The 86th meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on June 30, 2003. NIH Director Dr. Elias Zerhouni began by introducing NIH Deputy Director Dr. Raynard Kington, while also noting several additional administrative changes at NIH, including the appointment of Dr. Nora Volkow as Director of the NIH National Institute on Drug Abuse. He said that a recent $200-million grant from the Gates Foundation to the NIH Foundation marks a new model of collaboration between the private and public sectors.
Dr. Zerhouni told ACD members about a visit earlier this year by President Bush to the NIH campus, during which the President, Dr. Anthony Fauci, Director of the NIH National Institute of Allergy and Infectious Diseases (NIAID), and additional officials discussed the BioShield initiative and its impact on bioterrorism countermeasures research programs, which are now a core priority at NIH. Other priority activities include programs to support research on human stem cells, a leadership retreat to augment the NIH Roadmap, and appointment of a panel to plan for effective use of the Hatfield Clinical Research Center.
Dr. Zerhouni summarized recent interactions with Congress, and noted that several oversight committees are insisting on stringent NIH accountability, particularly in the aftermath of its budget doubling. The NIH budget for fiscal year (FY) 2004 is not yet set. The House of Representatives figure of $27.9 billion is in line with President Bush's request, while the Senate version is $318 million higher, representing a 3.7 percent increase over FY 2003 that potentially would reinstate a Buildings and Facilities initiative.
In addition, the NIH Director cited several important research advances, including completion of the mapping and sequencing of the human genome, reevaluation of hormone therapy as part of the NIH Women's Health Initiative, findings from another program intended to decrease the risk of prostate cancer, and development of a new screening tool to detect Alzheimer's disease.
Dr. Kington next described the NIH Administrative Restructuring effort, which is comprised of an advisory committee and eight working groups. Broad goals include addressing the presidential mandate to maximize the efficiency of NIH programs, develop a unified management system, and to streamline and harmonize decision-making procedures while maintaining transparency. Plans call for methodically analyzing NIH programs over the course of the next two years, then determining which components might be reallocated for performance by the private sector, and which others quality as core governmental functions.
NIH Senior Advisor to the Director Dr. Ruth Kirschstein summarized an ongoing effort to reassess NIH postdoctoral training practices and policies. A working group of the ACD plans to convene a meeting on this topic in mid September, and its report will be presented to the National Academy of Sciences and Institute of Medicine as part of a broader summit meeting next spring.
Dr. James Battey, Jr., Director of the National Institute on Deafness and Other Communication Disorders, reviewed NIH stem cell research programs, noting that overall NIH support in FY 2002 for such programs was $307 million. To help expand such research, NIH has provided infrastructure awards to support efforts to characterize eligible human embryonic stem cell lines and, to expand - from 5 to 12 - those lines ready for distribution and use. Additionally, NIH is funding a growing number of R01 grants and administrative supplements, five specific training programs, and other mechanisms such as exploratory centers grants, short courses, and mid-career fellowship support to promote this high-priority research field.
Dr. Zerhouni said that further development and implementation of the NIH Roadmap is vital for accelerating discoveries, speeding up translation of basic findings into medically useful technologies, and taking other measures to address national health needs in the face of rising healthcare costs. Successive leadership meetings and efforts of experts belonging to 15 working groups are helping to identify key scientific challenges and the means for attaining them. Three key areas include new paths to discovery, the challenges of developing multidisciplinary teams, and the importance of reengineering the clinical research enterprise.
Dr. Allen Spiegel, Director of the National Institute of Diabetes and Digestive and Kidney Diseases, summarized current Roadmap plans for building several vast datasets, molecular libraries, and for obtaining molecular imaging-based datasets for cells and organisms. These efforts will ensure the development of more systematic, computation-based approaches. Dr. Lawrence Tabak, Director of the National Institute of Dental and Craniofacial Research, described Roadmap plans focusing on public-private research partnerships and the development of multidisciplinary teams for studying complex biomedical problems, including high-risk undertakings. Noting that these efforts will involve a change in culture and will emphasize trans-NIH cooperation, he noted that several incentive programs were being devised together with a new Director's Incubator program. Dr. Stephen Katz, Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said that efforts to reengineer the national clinical research enterprise would entail development of an extensive network of regional centers that emphasize translational research. Success will depend on development of enabling technologies, better harmonization of reporting procedures, and other improvements, particularly in informatics, to centralize and streamline clinical research undertakings.
The 86th meeting of the Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) was held on June 30, 2003. NIH Director Dr. Elias Zerhouni welcomed several new ACD members, including Dr. J. Michael Bishop, former Senator Connie Mack, and Mr. Larry Sadwin, who also serves as liaison to the NIH Council of Public Representatives (COPR). Dr. Zerhouni introduced NIH Deputy Director Dr. Raynard Kington, who was recently appointed to this position after serving as Associate Director of NIH for Behavioral and Social Sciences Research and Acting Director of the National Institute on Alcohol Abuse and Alcoholism. Dr. Kington will focus on improving NIH efficiency and effectiveness, and also reformulating NIH governance and management practices.
Dr. Zerhouni noted that Dr. Nora Volkow became Director of the NIH National Institute on Drug Abuse two months earlier, that Mr. John Burklow became Associate Director for Communications, Mr. Don Poppke became Associate Director for Budget, and Dr. Belinda Seto is now Acting Deputy Director of Extramural Research, replacing Dr. Wendy Baldwin, who became Vice President for Research at the University of Kentucky. Surgeon General Dr. Richard Carmona addressed Commissioned Corps members of NIH, and forthcoming changes regarding the Corps will be monitored by NIH liaison Dr. Richard Wyatt.
