosing and recruiting reviewers to serve on study sections, and in predicting where the field is likely to grow or contract. Realizing that not all experiments are successful, CSR has established an Evaluation Office to monitor how well these changes in the system are working and to recommend corrections, where necessary.
Dr. Susan Horwitz said that the most important factor affecting the grant review process is the quality of people who serve on the study sections. She urged that workloads be reduced to encourage wider participation of senior scientists with the breadth and maturity needed for quality reviews.
Dr. Ehrenfeld said that NIH needs to accommodate changes in the academic world that have put increased demands on potential reviewers from many different specialty areas. One such change will be for NIH to be more flexible in the length of terms and other requirements for reviewers to meet, while still establishing a "culture" and group dynamic that leads to high quality reviews from highly interactive study section members. Another change will be to improve the way in which new reviewers are identified by moving away from a predominantly "old boy" and "old girl" network to one that includes a broader spectrum of investigators. She said that the fact that overall funding is increasing also will encourage wider participation of busy scientists in the review process.
Dr. Ezra Davidson pointed out that CSR conducts about two-thirds of all grant reviews, and the institutes and centers conduct the remainder. He asked whether changes similar to those being instituted at CSR are planned elsewhere at NIH and, in particular, whether unevenness in reviews of clinical research proposals will be dealt with at the centers and institutes.
Dr. Ehrenfeld said that a larger fraction of clinical research applications are reviewed in the centers and institutes rather than at CSR. Many of those non-CSR reviews, however, involve large and complex multicenter clinical trials that currently are best reviewed at the institutes and centers level. Thus, the focus of changes within CSR affecting clinical researchers is on smaller scale, hypothesis-driven proposals. She said that the improvements being tested by CSR may lead to solutions that will prove applicable to the institutes and centers.
Dr. Tilghman asked why clinical research proposals that are reviewed in study sections where many such proposals are referred ("high density") fare better than do those reviewed by study sections to which relatively few are referred ("low density"). She speculated that these outcomes might be due to unfairness because most of the reviewers do not understand clinical research or they may be fair, reflecting the reviewers' conclusion that the nonclinical proposals are a better investment.
Dr. Ehrenfeld said that, in addition to these two explanations, other factors contribute to why proposals from clinical investigators tend not to receive high scores when reviewed by "low density" study sections. Those factors include the investigators' lack of experience in writing research proposals, attending research meetings and presenting research results in formal settings, as well as differences in their formal training when compared to investigators who do basic research.
Dr. Tilghman also said NIH may want to set an explicit threshold for supporting clinical research or, instead, may prefer to insist on supporting the best science, which sometimes may lead to reduced support for clinically oriented studies.
Dr. Ehrenfeld pointed out that the institutes perform two levels of review, with the second permitting an opportunity to correct imbalances in their overall portfolios, and to address Congressional mandates or concerns raised by patient interest groups. Although proposal reviews are one part of the overall picture, it is important that study sections be properly constituted to handle them fairly.
Dr. Varmus said that because the process by which a proposal is assigned to an institute or a particular study section can have an impact on the outcome of its review, the Committee should also consider whether it is appropriate for institutes to override one another's review decisions. He said that the variation among institutes is substantial enough to raise concerns.
Dr. Eric Kandel said that, because neuroscience has become so interdisciplinary, it seems increasingly possible for someone who is considered a neuroscientist to be qualified to evaluate biomedical research proposals from a much broader array of specialty areas. Thus, he recommended including reviewers from disparate specialty areas on single study sections to achieve "cross-fertilization."
Dr. Kirschner said that decisions being made at the study section level, some of them reflecting unconscious policies, may be exerting even more fundamental effects than is realized. For instance, by channeling young researchers into spending longer periods at the postdoctoral level, study sections may be influencing and perhaps distorting the kinds of proposals they eventually submit as independent investigators. He recommended approaching the whole issue creatively and very broadly, pointing out that the institutes cannot readily override the main decisions of the study sections, and suggested specific changes, such as mandating much briefer grant applications, to encourage young investigators while improving the overall system.
Dr. Ehrenfeld said that the institutes cannot ignore or broadly override peer-review decisions made at the study section level if they want to foster high quality science. She also said that, although her focus was deliberately limited to reorganization-related issues at CSR, there are many broader "cultural" issues that influence research priority setting and decision making at NIH.
REPORT FROM THE CLINICAL RESEARCH PANEL
Dr. David Nathan of the Dana-Farber Cancer Institute summarized the findings and recommendations of the NIH Director's Panel on Clinical Research, which he chaired. The Panel defined clinical research broadly to include patient-oriented research, epidemiologic and behavioral studies, and outcomes and health services research.
Dr. Nathan used an anecdote to describe the paradoxical situation of this field which, despite unprecedented scientific opportunities, finds many investigators frustrated with what they see as perilously limiting opportunities. He cited correspondence regarding a patient with Fanconi's anemia where molecular genetic details about this condition, as well as the possibility for a gene therapy-based treatment were discussed. He said that such hopeful discussions are at odds with widely held beliefs that there is a paralyzing crisis in clinical research.
