NINDS Advisory Council Meeting Minutes, September 23-24, 1999

DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NATIONAL INSTITUTES OF HEALTH
NATIONAL ADVISORY NEUROLOGICAL DISORDERS AND STROKE COUNCIL

Summary of Meeting¹
September 23-24, 1999

In accordance with Public Law 92-463, the meeting was:

Open: September 23, 1999 -- 8:40 a.m. to 3:40 p.m.

for the review and discussion of program development, needs, and policy; and

Closed: September 23, 1999 - 3:40 p.m. to 4:55 p.m.

September 24, 1999 -8:35 a.m. to 11:30 a.m.

for discussion and consideration of individual grant applications.

Council members present were:

Council members absent were:

Ms. Jeanne Carpenter
Dr. Joshua Sanes

Council Roster (Attachment 1)

Ex Officio Members present:

Dr. John Booss, Department of Veterans Affairs
Dr. Andrew Dutka, Department of Defense

Members of the public present for portions of the open meeting included:

NINDS employees present for portions of the meeting included:

Other Federal employees present for portions of the meeting included:

Dr. Brent Stanfield, NIMH
Dr. Ruth Fischbach, OER, OD
Mr. William Fitzsimmons, NIMH
Ms. Susan Solomon, OBSSR, OD
Dr. John Fakunding, NHLBI
Dr. Elliott Postow, CSR
Dr. Sam Rawlings, CSR
Dr. Michael Nunn, CSR
Dr. Michael Martin, CSR
Dr. Christopher Platt, NSF
Dr. Donald Schneider, CSR
Dr. Anne Schaffner, CSR
Dr. Gillian Einstein, CSR
Dr. Christine Melchior, CSR
Dr. Michael Lang, CSR
Ms. Kristina Borror, OD
Dr. David Simpson, CSR
Dr. Carole Jelsema, CSR
Dr. Joe Marwah, CSR
Dr. Joanne Fujii, CSR
Dr. Herman Teitelbaum, CSR
Dr. Jay Joshi, CSR
Dr. Anita Miller Sostek, CSR
Dr. Lalita Palekar, NCI
Dr. Sidney McNairy, NCRR

I. Call to Order and Opening Remarks

Dr. Fischbach welcomed the Council members, guests, and staff to the 146th Council meeting. He introduced two new Council members: Dr. John Griffin, Professor and Director, Department of Neurology, Johns Hopkins University, and Dr. Peter MacLeish, the founding Director of the Morehouse School of Medicine Neuroscience Institute and Professor and Interim Chair of the Department of Anatomy. Two other new Council members, Ms. Jeanne Carpenter, Partner with McDermott, Will & Emery in Washington, DC, and Dr. Joshua Sanes, Professor, Department of Anatomy and Neurobiology, Washington University, were unable to attend this meeting. Dr. Fischbach introduced Dr. Michael Chopp, Vice Chairman, Department of Neurology, Henry Ford Hospital, Detroit, Michigan, and Chair of the NINDS Neurological Sciences Disorders A Initial Review Group, as a special visitor to the Council meeting.

II. Report of the Associate Director for Extramural Research

A. Council Procedures

Government in the Sunshine Act and Federal Advisory Committee Act:

These Acts require the DHHS to open to public observation as many advisory committee meetings as possible, including the meetings of the National Advisory Councils. The Council meeting, therefore, was open to public observation except when grant applications were being reviewed, at the times previously specified in these minutes. Notice of the date and place of the Council meeting was published in the Federal Register thirty days prior to the meeting.

Conflict of Interest:

The regulations concerning conflict of interest were reviewed, and Council members were reminded that materials furnished for review purposes and discussion during the closed portions of the meeting are considered privileged information. All Council members present signed a statement certifying that they did not participate in the discussion of, or vote on, an application from any organization, institution, or any part of a university system, except for those which have multi-campus institution waivers or are specifically designated as separate organizations under 18 U.S.C. 208(a), of which they are an employee, consultant, officer, director or trustee, or in which they have a financial interest.

B. Consideration of Minutes of Previous Meeting

The minutes of the Council meeting of May 20-21, 1999, were considered and accepted as written.

C. Consideration of Dates for Future Council Meetings

February 10-11, 2000 (Thursday and Friday)

May 25-26, 2000 (Thursday and Friday)

September 14-15, 2000 (Thursday and Friday)

February 15-16, 2001 (Thursday and Friday)

May 24-25, 2001 (Thursday and Friday)

September 13-14, 2001 (Thursday and Friday)

D. Other Items

Dr. Atwell reminded Council of the many Program Announcements (PAs) and Requests for Applications (RFAs) that NINDS has published in the NIH Guide for Grants and Contracts. Copies had been e-mailed to Council members since their last meeting. She then called Council's attention to the Report Book which included a list of all funding actions since the previous Council meeting. It also included a listing, as requested by Council, of the status of the applications nominated for High Program Priority at the last Council meeting.