Dr. Zerhouni said that a recent $200-million grant from the Gates Foundation to the NIH Foundation marks a new model of collaboration between the private and public sectors, and that these resources provide valuable flexibility for global health research programs and also for other high-risk, priority research activities. NIH also recently celebrated the 50th anniversary of the discovery of the structure of DNA and also of completing the sequencing of the human genome.
President Bush recently visited the NIH campus, toured the new Vaccine Research Center, and spoke about Project BioShield, which is designed to stimulate co-investment into research that can be translated into practical countermeasures against bioterrorist threat agents, according to Dr. Zerhouni. Civilian biodefense research is a new core priority at NIH, a prominent component of the budget, and the subject of a recently established trans-NIH Biodefense Research Coordinating Committee. National Institute of Allergy and Infectious Diseases (NIAID) Director Dr. Anthony Fauci is heading this coordinating effort, which is considering several related issues, including chemical radiation threats as well as psychological preparedness against biodefense threats.
National Institute on Deafness and Other Communications Disorders (NIDCD) Director Dr. James Battey, Jr., is heading the NIH Stem Cell Task Force, which convened a well-attended meeting in June, according to Dr. Zerhouni. Also in June, NIH leadership met to review Roadmap initiatives and also to deliberate about NIH reorganizational efforts entailing review of competitive outsourcing issues. An outside advisory group will be providing recommendations pertaining to making the best use of the Mark Hatfield Clinical Research Center, which is scheduled to open early in 2004. In addition, NIH continues to implement plans for improved communications with the public, a priority issue for the Council of Public Representatives (COPR).
Dr. Zerhouni summarized recent interactions with Congress, and noted that several oversight committees are insisting on stringent NIH accountability, particularly in the aftermath of the agency's budget doubling. For instance, Senator Judd Gregg (R-NH) is directing a study of NIH stakeholders to evaluate agency performance, while members of the House of Representatives Energy and Commerce Committee are reviewing the NIH grants oversight process. The NIH has been forthcoming on these and other matters, and recently provided the Congress with information about lecture awards received by NIH institute directors, including Dr. Richard Klausner, the former Director of the National Cancer Institute. No rules were violated in that case, according to Dr. Zerhouni. The House Energy and Commerce Subcommittee on Health is convening a series of NIH reauthorization hearings examining several issues, including the human genome project, the translation of laboratory research into clinical applications, and the administrative organization of the agency, a subject that is being considered as part of a forthcoming Institute of Medicine report.
Although the NIH appropriation for fiscal year (FY) 2004 is not yet set, the House of Representatives current $27.9 billion is in line with President Bush's budget request for NIH, which would compromise an increase of about $549 million over FY 2003. The FY 2003 final appropriation for NIH was $27 billion, which completed the agency's budget doubling and constituted an increase of 15 percent over the previous year. The requested budget for FY 2004 provides for an overall increase of 7.5 percent for NIH research, with increases in biodefense components accounting for slightly more than one-third of that increase (2.7 percent overall).
The Senate is requesting $318 million more for the NIH in FY 2004 than is the House of Representatives or the President's budget, representing $1 billion more, or a 3.7 percent overall increase over FY 2003. The Senate version potentially would reinstate several specific programs, including a $5 million allocation for the INSTITUTIONAL DEVELOPMENT AWARD (IDeA) Program, $7.4 million for General Clinical Research Centers, and $119 million for the Extramural Construction Program. The Senate version would provide $9.5 million for continuing to construct the Porter Neurosciences Research Center and would increase global AIDS spending by $50 million. Dr. Zerhouni said that NIH has submitted a preliminary FY 2005 budget proposal. A more complete proposal is due to the Secretary's Budget Council on July 22, 2003.
Dr. Zerhouni alluded to several important research advances, including completion of the mapping and sequencing of the human genome, sequencing of the Bacillus anthracis genome, reevaluation of hormone therapy as part of the NIH Women's Health Initiative, findings pertaining to decreasing the risk of prostate cancer, and development of a new screening tool to detect Alzheimer's disease at an early stage, which can be used in disease-prevention clinical trials.
In introducing Dr. Kington, Dr. Zerhouni explained that NIH and other federal agencies and departments are subject to the A-76 mandate from the Office of Management and Budget. It specifies that federal agencies review their programs and decide which programmatic components may be subject to competitive bidding and outsourcing. For example, mission-critical functions, including those with inherent decision-making power, such as judging grant proposals, cannot be delegated. However, other routine functions at the NIH, such as landscaping, may very well be subject to outsourcing through competitive bidding. A threshold of 10 percent below the in-house cost determines whether an outside bid will be accepted.
Dr. Zerhouni said that it is unlikely that NIH could be out-bid on any of its core functions, meaning that grant reviews will not be conducted by outside contractors, whereas grants management functions may be. Dr. Zerhouni said that Secretary Tommy Thompson of the Department of Health and Human Services (DHHS) has asked agencies within the department to integrate their activities more fully. Dr. Zerhouni requested that the NIH be allowed to define its own integration process and be permitted to maintain autonomy in managing its scientific programs. Broad goals of this department-wide effort include addressing a presidential mandate to maximize the efficiency of NIH programs, develop a unified management system, and streamline and harmonize decision-making procedures while maintaining transparency. Plans call for methodically analyzing NIH programs during the next two years, then determining which components might be reallocated for performance by the private sector and which will remain core agency functions.
Dr. Kington indicated that since April he has chaired the Administrative Restructuring Advisory Committee, since April. The committee includes several institute and centers directors (ICD), administrative staff, and eight working groups. The working groups completed reports early in June, supplying a series of recommendations for ways to improve NIH functions without harming its scientific mission. The reports also included suggestions pertinent to Secretary Thompson's request for making improvements within DHHS. The committee's provisional report was presented to Dr. Zerhouni, and additional discussions are being held with Secretary Thompson.