Dr. Nathan stated that the prevailing perception, particularly among young investigators, is that there are few opportunities for satisfactory careers in clinical research. Reasons for this perception include poor training to prepare them to embark on such careers, the burden of debt they carry when they emerge from medical school, the low prestige accorded clinical research careers at many institutions, the sense that competition for grant support is intense and perhaps unfair, and a widely held belief that a clinical research career in medical schools has become a slow and unreliable track to promotions and tenure.
NIH data indicate the grant success rate for Ph.D.s and M.D.s is the same, but fewer M.D.s are applying for grants. The number of Ph.D.s submitting grant applications is growing rapidly, while the number of M.D.s submitting applications has increased slowly, according to Dr. Nathan. During the past three years, first-time M.D. applicants have declined by 30 percent, whereas first-time Ph.D. applicants declined by only 6 percent.
Dr. Nathan cited other NIH data indicate that, overall, about 27 percent of the funded grants, accounting for 36 percent of the budget in 1996, fit the Panel's definition of clinical research. Moreover, in the narrower pool of R01 grants, 26 percent of the grants and 32 percent of the budget went for clinical research. In part, because of the large number of Ph.D.s applying for all grants; 52 percent of the principle investigators (PIs) were Ph.D.s, compared to 36 percent M.D.s and M.D.-Ph.D.s. (The remainder of the applicants were dentists and other health professionals.)
Dr. Nathan also referred to a study conducted several years ago by IOM that considered the relative success of clinical research applicants at NIH. He noted that, although half the grant applications in clinical research were being reviewed by the institutes, instead of by DRG (now CSR), IOM examined only those reviews conducted by DRG. The Panel concluded that this omission was a serious flaw in the earlier IOM study. The Panel also considered the IOM definition of clinical research to be too narrow.
The Panel recommends that NIH continue to monitor closely the clinical research situation and to be particularly careful about the balance of resources supporting and people pursuing careers in this field. The Panel also recommends that training programs be designed to enhance the attractiveness of clinical research careers for medical students, such as more formal programs with an emphasis on careful mentoring; new support mechanisms for young and mid-term investigators to pursue opportunities in clinical research; participation in the training of clinical investigators by the 70 academic health centers (GCRCs) and the integration of clinical research into their broader programs; and that the Warren Grant Magnuson Clinical Center at NIH play a critical role in these efforts.
The Panel also suggests that it, or a successor group, look at several issues, including how the Government might help medical schools and teaching hospitals deal with funding problems they now face; the recruitment of minority group members into clinical research careers; and the changing relations among private foundations, the pharmaceutical industry, and managed care organizations.
In responding to a suggestion from Dr. Kandel that increased clinical training of Ph.D.s could result in them contributing more to clinical research, Dr. Nathan said that Ph.D.s already contribute greatly in collaborative projects in clinical research, but physician investigators are an "endangered species." Dr. Varmus said that NIH supports programs in which Ph.D.s learn about disease processes and are encouraged to conduct clinically oriented research. He also said that if NIH establishes a graduate program, the Ph.D.s trained in the program will do at least some clinically oriented research.
Dr. Needleman asked whether the fundamental mission of NIH in clinical research should be reexamined. Should NIH focus its resources on improving the science underlying clinical research and not support large-scale clinical trials? Dr. Nathan stated that one-third of the NIH clinical research budget supports trials that probably would not be conducted in the private sector. He said it is unlikely that much NIH money supports unnecessary clinical trials. Dr. Varmus agreed and added that many of the studies of scientific fundamentals underlying clinical research is being conducted by Ph.D.s.
Dr. Eric Lander said that, although the reasons behind the complaints coming from young clinical investigators and would-be investigators remain unknown, the most important focus is on improving their training.
In responding to a question from Dr. Henney concerning the Panel's recommended expanded role for the GCRCs, Dr. Nathan said they could play a leadership role in translational clinical research and in large-scale clinical trials. Moreover, if better organized, the GCRCs could more readily form partnerships with industry.
Dr. Fuchs suggested that NIH foster M.D.-Ph.D. training that emphasizes Ph.D. candidates conducting clinical research under the supervision of appropriate mentors. She also said that determining what is really needed to train such individuals for clinical research careers represents a major challenge. Dr. Nathan stated that working toward such a M.D.-Ph.D. program goal would be valuable because it would give medical students research experience and it would help in reducing their debts.
Dr. Varmus said that adding a special clinical research training component to such programs raises concerns, in part because it significantly lengthens the overall time required to complete the program. Moreover, there are not enough mentors to supervise such training. He also said that more imaginative thinking is needed to improve the training of clinical investigators.
Dr. Kirschner suggested that "crossover" training is needed, meaning that Ph.D.s need more opportunities to be trained in clinical subjects and M.D.s in basic sciences.
Dr. Tilghman asked whether any institutions have good training programs that could serve as models. Dr. Nathan said several newer programs may prove to be such models, but there is a shortage of mentors needed to oversee the training that is needed across a broader range of academic institutions.
Dr. Tilghman also asked why the majority of M.D.-Ph.D.s trained during the past decade are conducting basic research. Dr. Nathan said that this skewing reflects the recent fascination with basic research and what can be efficiently accomplished in such work.