Dr. Atwell solicited Council's comments about the recent shift to transmitting some Council correspondence via e-mail and by posting information to the Council website. She pointed out that this mailing method uses less paper and staff time. Council responded that this shifts the printing on their end. Council expressed frustration at being disconnected from the Electronic Council Book if they had been inactive for a short time. Dr. Atwell explained that since the site contains confidential data, it was designed to automatically disconnect the user if there is inactivity for a certain duration. Staff will examine the possibility of increasing the length of time before a user is disconnected due to inactivity. Council also raised the question of having to log back in and out of the ECB and back into the website to view summary statements. Council was reminded that there was a link to the summary statements for all applications that appeared on the Specials Considerations list.

Council was reminded of the Council Expedited Review Process wherein a subset of Council members (on behalf of the full Council) approve a list of applications within the payline. It was noted that this has been working very well and allows the Institute to process the grants sooner. For this Council round, which is at the end of the fiscal year and produces one of the tightest workloads, staff was nevertheless able to make 25 awards before the Council meeting. They also hope to make additional awards by the end of the fiscal year. These grants would otherwise not be funded until at least December 1.

Dr. Atwell reminded Council that they are required annually to receive special training on the standards of ethical conduct. Each Council member had been mailed prior to the meeting written materials regarding ethics rules. No questions were raised by Council regarding these materials.

Council was reminded of the recent revision to the Javits Neuroscience Investigator Award; namely, that instead of a seven-year award, the Notice of Grant Award would be issued as a four year award and then a three year award (conditional based on additional information following the first four years). This change was made to help the Institute in meeting its average four year length of grant award as part of the financial management plan of the Institute, which is a requirement of the whole NIH. Staff is now asking for Council concurrence to nominate and recommend for funding Javits nominations at each Council meeting instead of just at the June meeting each year. The original reason was to make sure that there were not so many candidates nominated at the first two rounds that staff felt constrained at the end of the year. Since the policy change to only one Javits per person, numbers of nominees have not exceeded the cap of twelve per year, so this does not seem to be a problem. Council concurred with this recommendation.

Next, Dr. Atwell introduced the following new extramural staff: Ms. Sandra Talley, Program Analyst, in the Office of the Director, Division of Extramural Research; Dr. Jill Heemskerk, Program Director, Neurodegneration Program; Dr. Robert Finkelstein, Program Director, Genetics and Development (effective October 1); Dr. Emmeline Edwards, Program Director, Systems and Cognition (effective January 2000); and Dr. Tom Miller, Program Analyst, Technology Development. Dr. Atwell announced the retirement of Dr. Joseph Drage, who will be retiring the end of the calendar year, and thanked him for his loyal service. With the increase of extramural staff, Council requested that a new staff photo directory be updated and distributed.

III. Update on Neuroscience Review in the Center for Scientific Review

Dr. Robert Baughman, Associate Director for Technology Development, NINDS, updated the Council on several issues related to Neuroscience Review at the Center for Scientific Review (CSR).

At the last Council, concerns were raised regarding the amount of time being taken by CSR to release summary statements. Dr. Baughman reported that the situation had improved, with summary statements being released three to four weeks earlier. This was mainly due to the hiring of more Scientific Review Administrators (SRAs) and Grants Technical Assistants (GTAs), better coordination between Initial Review Group (IRG) chiefs, fewer computer problems, and the cooperative team effort of the SRAs. Thus, some of NINDS's concerns had been resolved.

With regards to the referral process, the process is working well due to the success of the self-referral process (over 90 percent of self referral preferences were appropriate) and an improvement in the CSR referral process. A more efficient referral process shortens the time to award.

CSR is establishing working groups for each of the IRGs, with plans to have them in place for the June 2000 review. These working groups will participate in the review and report back on all aspects of the process, including the quality of the review, the adequacy of coverage, and issues related to the science. NINDS, along with the other Institutes and Centers, will be asked to nominate members for these working groups.

With regards to the newly reintegrated neuroscience study sections, Dr. Baughman distributed a handout describing an evaluation effort currently being planned by CSR. This effort will include a statistical evaluation of records of the review process and a survey of applicants, SRAs, IRG chiefs, and other stakeholders, including institute staff on how the reintegrated review process is functioning and an evaluation of the review process by scientific experts.

On the subject of reviewer conflicts of interest, CSR is undertaking a careful review of the current conflict-of-interest rules to determine if they are too rigid and how they might be altered. This is necessary because of the difficulty of finding reviewers for the increasing number of large multi-investigator, multi-institute applications that NIH is receiving.