Dr. Zerhouni introduced committee members to a number of institute and center directors who were attending the ACD meeting, noting that they all participated in preparing the report described by Dr. Kington. He said that a smaller group of several such directors would be part of a new NIH Steering Committee, whose role will be to coordinate decision-making for the NIH. In addition, Dr. Kirschstein will be streamlining internal NIH committee structures, while forming several committees to consider specific functions, including one to dvaulate facilities and another to review budgets.
Discussion
In response to a question from Dr. Linda Waite about the Intramural Research Program (IRP) coming under the provisions of A-76, Deputy Director for Intramural Research Dr. Michael Gottesman said that certain IRP components involving senior scientific and support staff are considered inherently governmental, but other administrative support functions may be subject to out-sourcing under competitive bids. Deputy Director for Management and Chief Financial Officer Mr. Charles Leasure added that the NIH is currently reviewing positions in facilities and in grants management support to determine their eligibility for out-sourcing. Overall, about half the 17,500 full-time equivalent positions at NIH are considered potentially eligible for performance by the private sector, and the goal is to complete half this review by the end of FY 2005. NIH already has developed a tentative list of eligible positions for FY 2004 that does not contain a major number of scientific positions in the IRP, and there are also no plans to consider the health science administrators for out-sourcing, according to Mr. Leasure.
In response to a question from Senator Connie Mack about who has the ultimate responsibility for making out-sourcing decisions, Mr. Leasure said that the Office of Management and Budget has issued guidelines that apply to all federal agencies. He added that Dr. Zerhouni has determined that anyone in a decision-making position, particularly with the authority to commit federal resources for projects, is considered to have an inherently governmental position. However, those who are in support positions may be subject to out-sourcing. Ultimately, Dr. Zerhouni will decide whether to agree to accept particular competitive-bid proposals, after they are subject to review.
In response to a question from Dr. J. Michael Bishop about this process potentially compromising the autonomy of individual institutes and centers, Mr. Leasure said that this problem is unlikely to occur. The A-76 review is intended to consider issues and functions that affect the entire NIH.
Dr. James Martin said that a similar effort in which functions within the Department of Defense were subject to competitive out-sourcing led at first to savings of 20 percent but later such savings were more difficult to achieve because of efficiencies gained among personnel within the department. In response to a question from Dr. Donald Wilson about the fiscal impact of this review, Mr. Leasure said that this effort itself is proving expensive in the short run, costing from $2,000 to $5,000 per position studied. However, in the long run, this effort is expected to realize substantial cost savings.
Dr. Thomas Cech raised questions about how the NIH will adjust to slower budget increases during this period following its budget doubling. Dr. Zerhouni said that the NIH has been seeking a soft landing, and plans to maintain numbers of new research grants during this transition period. He also said that specific effects may vary among the Institutes and Centers depending on the extent of their R01 portfolios, and that it may take several budget cycles before the system equilibrates. Mr. Donald Poppke, the Acting Associate Director for Budget said that, although new grant numbers will be maintained for FY 2004, it would become more difficult to sustain new grant numbers in FY 2005. However, there will be some recycling of resources from early in the doubling period that will help mitigate this effect. Another lessening strain on resources is the fact that the biomedical inflation rate has dropped from 4.3 percent to 3.3 percent, providing an opportunity to adjust grants downward that were pegged to higher inflation rates. Dr. Zerhouni said that the Institutes will face a considerable crunch in FY 2004 and 2005 because of the rolling forward of continuations, but relief can be expected in the following out-years.
Mr. Larry Sadwin asked about the two-year review process under the A-76 mandate, and whether some NIH employees would face extended periods of uncertainty regarding job security. In response, Dr. Zerhouni said that Secretary Thompson has said that no one will lose a job because of this review process, but that employees would be retrained and placed in new positions. Nonetheless, NIH employees are expressing concerns about this review, and the best way to alleviate that anxiety will be for them to prove successful in the anticipated competitive bidding process. He also said that it would be helpful not to prolong this review but to resolve matters soon.
Postdoctoral Training and Career Development Report
Dr. Zerhouni said that he asked for the demographics of NIH grantees to be reviewed as part of a more general effort to address community concerns about the career paths of new investigators. That review indicates that first-time independent investigators younger than 35 dropped from 27 percent 20 years ago to 4 percent today. Moreover, 30 percent of current NIH grantees are first-time recipients of such awards, but they tend to be older than they once were. This trend is attributable, in part, to the fact that it is taking about two years more than it once did to complete doctoral work; in addition, postdoctoral training is lasting longer than it previously did. Young scientists are beginning to consider this extended training to be a disincentive for pursuing research careers. Another important change is the size of research teams, their multidisciplinary character, and the fact that some postdoctoral members of such teams are no longer being trained but are serving in specialized support modes.
Because of the complexity of these issues, Dr. Zerhouni has asked the Senior Advisor to the Director Dr. Ruth Kirschstein to lead a working group of ACD members and other representatives of the research community in a comprehensive study of these issues.
Dr. Kirschstein referred to several reports issued over the past several years pertaining to research careers for young scientists including:
A 1998 report by a group chaired by Dr. Shirley Tilghman of Princeton University
A 2000 report from a committee of the National Academies of Science (NAS) that was chaired by Dr. Maxine Singer of the Carnegie Institution of Washington ·
A congressionally mandated periodic update on national needs in the biomedical and behavioral sciences. Its next installment is due in 2004 and the committee is chaired by Dr. Gordon Hammes. Dr. Christine Cassel, a member of the ACD, is also on the committee.