Dr. Horwitz observed that graduate schools seem to be expanding while medical schools are contracting. She also asked whether physicians are giving young investigators opportunities to do independent research. Dr. Nathan said that medical school budgets and pool sizes have grown, albeit not so much as graduate schools. Dr. Varmus said that, during a 30-year period, a steady 25 percent of medical students have declared an interest in doing research.
Dr. Kandel said that an important inducement for medical students to embark on research careers is that training programs can help them reduce their debts, making it more possible to pursue a career in academic medicine. Dr. Kirschner added that a program to forgive debts would be helpful.
Ms. Rebecca Eisenberg asked about the relationship between funding of training programs and that of research programs in the clinical sector. She said that supporting training programs without providing adequate funds for clinical research raises serious concerns.
Dr. Lander observed that, in the absence of good training programs for careers in clinical research, pump priming is needed to rejuvenate this field. Once the pool of trained clinical researchers is replenished, better grant proposals will be forthcoming in this area.
REPORT ON NEW INVESTIGATOR AWARDS, MODULAR AWARDS, AND CLINICAL RESEARCH TRAINING
Overview: New Investigator Awards
Dr. Wendy Baldwin, Deputy Director for Extramural Research, outlined plans and the reasoning behind the decision to eliminate the R29, or FIRST, category of grants for first-time proposals from new investigators. This category of grants incorporated certain limitations, such as a $350,000 cap at $70,000 per year for five years, as well as a requirement for a 50 percent time commitment. Although it is designed for first-time investigators, only about one-third of them ever use the R29 mechanism, with the majority relying on R01 grants.
Dr. Baldwin also referred the Committee to the key conclusions of the report, prepared by Dr. Ehrenfeld of CSR and Dr. Marvin Cassman, Director, National Institute of General Medical Sciences (NIGMS), that compares long-term outcomes and performance of investigators supported by R29 or R01 grants. (Dr. Cassman presented an in-depth review of that report during the 74th ACD meeting in June 1997.) Recommendations from that report to eliminate the R29 and rely instead on the R01 grant mechanism for young investigators are now being implemented.
Dr. Baldwin stated that to maintain its commitment to young investigators, NIH plans to support the same number of new investigators this year as last and will take additional steps to educate scientific peer reviewers regarding this policy. For example, forms used for filing R01 applications are being modified to indicate clearly which are submitted by first-time investigators, and reviewers will be briefed about these changes beginning in February 1998. Other changes are being instituted to make the application submission process more "user friendly" for postdoctoral level researchers, including the development of a Website containing guidance geared to this target audience.
Dr. Baldwin said that these changes should prove beneficial to first-time clinical investigators because the R29 mechanism imposed problematic constraints on how investigators were to use their time and on the size of the budgets with which they could support their projects.
Dr. Tilghman said that eliminating the budget cap associated with the R29 grant is extremely positive. She also urged NIH to be especially vigilant advising review groups to distinguish between young and seasoned investigators to ensure that applications from the former group do not fail because of their limited experiences. She asked whether proposals from first-time applicants might be reviewed as a separate cohort.
Dr. Baldwin responded by saying that, although reviews of applications from first-time investigators will not be reviewed separately from those from other researchers, NIH plans painstaking efforts to notify reviewers that first-time applicants are to receive special consideration. Dr. Varmus added that the institute directors also have agreed not to permit the number of new investigators to decline, even if it entails going below paylines.
Dr. Kirschner said that dropping the R29 grant category while ensuring that young investigator numbers are maintained is an appropriate policy decision. He added, however, that the new policy may not go far enough toward encouraging young investigators to propose bolder or more creative projects than typically survive the current R01 review process. Dr. Varmus said that other changes, such as relying on newer expanded criteria for evaluating grant applications and improving the composition of study sections, will help to achieve such goals.
Dr. Henney suggested that changing the format of the application used by young investigators, such as reducing its length and the preliminary data required to accompany it, would help to set proposals from young investigators apart from those submitted by seasoned investigators. Dr. Horwitz and Dr. Fuchs agreed about the value of omitting preliminary data requirements from grant applications submitted by young investigators, noting that this requirement often prevents them from entering into new fields.
Dr. Varmus proposed conducting an experiment in which some study sections do not distinguish among applications from new and seasoned investigators, whereas others do keep applications from those two groups clearly separated.
Dr. Tilghman said that, valuable though these impending changes may be, they will not address an important fundamental problem for young investigators — namely, how to begin working on different scientific problems than what they did under their scientific mentors. In response, Dr. Varmus said that he has recommended to institute directors that they develop programs allowing talented postdoctoral researchers to begin working as independent investigators while working in the laboratories of their mentors. He also said that the challenge of investigators changing fields is a broad one and perhaps an appropriate subject for a forum.
Dr. Lander suggested that there be large-scale grants that enable investigators to take on high-risk projects or switch fields. Dr. Needleman said that the American Heart Association sponsored advanced research fellowships that helped postdoctoral researchers establish themselves as independent investigators before they became encumbered with teaching duties. Dr. Judy Vaitukaitis, Director of the National Center for Research Resources, said that several institutes offer R21 grants for meeting some of these purposes; this award provides an investigator $75,000 to $100,000 per year for a maximum of two years.
Dr. Baldwin said that Requests for Applications (RFAs) offer another means for investigators to change fields and try new ideas with adequate support. She also said that greater flexibility on the part of reviewers, rather than new grant mechanisms, is critical to achieving these goals. Thus, the reviews scheduled for February 1998 will be illuminating because reviewers will be using new evaluation criteria as well as adjusting to the phase-out of the R29 mechanism.
Dr. Kirschner said that expanded resources should enable NIH to experiment beyond reforming grant mechanisms, such as dropping the R29 category. He recommended instituting new mechanisms, including grants intended to give investigators full support as they switch fields. Dr. Kandel said that he and several other senior investigators are working with Mr. Larry Ellison of the Oracle Corporation, who has established a foundation to support research on aging. One foundation goal is to attract established researchers into this field.
Dr. Needleman said that perhaps a hybrid mechanism, one that is part training grant and part research award, could be developed to support young investigators with a good idea, but little or no data to support it. He likened such a mechanism to venture capital used for making high-risk investments.
Overview: Clinical Research Training
Dr. Baldwin summarized draft guidelines outlining how NIH will strengthen the training of clinical investigators. The core of this new program is the K30 clinical research curriculum award. It will provide institutions with support for flexible two-year didactic training programs, with an emphasis on matters such as research design and analysis, as well as relevant ethical issues.
Although several institutions already sponsor training programs in this area, the goal is to expand the availability of such training, according to Dr. Baldwin. She said that perhaps ten such renewable K30 grants will be awarded for five-year periods during the initial phase of this NIH program. The K30 program will allow clinical investigators in otherwise disparate programs at an institution to join forces for training purposes.
While the K30 is being implemented, NIH also will revitalize the K08 awards, which are intended to support M.D.s who move into clinical research. Dr. Baldwin pointed out that K08 awards are more frequently being used to support laboratory rather than clinical research.
Dr. Baldwin said that another type of program, supported by K12 awards, may be established sometime soon. Several K12 awards already support comprehensive clinical research and training programs at medical research institutions, but use of this mechanism is in a pilot phase.
Responding to a question from Dr. Henney, Dr. Baldwin said that, although GCRCs certainly may participate in these clinical training programs, the programs are meant for the wider community. Dr. Varmus said that an institution's eligibility for K30 awards does not depend on its clinical trainees receiving NIH support. Dr. Ting-Kai Li said that involvement of GCRCs in these programs will be critical for their overall success.
Responding to questions from Dr. Horwitz, Dr. Baldwin explained that K30 training awards will not support research, but that K08 awards will provide support for research while an individual is receiving training. A concern, however, is that recipients of K08 awards are not being trained systematically to do research. Dr. Varmus said that these programs will help to add a didactic component to the training of clinical researchers that is now largely absent from the system. Single institutions and groups of institutions are eligible for these awards, and academic institutions may seek additional participation from industry.
Dr. Lander said that merely adding courses on subjects such as biostatistics would not be adequate for producing good clinical investigators. He said that meeting that challenge will require new mechanisms, as well as a major increase in funding to support clinical research. For instance, if the NIH budget doubled, setting aside $1 billion for this purpose would be appropriate, according to Dr. Lander.
Dr. Needleman pointed to a program, directed by Dr. John Oates of Vanderbilt University, that could serve as a model for excellence in clinical training, research design, and translational research.
Dr. Nathan said that these new and revitalized NIH programs, along with the efforts behind them, will prove encouraging and influential in the biomedical research community.
In responding to a comment from Dr. Davidson that Ph.D.s be encouraged to participate in these programs to better prepare them to conduct clinical research, Dr. Baldwin said that the K30 program will be open to Ph.D.s, and their involvement could lead to collaborations on clinical research teams.
Overview: Modular Awards
Dr. Baldwin said that the modular grants concept arose from fundamental Government reinvention deliberations at NIH and a realization that reviewers evaluating research proposals have tended to shift away from focusing on science and more toward budget considerations. This trend has encouraged investigators to provide ever more detailed budget information in their research proposals. Thus, the research grant "assistance" mechanism has become more like a "procurement" procedure. Modular grants are intended to counteract this trend by refocusing reviewers' attention on the science instead of detailed budgets, and to streamline the preparation of grant applications and subsequent reviews. The modular grant does not address issues of allowable and allocable costs, and it is not a cost-cutting strategy.
Modular grants will support research efforts, from $50,000 up to $150,000 per year, at fixed dollar increments of $25,000. Proposals for grants in the higher $150,000 to $500,000 range will be eligible for streamlining, but will not be eligible for consideration under the new modular paradigm. Proposals for awards over $500,000 are still to include detailed budgets as part of the application.
Applications for modular awards from investigators would reflect their view of the overall scope and budget of their own project — for example, $125,000 instead of either $100,000 or $150,000, or some other figure within this range. In turn, reviewers would focus nearly exclusively on the value of an application's scientific content. In addition, if they approve the proposal but disagree with how much money should be used to fund it, they could adjust the award not by percent, as in the past, but by shifting it by a module. Unlike conventional awards, modular grants do not include budget escalation for the final years of a five-year reward, although they may permit the moving of particular grants to the next higher module.
Dr. Baldwin said that, in tests by the National Heart, Lung and Blood Institute, the modular grant concept is operating successfully and has been well received. Applications still contain specific budget information and any unusual items for reviewers to see. The overall effect, however, has been to move NIH and reviewers away from focusing on the costs of research proposals and toward their scientific content and quality.