To begin to reassess NIH postdoctoral training practices and policies, Dr. Kirschstein consulted with various researchers and organizations before preparing a draft report on this subject for the ACD. Recent trends indicate that postdoctoral training is virtually mandatory, and that it often lasts for five or more years. By the end of this period, such individuals are no longer being trained but, typically, are performing research and related services at the request of their mentors. Moreover, they are not close to becoming independent investigators. The stability and level of their support, and the types of health and other benefits that they can expect, often depend on the type of NIH (or alternative) support that they are receiving — sometimes directly as fellows, in other cases, indirectly under research grants to other investigators. Concerns over these and related issues led postdoctoral fellows to establish the National Postdoctoral Association.
Dr. Kirschstein said that the ACD working group conducting this reassessment would focus primarily on three groups — the trainees, the academic biomedical research community, and the NIH. The working group will convene October 23–24, 2003, at the NIH Cloisters, along with representatives from other federal agencies, and stakeholder groups such as professional societies and organizations representing the academic research community. The working group will examine a broad range of questions regarding training practices, what needs to be changed, and how those changes may be implemented. The report will be presented to a group at the National Academy of Sciences (NAS) and Institute of Medicine (IOM) as part of a broader summit meeting in the spring of 2004.
Discussion
In response to a question from Dr. Zerhouni, Dr. Linda Waite called the training issue extremely important and said that the quality of people being trained is crucial for the future of scientific research. She pointed out that there is little consistency among training programs in terms of requirements imposed on sponsoring investigators and institutions, or in term of salaries and benefits provided to trainees. In some cases, it is difficult to integrate postdoctoral scientists who are being sponsored by private foundations with other postdoctoral researchers whose support comes from the NIH. Restrictions stipulated by private sponsors sometimes complicate efforts to broaden the experiences of postdoctoral trainees, who at times are effectively prohibited from teaching or interacting with graduate students.
Dr. Donald Wilson indicated that he is concerned about postdoctoral scientists, noting that some end up in limbo and remain stymied in their career development efforts. He urged that Dr. Kirschstein include a senior representative from the Association of American Medical Colleges (AAMC) in this ACD working group because medical schools can be expected to play an important role in reforming postdoctoral training practices.
In response to questions from Dr. Charles Francis about fewer M.D.s pursuing research careers and the role of non-U.S. citizens, Dr. Kirschstein said that M.D. researchers would be included in this study but the working group did not plan to address issues relating to foreign postdocs. She said that several organizations in addition to AAMC would be asked to provide views on the training of postdoctoral scientists who are working in clinical research areas.
Dr. Steven Paul endorsed Dr. Waite's assessment, and asked about the nature of the report that the working group would be producing. Dr. Kirschstein said that the initial report would consist of a discussion paper for the NAS meeting planned for early 2004, but eventually the NIH would likely issue new guidelines regarding postdoctoral training. Dr. Zerhouni said that the NIH role is not clear because universities and medical schools have primary responsibility for training young scientists, and these institutions often have entrenched policy positions, particularly regarding the value of trainees for conducting research as part of large, multidisciplinary teams.
Dr. Michael Gottesman said that postdoctoral training issues are an important concern within the NIH Intramural Research Program (IRP) and that, following the Marks-Cassell review of that program about a decade ago, the IRP developed innovative rules regarding postdoctoral trainees. For instance, the IRP sets a five-year limit for the tenure of postdocs, with the actual average being about three and a half years. Nonetheless, staff scientists supervising such postdocs often try to prolong the stays of these young scientists, who represent a relatively inexpensive source of talented labor. The IRP also developed a research fellow and staff scientist track at the NIH that permits some postdocs to achieve employee status in terms of salary levels and other benefits. These are not permanent positions but may be renewable for as long as five years; currently, about 800 such staff scientists are working within the IRP.
Dr. Paul noted that this extended postdoctoral training program within the IRP is exemplary and would prove beneficial if widely adopted by universities. Dr. Kirschstein said that its adoption would entail a major cultural change. Dr. Wilson suggested that such a change would be more than cultural, pointing to serious financial difficulties that would show up after the fifth year when the tenure of a cohort such as the staff scientists in the IRP would lapse, forcing them into the job market. He agreed with others that postdoctoral scientists provide a relatively inexpensive source of talented labor, but pointed out that universities could not afford to hire all these young scientists as faculty members.
Dr. Michael Bishop added that NIH cannot solve the postdoctoral problem but could establish some helpful ground rules. He said that, to be considered competitive for faculty positions, postdoctoral scientists need to have developed their own projects and the prospects of obtaining R01 support — a level of sophistication that typically requires more than a few years at the postdoctoral level. He also indicated that universities are aware of a need to develop academic positions other than those on the traditional tenure track, but developing these positions will require more resources than are available. Dr. Waite said that those who spend longer periods at the postdoctoral level tend to become poorer candidates for tenure-track academic positions.
In response to a question from Dr. Kirschstein about the NIH supporting the training of fewer people, Dr. Bishop replied that this question needs careful study.
In response to a question from Dr. Paul about the average tenure of postdoctoral scientists, Dr. Bishop stated that three to five years seemed typical.
Dr. Thomas Cech said that the treatment of postdoctoral scientists across the academic community is not uniformly bad and that the NIH might help to introduce new practices that could change exploitive practices and lead senior scientists to help postdoctoral scientists in their career development efforts.
In response to a question from Dr. Zerhouni about the quality of postdoctoral scientists coming into industry, Dr. Paul said that overall quality is high and that industry sometimes directly hires organic chemists without postdoctoral experience.
Dr. Zerhouni said that NIH will need to be cautious in going forward with proposals for changing postdoctoral training practices, and that the overall system is far from uniform in its scope and practices.
In response to comments from Senator Connie Mack about whether the NIH has the responsibility for overseeing training and workforce issues, Dr. Kirschstein said that the Congress mandated the NIH to study biomedical research training needs. Dr. Zerhouni said that the key question is whether the current system is yielding young scientists with the highest creativity and productivity. A big concern is that newly trained scientists are not being permitted sufficient independence during their most potentially creative years. Dr. Paul said that the system, including the IRP at the NIH, tends to abuse young scientists and keep them from becoming independent and entering tenure-track (or equivalent) positions. In many cases, incentives within the system maintain this status quo.
Dr. Zerhouni introduced Dr. James Battey, Jr., Director of the National Institute on Deafness and Other Communication Disorders, who chairs the NIH Stem Cell Task Force, asking him to update members of ACD on the status of this field.
Dr. Battey said that overall NIH support in FY 2002 for stem cell research programs was $307 million, and about $10 million was invested in human embryonic stem cell research during that period. To help expand such research, NIH has provided infrastructure awards that support efforts to characterize eligible human embryonic stem cell lines and, recently, to expand from 5 to 12 those lines that are ready for distribution and use by researchers. Additionally, NIH is funding a growing number of R01 grants and administrative supplements, five specific training programs, and other means such as exploratory centers grants, short courses, and mid-career fellowship support to promote this high-priority research field. At this stage, it is important to develop a fundamental understanding of how these cells enter particular differentiation pathways, according to Dr. Battey. It is also valuable to produce uniform populations of differentiated cells for the purpose of testing efficacy and toxicity of drugs in vitro.
Dr. Battey outlined the differences among different kinds of stem cells and the steps required for extracting and producing new cell lines in culture. Because these and other steps are highly technical, an important priority for the NIH is to build the scientific capacity for working with such cells and learning how to handle them. He said that the task force is mandated to advise the ACD, Dr. Zerhouni, and other members of the administration. It also will provide information to an implementation committee comprised of NIH representatives from all institutes and centers, whose members will be developing research initiatives.
Dr. Battey described the extensive human embryonic stem cell research and research-capacity-building programs now under way. For example, eight initial infrastructure awards committed $6 million to institutions to develop distribution-quality stem cells. Twelve lines now are ready for distribution, up from a mere 1 or 2 about a year ago. A new program announcement is being issued to increase the number of such infrastructure awards. In addition, 11 institutes committed $1 million in FY 2002 to support short-term courses in human embryonic cell culture techniques through a T15 mechanism, allowing individuals to spend several weeks learning the skills needed for growing and manipulating such cells.
Another support mechanism targets career enhancement awards to encourage mid-level investigators to spend from six months to two years learning stem-cell techniques, according to Dr. Battey. A program under the P20 mechanism provides multi-investigator exploratory center grants to support infrastructure and research needs involving human embryonic stem cells. The National Institute of General Medical Sciences committed $2 million in FY 2003 to support two to four such centers. Within the NIH IRP, six laboratories are using human embryonic stem cells in research, and a unit within this program will be conducting side-by-side comparisons of different cell lines.
The NIH sponsored a symposium in June 2003 on human embryonic stem cell research, holding it immediately following the International Stem Cell Meeting and General Motors Stem Cell Symposium. The NIH meeting was very well attended. Dr. Battey reported that extensive information is available on several websites describing stem cell-related activities at the NIH.
Discussion
In response to a question from Dr. J. Michael Bishop about the development of additional human embryonic stem cell lines, Dr. Battey said that current efforts by the NIH focus on characterizing and developing frozen cell lines from among the 78 that meet President Bush's eligibility criteria. In response to a question from Senator Connie Mack, Dr. Battey said that 12 such lines are now ready for distribution, but how many other lines among the 78 will eventually be ready for research use is not yet known. Senator Mack inquired about an overall shortage of cell lines, and Dr. Battey noted that this concern is widely held throughout the research community. However, he added, for the purposes of conducting basic studies, the available number of cell lines should be adequate.
Dr. Bishop remarked that, in terms of meeting eventual clinical needs, it will be necessary to develop cell lines that have never been exposed to non-human cells. In response, Dr. Battey said that the task force is consulting with officials at the Food and Drug Administration (FDA) about anticipated safety requirements if such stem cell-related materials were going to be used in human recipients, particularly if those cells were previously exposed to non-human cell feeder layers. As a result of such concerns about safety Dr. Battey indicated there is keen interest in the field in developing feeder- and serum-free culture systems for such cells.
In response to a question from Dr. Zerhouni about the status of the 78 eligible human cell lines, Dr. Battey replied that some of those lines held in Sweden have not been exposed to non-human feeder cells.
Dr. Paul asked about the relative homogeneity of the available 78 human embryonic stem cell lines. In response, Dr. Battey said that some of the cell lines, even after being frequently passaged, maintain a normal karyotype and remain capable of differentiating. Other cell lines are not so fully characterized, making it difficult to assess their status.
In response to a comment from Dr. Zerhouni, Dr. Battey indicated that scientific progress in this area is impressive, citing findings by Austin Smith about the transcription factor called NANOG that is expressed only in embryonic stem and germ cells of mice, other findings by Irving Weissman who reported that hematopoietic stem cells can renew and expand in culture, and by Ronald McKay, who described a five-stage differentiation protocol whereby human embryonic stem cells are converted into cells like those in the mature mid-brain with dopamine-producing neurons, which are the cell type that is lost in individuals with Parkinson's disease.
In response to a question from Senator Mack regarding the political climate surrounding stem cell research, Dr. Battey said that some people may be avoiding such research over fears that federal support could be withdrawn. However, he added, there is no indication that research will be further restricted, and there are plenty of opportunities to pursue. Dr. Zerhouni added that this field was not federally funded before 2001, but since then the number of applications has been growing. Dr. Battey said that the atmosphere is also ethically charged and that complex intellectual property challenges face those entering this field. Moreover, it costs about $5,000 simply to obtain a vial of human embryonic stem cells to begin work in this field, which represents another barrier that may be hampering investigators with limited funding.