Dr. Lander asked whether the modular awards could be adjusted for inflation during the late years of a multiyear award. He pointed out that salaries for individuals supported by the grant and other costs will certainly rise over a several-year period. Dr. Baldwin said that such escalations will need to be considered when the proposal is assigned to a level-of-support module. In general, large but non-recurring purchases might be made in early years to pave the way for escalating recurring costs. Although reviewers might assign a proposal to a different module, the institutes would not be permitted to adjust budgets for modular awards across-the-board by arbitrary percentages. In special cases, investigators could request supplements for the out years. Dr. Varmus added that cost management approaches may be considered for addressing the problem of annual budget increments.
Dr. Kirschner asked whether the modular concept reflects a shift in policy to link funding levels directly to scientific priorities. He also asked whether budget information would still be included as part of grant applications and what the risk would be for investigators routinely asking for the highest module of $150,000. Dr. Varmus said that applications for modular grants would contain budget information only for unusual items. Dr. Baldwin said that grantees have wide latitude to reprogram the use of their awards and shift outlays as their project needs dictate. She also said that, currently, the levels of grant awards provide a good, nearly formulaic indicator of the categories in which investigators are spending that money.
Dr. Kirschner said that the modular grant concept may lead to reviewers making funding decisions that reflect their general assessment of a proposal's worth. In other words, study sections are asking whether a proposed project is worth doing and, if so, how large an effort should be put into it. He suggested that the system might benefit if exceptional costs are dealt with by being identified as exceptional and other budget matters are handled routinely. Dr. Baldwin said that the modular awards are meant to overcome the current budget-focused reviews, which developed that focus to deal primarily with exceptional rather than ordinary items within research proposals.
Dr. Kandel said that the modular grants will simplify cost-sharing arrangements for those investigators who are being supported through a combination of NIH- and non-NIH mechanisms. The modular concept will also help in changing the mindset of reviewers in study sections.
REPORT FROM THE WORKING GROUP ON RESEARCH TOOLS
Ms. Rebecca Eisenberg, member of the ACD and Professor of Law at the University of Michigan Law School, was asked by Dr. Varmus to chair a working group to examine how the biomedical research community is handling research tools and intellectual property issues. The primary stimulus for establishing the Working Group is concern over universities and corporations becoming increasingly aggressive about seeking to profit from uses of research materials, methods, and data, whose initial uses are mainly to generate more research. In trying to control those downstream uses and putative profits derived from research tools, however, these universities, corporations, and the scientists who work in these institutions may inadvertently be impeding research progress and blocking commercial development.
Members of the Working Group on Research Tools includes intellectual property lawyers and representatives from universities, biotechnology companies, pharmaceutical corporations, and from the Howard Hughes Medical Institute. Staff support is provided by the NIH Office of Technology Transfer (OTT). The specific charge to the Working Group is to consider and devise solutions to problems encountered by NIH-funded investigators in obtaining access to patented research tools, including being refused licenses to technology, onerous royalty demands, and restrictions on collaborations or the dissemination of materials and information. The Working Group is concentrating on fair access to research tools and materials rather than on patented intellectual property.
The Working Group is currently gathering information to address a series of questions including: Are researchers having greater problems now than in the past gaining access to research tools? Are license agreements impeding research or publication of research results? If so, what institutions are imposing these restrictions? Are any of them NIH-funded? Are these problems common or are they mainly feared as common in the future?
The first round of responses to such questions came mainly to the NIH OTT from technology licensing officers at universities, according to Ms. Eisenberg. In the next round of information gathering, the Working Group will seek input from researchers at universities and in the private sector, as well as from trade groups representing small biotechnology companies and large pharmaceutical corporations. Plans call for attending meetings to raise some of these issues on an impromptu basis in order to receive wider inputs.
An early specific consideration of the Working Group is concern over potential restricted uses of single nucleotide polymorphisms (SNPs), a research tool of importance for human genetics studies. Dr. Francis Collins, Director, National Human Genome Research Institute (NHGRI), is concerned that researchers in the private sector may claim proprietary rights in so many SNPs that they may restrict information and impede progress, even in publicly funded research in this area, according to Ms. Eisenberg. In preparing a request for proposals from researchers to identify SNPs, NHGRI officials may ask applicants to plan how they will ensure their findings are made widely available. This approach, insisting that applicants disseminate their research findings, does not seem to violate the Bayh-Dole Act as they remain free to file patent applications.
The Working Group also is evaluating what NIH can do, in general, to overcome research tools restrictions problems that are identified. NIH has considerable discretion over intellectual property and materials developed in the Intramural Program, but much less over developments that arise through extramural NIH-funded research, which is governed in part by terms of the Bayh-Dole Act. It permits institutions receiving Federal funds to file for patent protection and retain intellectual property rights, so long as they are diligent in commercializing such discoveries.
The Bayh-Dole Act also contains provisions conferring certain options on NIH. For example, NIH retains a paid-up, non-exclusive license to use NIH-funded discoveries for Government purposes. The statute also provides that, under exceptional circumstances, proprietary ownership may not necessarily reside with the discoverers of research tools or other intellectual materials. In addition, NIH retains "march-in rights" to take over discoveries that are not being diligently used or developed. The statute is not explicit about whether NIH may control licensing terms or access to discoveries of NIH-funded research.
In cases where NIH has not funded the research, there are far fewer options open to NIH to ensure that the findings are broadly used. It can encourage grantee institutions to follow similar policies for NIH- and non-NIH funded research programs, and it can offer guidance on what seem to be unreasonable or inconsistent policies. NIH can also appeal to the enlightened self-interest of such institutions and set limits on what it is willing to tolerate in terms of restrictions on discoveries.
Dr. Fuchs said that many scientific journals require that reports disclosing DNA sequence information also provide gene bank accession numbers as a way of assuring widespread availability of such information. She suggested that NIH consider imposing similar requirements for materials and reagents developed with Federal grant support, perhaps with those materials maintained at a central repository comparable to the American Type Culture Collection.
Dr. Collins said that information about SNPs and other nucleotide sequences is maintained electronically, and there is not the same need for physical storage of samples. Researchers supported by NHGRI grants, who are determining sequences of large blocks of DNA, are required to state their plans for making such information available and for applying to patent it. He said that maintaining SNP information in a similar, publicly accessible database would be helpful.
Dr. Lander said there should be a truly workable research exemption, which would distinguish clearly between exempt, fundamental versus potentially commercial, non-exempt uses of patented materials for research purposes. If the current unworkable research exemption could be made workable, it might be a mechanism for providing investigators broader access to research tools.
Ms. Eisenberg said that the research exemption is very narrowly defined, being essentially restricted to testing of products for clinical uses. The Federal patent statute has rarely been amended, and efforts to do so have proved difficult. Moreover, private corporations that develop research tools would likely resist such changes because they would probably undermine many legitimate patent monopolies that companies depend on for producing income on commercially valuable products. She said that it may be feasible to amend the Bayh-Dole Act to create a research exemption for uses of Federally supported research discoveries. However, universities hoping to profit by licensing such discoveries would likely oppose such an amendment. Indeed, part of the problem is that universities represent users and owner-sellers of such technologies.
Dr. Lander also asked whether there are striking examples of investigators having to pay high sums to use particular research tools, or of such tools being inaccessible. Ms. Eisenberg said that such questions cannot be addressed in a straightforward manner because patents are meant to restrict information and materials to raise their prices. Dr. Varmus said that access, not cost is often the critical issue in cases where research is not being done.
Dr. Kirschner said that, because little can be done about changing access to materials discovered at companies, the focus should be on influencing these policies at universities, with permission to publish serving as a sanction. He also recommended establishing uniformly followed practices on material transfer agreements and on providing sequence accession information.
Responding to a follow-up suggestion from Dr. Lander, Dr. Maria Freire, Director of OTT, said that NIH and more than 100 research universities signed the Uniform Biological Material Transfer Agreement in an effort to set uniform practices. That agreement, however, is rarely followed, except as a guide for writing terms for smaller-scale material transfer agreements. Ms. Eisenberg said that applying such uniform-agreement documents to many different situations, some involving lucrative therapeutic products and others research tools of more restricted commercial potential, helps to explain the practical shortcomings of this approach.
Dr. Lander said that members of the Committee and most other researchers in the academic community do not appreciate the intricacies of patent law and their impact on the research tools issue. Hence, preparing an explanatory article or brochure for this audience would help scientists who want to provide useful information to the NIH Working Group. Dr. Varmus said that such information could be presented on the policy forum homepage.
REPORT ON IMPLEMENTATION OF THE GOVERNMENT PERFORMANCE AND RESULTS ACT
Dr. Lana Skirboll, Associate Director for Science Policy, described current NIH efforts to implement the Government Performance and Results Act (GPRA) of 1993. This Federal statute is intended to improve Federal program management, effectiveness, and accountability, as well as to increase public confidence in the system; it also is meant to help Congress in budget decision making. In meeting the GPRA mandate, NIH is required to report to the Congress through the Department of Health and Human Services (DHHS).
GPRA mandates that DHHS develop a strategic plan, a performance plan and report, according to Dr. Skirboll. She said that, although NIH has been given the option to develop its own strategic plan for planning purposes, the primary responsibility for doing so resides at the Department level. Hence, current efforts to meet the GPRA mandate at NIH focus on developing a performance plan, report, and assessment of the report, based on two important principles. First, the report will reflect NIH as a whole. Second, the report will provide a mixture of qualitative and quantitative indicators to describe the overall NIH performance.
Dr. Skirboll summarized key features of the current NIH GPRA plan. For instance, the mission of NIH is to sponsor and conduct research that leads to better health for all Americans. Under this mission, broad NIH goals include advancing medical knowledge through research and maintaining and enhancing research capacity in the complex environment where medical research is done. These goals are addressed through three programs: research, research training and career development, and facilities.
Dr. Skirboll said that the performance plan is separated into two broad components, the outcome goals and the means goals, with separate measurements and indicators for both of those components. In terms of the NIH research program, two sets of outcomes are expected: the straightforward research advances that investigators readily can recognize and specific goals in designated areas.