Dr. Bishop again stated that there will be difficulties in developing additional human embryonic stem cell lines and cited British estimates indicating that at least 200 distinct cell lines would be needed to match its population diversity needs, suggesting that even greater numbers of such lines will eventually be needed in the United States to meet clinical needs.
Dr. Zerhouni said that further development and implementation of the NIH Roadmap is vital for accelerating basic discoveries, translating basic findings into medically useful technologies, and addressing national health needs in the face of rapidly rising healthcare costs. Successive leadership meetings and efforts of about 300 experts belonging to 15 working groups are helping to identify key scientific challenges and the means for attaining them.
In April 2003, members of the NIH COPR were briefed on the status of the Roadmap initiative. Roadmap Working groups proposed additional initiatives in May, which were reviewed in June, during a Director's retreat. At that time, participants reviewed the proposals and recommendations, ranked them, and considered the challenges involved in launching initiatives in the face of reduced budget growth. Dr. Zerhouni said that, although there is considerable enthusiasm over identifying core priorities for these initiatives, there is wide agreement that they will need to be introduced through a process that he called adaptive implementation. The working group members took a matrix approach to determining which initiatives might be launched with minimal activation energies.
The three key areas of the Roadmap include new pathways to discovery, the challenges of developing multidisciplinary research teams, and the importance of reengineering the clinical research enterprise, according to Dr. Zerhouni. In identifying these major priority areas, Dr. Zerhouni and others learned a good deal about existing collaborations among institutes and centers within the NIH. He said that it will be important to emphasize initiatives that are synergistic with ongoing activities across NIH and that are considered compelling by NIH constituencies and stakeholders.
Dr. Zerhouni reported that both the pending House of Representatives and Senate appropriations bills are recommending $45 million for activities within the NIH Office of Director, and include explicit language encouraging use of these funds to implement the Roadmap.
Dr. Allen Spiegel, Director of the National Institute of Diabetes and Digestive and Kidney Diseases, summarized the Roadmap component, "New Pathways to Discovery" that focuses on discovering novel approaches and developing innovative technologies. Part of this effort will be to examine systematically the molecular constituents of living cells, including genomes, RNA species, proteins, carbohydrates, lipids, and smaller metabolites. Dr. Spiegel explained that some of these molecules, such as the glycolipids known as gangliosides, play dual roles, acting both as signals and as structural constituents of cells, thereby adding considerable complexity to this analytic challenge.
Approaching this challenge systematically and utilizing the new analytic tools that will be developed will help to moderate costs. Additional element within this effort will be to build and provide molecular libraries for use by researchers as they develop new therapeutic products for treating the broad spectrum of human disease. Researchers within the academic community will then be able to draw from these molecular libraries as well as from genomic and other biologically useful databases to screen for promising new therapeutics and for agents that could help prevent disease.
Dr. Spiegel added that investigators would also focus on structural biology and begin characterizing integral membrane proteins, whose analysis has remained largely elusive. This focus, particularly as investigators try to understand in exacting detail how individual proteins function, will depend upon development of new analytic tools derived through the collaborative efforts of multidisciplinary teams. Another important goal is to understand in quantitative terms how gene regulatory networks, signal transduction pathways, and complex metabolic pathways are integrated, both in orchestrating normal development and in causing perturbation disease. For example, such an integrated research approach, spanning molecular genetics and physiology to behavioral psychology, may help to explain, and to begin to solve, the current epidemic of obesity.
Dr. Lawrence Tabak, Director of the National Institute of Dental and Craniofacial Research, described the Roadmap component focusing on their development of multidisciplinary teams for studying complex biomedical problems. He said that, despite widespread recognition that scientific advances often come at the interface of separate disciplines, cultural barriers make it difficult to establish multi- and interdisciplinary research teams. Those barriers include a reward system favoring independent professors, department-based research institutions where there are few interactions among departments, and risk-averse atmospheres that discourage longer-term, higher-risk projects by interdisciplinary teams.
The working group considered different approaches to overcoming these barriers, Dr. Tabak noted, including policy changes to encourage formation of multidisciplinary teams, special training grants to encourage their development, and additional initiatives, for example, to develop behavioral and social science tools that would help these disciplines integrate with others in the biomedical sciences. The general strategy for fostering multi- and interdisciplinary teams is to find ways to catalyze their formation, particularly for the purpose of working on complex diseases. Such diseases would be those that involve a complex interplay of genetics, environment, dietary, behavior, and other factors.
Dr. Tabak stated that research teams are expected to pursue high-risk research. As part of this initiative, NIH will establish an Exceptional Projects Program with rapid reviews. In addition, NIH will establish the NIH Director's Inventor Award to support individuals at all career levels and to recognize high-risk research projects. Another initiative, the Grand Challenges Program, will support large, complex, expensive projects that would be selected and managed by scientific officers. A fourth initiative, the Director's Incubator for Innovative Research, is considered complementary to ordinary institute and center activities. It, too, would feature accelerated reviews and other new mechanisms.
Dr. Stephen Katz, Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said that the effort to reengineer the clinical research enterprise covers the spectrum from molecules, to animal model systems, to clinical interventions. It includes emphases on the development of clinical research networks, the strengthening of the clinical workforce, the advancement of informatics, and the building of public trust, leading to broader participation in clinical trials.