For instance, one set of goals is improving prevention and diagnosis of human diseases, and that includes developing insights that lead to diagnostic methods and therapeutic treatments, according to Dr. Skirboll. To show these goals are being met, NIH plans to furnish DHHS with selected anecdotes of past and current scientific advances. This documentation is primarily qualitative so far.
To satisfy other GPRA requirements, however, documentation of how NIH meets these goals must also be presented. Dr. Skirboll said that presentation of such information will be divided into six components: priority setting, grants administration and peer review, communications and results, technology transfer, management and administration, and collaboration and coordination. She said that NIH has identified a series of corresponding goals in these six areas, including: review and modify administrative structures to provide more effective support for research; ensure that grant applications receive fair and appropriate review by assessing the NIH study sections; communicate the results of NIH research to the public through four information and education programs; encourage commercialization of unique technologies; implement recommendations of the Arthur Anderson study; and promote coordination and collaborations with other Federal research agencies.
Dr. Skirboll said that important challenges are to assemble this material into a performance report following FY 1999 and to prepare an assessment for presentation. How to conduct the assessment and who should do it are important unanswered questions. Although officials at the NSF have established an elaborate public review as part of the Foundation's assessment, NIH may not need to follow that model. The performance plan runs through September 1999, the report the following March, and the assessment is to start sometime after that, possibly as late as the year 2001.
Dr. Kirschner said that many of these GPRA-related efforts appear to be wasteful because they were not designed specifically for NIH but intended for the entire Federal Government. He suggested that NIH officials consult with members of Congress to learn what information from NIH would be particularly useful to them.
Dr. Lander said that the GPRA-mandated NIH self-assessment might serve a useful purpose before Congress. Dr. Skirboll noted that NSF has been given very specific directions on compliance with GPRA from The House of Representatives Committee on Science, which is chaired by Rep. F. James Sensenbrenner (R-WI). Dr. Larry Smarr, whose research support comes mainly from NSF, urged other ACD members to take the GPRA review seriously and to use this review opportunity to their advantage, such as to improve congressional understanding of what NIH does.
Dr. Needleman, who sympathizes with Dr. Kirschner's misgivings about meeting the GPRA mandates, agreed with Dr. Smarr that the burdens of the GPRA can also be taken as an opportunity for better informing members of Congress what NIH is doing. Dr. Kandel also recommended summarizing for Congress key NIH accomplishments in basic and clinical science. Dr. Skirboll said that this year, for the first time, each institute director is to furnish one example to be assembled into a "Stories of Discovery" for NIH. Part of the challenge is to show how collaborations among the public, private, and academic sectors can lead to new health treatments.
Dr. Davidson said that, as part of this process, Congress should also be notified of NIH goals and prospects. Dr. Varmus and Dr. Skirboll pointed out that, although retrospective analysis of NIH accomplishments is relatively straightforward, setting near-term quantifiable goals for NIH programs to meet is problematic. Dr. Varmus added that for particular programs, such as the human genome program, setting goals and timetables is a reasonable undertaking. However, convincing Congress that this approach cannot be generalized then becomes more difficult than before.
Dr. Henney said that NIH does more goal setting than is generally realized, but that it is not done within a conventional structure. For example, NIH-supported training of young investigators probably could be described in terms of meeting quantifiable targets. Describing research programs in such terms is more difficult but not impossible.
Dr. Kandel said that research leaders in the field of neuroscience were asked to describe near-term prospects and expectations from continuing scientific investigations. Although the results of this analysis were not altogether satisfying, they provide a model for how this kind of problem can be tackled.
Dr. Davidson said that much of what Congress is looking for concerns how NIH administers its programs and how to streamline its operations for greater efficiency. He also said that the important point to emphasize is how well the current NIH system works in applying Federal resources for useful health-related research. Thus, he recommended that the focus be away from specific research achievements and toward questions of how well budgets are invested. Dr. Fuchs said that NIH should emphasize the science to Congress but concentrate on near-term expectations.
Dr. Skirboll reminded ACD members that the GPRA-stipulated performance plan is for one-year only. Dr. Varmus said that describing milestone expectations for research programs is a reasonable undertaking that can be done in terms of indicators and embellished with anecdotes of unanticipated breakthroughs.
Dr. Menken recommended that contributions from research findings built over a decade be included in an assessment when NIH summarizes its one-year performance in terms of helping to meet public health needs. For example, the declining rate of infant mortality and the survival of low birthweight babies reflect aggregate research developments.
Dr. Lander suggested describing NIH research programs in terms of short-, mid-, and long-term investments, noting that some of the investments in the research portfolio have highly predictable outcomes, whereas others are less predictable, but may have bigger pay-offs.
Dr. Kirschner said that it may be a mistake not to include mention of failures and efforts to correct them as part of this overall GPRA-mandated assessment of NIH. Dr. Skirboll said that earlier discussions about decisions to drop the R29 grant mechanism reflect the kind of reevaluation process to which Dr. Kirschner alluded. Dr. Henney said that similar failure-and-redirection processes are at work more directly among investigators conducting research projects. Dr. Kandel pointed to the Federal Government's handling of the research agencies within the Alcohol Drug Abuse and Mental Health Administration during the past decades as a large-scale example of research administration misdirection and reevaluation.