An important priority is to establish a National Service Corps that will be modeled on the Rapid Access to Intervention Development program of the National Cancer Institute, according to Dr. Katz. Its purpose would be to prepare novel candidate drugs for animal toxicity testing in anticipation of clinical studies. Yet another priority is to improve important technologies and measures that are being used to assess clinical outcomes. For example, some measurements of quality-of-life outcomes could be made more robust and reliable. In addition, surrogate-marker measurements need to be validated, and improved approaches are needed for monitoring patients with chronic diseases and co-morbidities. The working group also recommended seeking greater involvement with patient groups in all phases of research.
One key recommendation for reengineering the national clinical research enterprise Dr. Katz noted, is to establish a network of 20 to 30 regional translational research centers that might be integrated with existing NIH General Clinical Research Centers (GCRCs), which will emphasize translational research. The new centers would support varied activities, including biostatistics, clinical pharmacology and pharmacogenetics, and also sponsor pilot projects. The forthcoming centers within the National Clinical Research Network would produce data on quality of care and clinical outcomes, be involved in large clinical trials, and eliminate many of the stumbling blocks that currently impede such trials. This effort would entail NIH catalyzing an effort among federal agencies to lead other federal agencies to harmonize clinical trials, including adverse event reporting practices, harmonize human subjects protection measures, consent procedures, as well as auditing and monitoring such trials across the United States. An early stage of this effort will focus on evaluation of existing clinical networks in both the public and private sectors, respectively. The new Network will eventually include a National Clinical Research Corps of community-based caregivers.
Dr. Katz indicated that a third working group focused on enhancing the clinical research workforce, recommended training clinical investigators at regional centers of excellence. These training efforts would be integrated with other training programs that aim to build multidisciplinary and translational research teams.
Clinical informatics will provides an essential link for integrating many of these efforts and programs, according to Dr. Katz. The idea is to develop a National Electronic Clinical Trials and Research (NECTAR) Network that would maximize connectivity within the overall Network while also accelerating the clinical research process. Development of NECTAR will call for the development of appropriate shared data standards, systematic tools, and uniform infrastructure.
In response to questions from Dr. J. Michael Bishop about the dollar scale being planned for the Roadmap initiatives and their scope in terms of encompassing the Intramural and Extramural Programs, Dr. Katz said that the new programs, such as the one involving the National Clinical Research Corps, would grow substantially by FY 2007 and beyond. Dr. Zerhouni noted that the initiatives would likely begin as experimental and pilot programs, with different institutes taking different approaches to establishing multidisciplinary programs. Dr. Zerhouni cited glue grants as one such early approach.
Dr. Katz clarified that these initiatives would mainly affect extramural research. Dr. Michael Gottesman added that the Intramural Research Program (IRP) will complement many of these proposed activities and, for example, the new Clinical Research Center at the NIH will play a role in clinical research activities that are part of the Roadmap. Dr. Spiegel noted that while the IRP does not typically participate in large-scale phase III clinical trials, it is adept at moving quickly into early-phase translational work. The IRP could also participate in other early stage components of the Roadmap, such as structural biology analyses and molecular library building.
Dr. Larry Smarr noted that the Medical Informatics Research Network (MIRN) might represent a good model, given that it was established as a shared repository for handling and sharing molecular imaging and central nervous system data among several institutions. These same organizing principles could be applied to clinical trials. He added that, following recommendations from the Presidential Information and Technology Advisory Committee, the National Science Foundation (NSF) move to establish multidisciplinary, information technology teams. These might also provide an illustrative research-community-inspired model, useful for what will be needed to reengineer the clinical research enterprise.
In response, Dr. Zerhouni emphasized that the Roadmap contains some radical proposals regarding clinical research, noting that such approaches are needed because of concerns regarding rising healthcare costs, the increased difficulties facing researchers aiming to undertake clinical research projects, and the need to conduct large-scale multidisciplinary clinical trials to obtain statistically significant results, which can be difficult to arrange because of the decentralized nature of the U.S. healthcare system. Additional challenges accrue because clinical research often deals with complex, chronic diseases; and patients are increasingly being treated as outpatients or only have very short hospital stays. There are also difficulties in recruiting patients into clinical trials. Dr. Katz added that the proposed National Clinical Research Corps would actively reach out to vulnerable and to minority patient populations, in order to study their respective healthcare needs.
Dr. James Martin suggested that the testing of combination drug therapies be considered a priority as part of the Roadmap, pointing out that drug companies typically do not test the products of other companies. Dr. Siegel said that this idea is sound and there are examples in which the NIH has arranged for such combination drug trials. He noted that NIH should try not to duplicate what industry does but rather should go further in terms of probing the underlying mechanisms of action among combination drugs. Both Drs. Siegel and Katz agreed that some combination drug testing would fit closely with institute-specific missions. Dr. Zerhouni said that several institutes are reviewing FDA-approved drugs for their ability to treat 600 known neurologic diseases, many of which are very rare and therefore considered "orphan" diseases. Similarly, the NIH conducted a comprehensive clinical review of hypertensive agents to determine which ones, and which combinations, are most effective. Dr. Steven Paul agreed that combination drug therapies are important for meeting healthcare needs, and that the NIH has an important role to play in evaluating them.
In response to a question from Dr. Paul, Dr. Zerhouni noted that, in light of anxieties about the costs involved in implementing the Roadmap, current plans call for using one-third of the funds available through exercise of the transfer authority of the Director for FY 2004, and also entail plans for institutes to identify priority items to support. In fact, institutes already are supporting a number of the items outlined in the Roadmap — proteomics, for instance, is budgeted for $149 million this fiscal year. Thus, in many cases, the goal is to find synergies for projects within current research portfolios rather than to create new portfolios. Because the NIH currently invests one-third of its resources into clinical research, an immediate goal is to ensure that this investment is made more efficient.