Dr. Varmus suggested that an ACD subgroup serve as an assessing group for NIH compliance with GPRA. He also reminded ACD members that, to comply with this Federal law, NIH needs to answer not only to Congress but also to the DHHS and the Office of Management and Budget.
Dr. Lander said that he was not sure that an ACD subgroup is distanced enough from NIH to have credibility as an outside reviewing body. He recommended forming a review panel with a core of members who are familiar with NIH but with other members and a chair who are not NIH grantees. Dr. Varmus and Dr. Skirboll agreed that an ACD subgroup would form the core but that the review group also should include representatives of consumer advocacy groups and other constituencies. Dr. Coble said that the composition of the NIH Director's Panel on Clinical Research provides an excellent example on which to draw.
REVIEW OF ADMINISTRATIVE FUNCTIONS AT NIH
Mr. Jack Mahoney, former Deputy Director for Management, described a recent review of NIH administrative practices, which is part of a broader effort within the Federal Government to streamline such activities. The NIH review grew from a request from the House of Representatives Committee on Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies, which is chaired by Rep. John Porter (R-IL). The request reflected the Subcommittee's interest in seeing how administrative practices could be improved to better serve the NIH scientific mission, according to Mr. Mahoney.
Mr. Mahoney explained that the review of NIH administrative structure and practices was conducted by Arthur Andersen Consulting, with assistance from an advisory committee that included NIH senior managers. After examining 18 administrative and management functions, the consulting firm provided an evaluation and proposed a series of recommendations to improve NIH services and efficiency. The advisory committee subsequently reviewed the Andersen recommendations and assigned them to priority categories for implementation.
According to the final report from Andersen, NIH research management and support practices are functioning well, but the quality of administrative services is uneven. The report also endorses the decentralized administrative structure at NIH and the soundness of the planned NIH information technology framework. The consulting firm also concluded that public and legislative affairs staffing levels at NIH are appropriate, noting that the public affairs staff is comprised of individuals who support the important NIH mission of disseminating health information to the public. Finally, the report notes that, in some areas, such as the extramural research program, NIH operates as well or better than other governmental organizations.
Mr. Mahoney stated that the Andersen report provides more than 80 recommendations organized according to four main themes. First, NIH needs to refine the role of the Office of the Director and to further decentralize services. Second, NIH should continue to strengthen the scientific-administrative partnership. Third, NIH needs to develop greater administrative accountability and leadership, in part by making use of administrative performance standards. Fourth, NIH should implement a new budget and organizational paradigm.
After Dr. Varmus asked the advisory committee to evaluate the Andersen recommendations, the committee recommended implementing the first three series of recommendations but deferring the fourth set. As part of that fourth set, Arthur Andersen recommended that NIH disaggregate the research management and support budget item into four components, namely intramural research, extramural research, health information and education, and general administration. Without modeling this recommendation, however, the impact of its implementation cannot be predicted.
The Advisory Committee, however, classified the over 80 specific recommendations in the Andersen report into four categories for implementation: priority one, short-term items to implement quickly; priority one long-term, complex items to implement as quickly as their complexity permits; priority two, less serious items that do not require NIH-wide oversight; and deferred, items to receive further study. The only recommendation in this latter category is the one related to the new budget and organizational paradigm. Within these categories, some items will receive expedited treatment.
Dr. Tilghman asked whether any special episode prompted the House of Representatives Subcommittee request for a study of NIH administrative practices. Dr. Varmus said that the highly decentralized structure of NIH raised concerns in Congress. Some of those concerns were addressed when NIH developed a competitive service center model several years ago that enables separate institutes to pool resources for procurement, technology transfer, and other administrative activities.
Dr. Davidson said that the GPRA issues are closely linked to those addressed in the Andersen report. Dr. Varmus agreed, noting that recommendations from the report will be followed as part of the GPRA plan for the administration and management of NIH programs.
SUMMARY AND CONCLUSIONS
The Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) met on December 4, 1997, and considered efforts to reorganize and make other improvements to grant review study sections in the Center for Scientific Review; reviewed a report recommending steps to encourage and improve the training of clinical research investigators; discussed several changes affecting NIH grants programs; considered potential constraints on the use of valuable research tools; initiated efforts to meet the requirements of the Government Performance and Results Act; and considered a recent review of NIH administrative structure and practices and efforts to implement recommendations to improve them.
The ACD acknowledged and endorsed these programs and reports and recommended that clinical research issues continue to be monitored.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Ruth L. Kirschstein, M.D., Executive Secretary, Advisory Committee to the Director, NIH
Harold Varmus, M.D. Director, NIH
TABLE OF ACRONYMS
Advisory Committee to the Director
U. S. Agency for International Development
Acquired Immunodeficiency Syndrome
AIDS Vaccine Advisory Committee
Clinical Research Center
Center for Scientific Review
Cytotoxic T Lymphocytes
U. S. Department of Health and Human Services
Division of Research Grants
Government Performance and Results Act
Human Immunodeficiency Virus
National Academy of Sciences
National Bioethics Advisory Committee
National Cancer Institute
National Human Genome Research Institute
National Institute of Alcohol and Alcohol Abuse
National Institute for Allergy and Infectious Diseases
National Institute on Drug Abuse
National Institute for Diabetes and Digestive and Kidney Diseases