Dr. Paul said that, with limited new funding, progress in implementing the Roadmap may be slow, suggesting that the NIH should focus on finding creative ways to harmonize ongoing activities as a first step toward along this path. Dr. Smarr agreed, urging that the NIH leverage resources, for instance, by bringing in bioinformatics experts to participate in ongoing clinical trials. Dr. Katz added that issuing small grants to improve interconnectedness of clinical trials would also help to meet this challenge. Dr. Charles Francis suggested that this concept be extended to the basic sciences, providing an economic means for pooling resources through integrated research networks that, for instance, could take fuller advantage of undergraduate students.
Dr. Linda Waite said that sample selectivity can be a confounding issue in clinical trials and in research surveys. For instance, advertising for people to participate in clinical trials may lead to biases in who joins the study. She also inquired whether, without any additional costs, the NIH could eliminate procedures that tend to bias against supporting interdisciplinary research projects?
In response, Dr. Zerhouni replied that the problems associated with forming interdisciplinary teams sometimes lie with the institutions that are applying for NIH support. For instance, few medical schools have chemistry departments. Dr. Charles Wilson added that medical schools nonetheless are trying to break down barriers between departments and to encourage interdisciplinary collaborations. However, even when several separate institutions undertake a project, the NIH permits only one principal investigator, thereby providing the PI's institution a greater share of the credit for, what in actuality may be a widely distributed project.
In response to Dr. Wilson's request for more details about the proposed National Clinical Research Corps, Dr. Katz said that this initiative would likely entail recruiting healthcare providers from throughout the country. One such local example brings the NIH Clinical Center into contact with a small clinic within Washington, D.C., that serves an African American and Hispanic population, encouraging them to participate in clinical trials. In response to Dr. Wilson's question whether patients or caregivers would be recruited, Dr. Zerhouni said the idea is to develop close partnerships between academic health centers and community healthcare providers, leading to a credential-certified clinical research corps. He added that the University of Maryland School of Medicine represents an example of how this concept can work. Another example is the Cystic Fibrosis Network, which works with the NIH and with community healthcare providers, and has substantially extended the life expectancy of individuals with cystic fibrosis. The network ensures that individuals with this relatively rare disease are recruited, while it also very efficiently delivers new treatments or other developments to patients within the network.
Dr. Wilson said that this approach does not really entail building a corps but would be a more widespread effort to partner with community practitioners throughout the country. Dr. Zerhouni agreed, but said that caregiver participants would need training and other provisions would be needed to meet regulatory and patient privacy standards. Dr. Francis said that the recent clinical reevaluation of drugs to regulate blood pressure depended on recruitment of community practitioners, but was not easy to accomplish.
In response to a comment from Mr. Larry Sadwin, Dr. Zerhouni indicated that an increase from the current 3 percent participation level in clinical trials should be an explicit outcome measure for the Roadmap.
In response to comments from Dr. Smarr about the institutes competing for challenge grants to conduct particular clinical trials, Dr. Zerhouni said that the Roadmap is intrinsic to the NIH mission and that the very process of developing the Roadmap has proved useful for removing barriers between institutes. Dr. Tabak said that his institute faces both generic and specific issues, and thus does not expect other institutes to solve the problem of, say, dental caries. However, there are many other areas in which the institutes can work together. Dr. Katz said that changes in budget prospects make it important for institute directors to work together on accelerating research progress for initiatives that cut across individual institute missions.
In response to comments from Dr. Paul, Dr. Zerhouni said that the Roadmap provides an ambitious framework, outlining many real needs of the scientific community. Particularly in the case of clinical research, where costs continue to grow, it is critical to find new efficiencies. Dr. Smarr suggested reviewing the 1999 BISTI report, noting that it provides a set of recommendations for encouraging the wider use of computational science and bioinformatics in biomedical research — in part, as a way of encouraging greater use of this branch of science, and in addition to use informatics t to improve efficiency. He said that institute directors might devote 5 percent of their budgets for supporting multidisciplinary projects in this area, noting that a similar strategy proved effective at NSF.
Dr. Francis added that multicenter clinical trials often tend to recreate infrastructure instead of taking advantage of past experience in conducting such trials. It would be advantageous to pool such experience and avoid repetitious efforts.
In response to a question from Dr. Paul about molecular libraries, Dr. Zerhouni said that the Roadmap calls for this being an activity involving all the institutes and centers. Dr. Spiegel said that the Center for Inherited Disease Research (CIDR) provides genotyping services for extramural and intramural investigators who are supported by virtually all the institutes and centers. Each investigator's request to CIDR is evaluated. The molecular library service might provide similar high-throughput screening for potential for therapeutic agents for investigators studying particular diseases. This molecular library also would conduct stand-alone research.
Dr. Zerhouni concluded that, in summary, the NIH is restructuring at the administrative level while also carefully evaluating how it is spending its resources. In addition it is reevaluating postdoctoral training issues, fostering a build-up of human embryonic stem cell research, and developing a comprehensive Roadmap to delineate the future of the NIH.
Dr. Guttmacher of the National Human Genome Research Institute distributed to ACD members DVD disks containing information about the sequence of the human genome, and interviews with scientific leaders in genetics and genome research.
The Advisory Committee to the Director (ACD) of the National Institutes of Health (NIH) convened on June 30, 2003, to review recent events affecting NIH, and learn about administrative restructuring activities, an ongoing evaluation of postdoctoral training, an update on stem cell research, and activities regarding the future Roadmap of NIH.
The ACD acknowledged and commented on these programs and issues and encouraged the NIH to begin to implement the Roadmap.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Raynard Kington, M.D., Ph.D. Executive Secretary, Advisory Committee to the Director, Deputy Director, NIH
Elias A. Zerhouni, M.D., Chairman, Advisory Committee to the Director, Director, NIH