Finally, Dr. Baughman reported that CSR is increasing its efforts to encourage the participation of extramural scientists as reviewers, in particular those from minority backgrounds.

Dr. Fischbach reminded Council members that the report of the Boundaries Committee reviewing the current CSR study section organization has been published and is open for comment until October 15. Dr. Baughman pointed out that this review does not include the neuroscience study sections, but said that the report does include some interesting philosophical discussions of general interest regarding the review process.

IV. NINDS Intramural Acute Stroke Program

Dr. Stephen Warach, Chief, Section on Stroke Diagnostics and Therapeutics, Stroke Branch, Division of Intramural Research, NINDS, reported that the Section was established in the spring of 1999. The general long-term goals of the Section are to develop a clinical management and investigation unit at Suburban Hospital. Clinicians and investigators in the Section will :

• Provide on call service to administer tPA and other emerging therapies to appropriate patients;
• Conduct clinical investigations with the aim of improving imaging diagnosis of stroke patients, elucidating mechanisms of human stroke pathophysiology and response to pharmacological interventions, and determining if the therapeutic window for stroke may be prolonged;
• Develop and optimize magnetic resonance diffusion and perfusion imaging as a selection tool and as a surrogate marker for stroke outcome studies;
• Develop and screen novel therapeutic strategies using MRI methods; and
• Establish registries and databases to ask questions about the natural history of human stroke.

V. Cerebrovascular and Cardiovascular Prevention-Intervention Initiative

Dr. Joana Rosario, Program Director, Office of Special Programs in Neuroscience, NINDS, presented some statistics on stroke. In the United States, there are 731,000 strokes a year, with 4 million stroke survivors currently in the country. These numbers are expected to increase as the baby-boomers grow older. Stroke affects minorities disproportionally, and is more prevalent in the stroke belt (Southeast United States). The NINDS, partnering with the National Heart, Lung, and Blood Institute (NHLBI) and the National Center for Research Resources (NCRR), will develop a pilot prevention program at a minority medical school. The goals of the program are to develop sustainable, replicable, and culturally appropriate prevention/intervention strategies to decrease the frequency of stroke in underserved populations, to foster collaborations between minority institutions and those with established research on stroke, and to augment and strengthen research capacity at minority institutions. Consideration will be given to an institution located in an area where stroke is more prevalent; with a history of serving medically underserved communities; with a strong, proactive leadership; and with current experience in working with the NINDS, NHLBI, and NCRR. The current Morehouse School of Medicine Specialized Neuroscience Research Program will be used as a model. The program will have two phases (two plus four years), starting in Fiscal Year 2001.

VI. Opportunities for Cooperation Between the National Heart, Lung, and Blood Institute and the NINDS

As an introduction, Dr. Fischbach noted that there are many common areas of research shared by the two Institutes. Dr. Claude Lenfant, Director, NHBLI, expanded on this theme, describing the cooperative effort on the new Suburban Hospital partnership program. This ground-breaking study will be using MNR in an emergency room to detect and evaluate stroke and coronary events. He reminded the Council audience that the famous Framingham longitudinal heart study is headed by a neurologist. Dr. Lenfant pointed out that the NHLBI has a Historically Black College and University (HBCU) enhancement program, similar to that of NINDS. NHLBI has instituted a study in Jackson, Mississippi, that will capture long-term minority data, a missing component in the Framingham study.

Other common interests are research and regulatory issues related to Creutzfeldt-Jakob disease, studies of other blood viruses, sleep research, the women's health initiative, and the rat genome project.

VII. Report of the Director, NINDS

Overview

Budget Update

The discussion of FY 2000 was necessarily speculative, since action has not been completed on the appropriations bill and anticipated Congressional levels are substantially higher than the President's budget request. Dr. Fischbach discussed the impact of a 2.4 percent increase (budget request) vs. 10 percent (hypothetical appropriation.)

NINDS Reorganization

Requests for Applications (RFAs).

Dr. Fischbach reviewed the factors that normally underlie the issuance of an RFA: unusual research opportunities, a need to stimulate research in a particular area, a desire to promote targeted technology development, or a need for specialized review. RFAs differ from ongoing program announcements (PAs) in that they involve a set-aside of funds and a single receipt date. Applications are reviewed by a special committee established by the sponsoring Institute and all applications submitted in response to the RFA compete with each other for funding. Contrary to popular perception, the success rate for RFA-based applications may be lower than that for NIH as a whole; for NINDS it has been dramatically lower. NINDS has been sparing in its use of RFAs in the past. For NIH as a whole, about 10 percent of funded applications have been in response to RFAs; the comparable figure for NINDS is much lower, ranging from 0.1 percent to 1.3 percent in the past four years. This figure can be expected to increase as NINDS embarks on more initiatives on its own and in collaboration with other institutes.

Dr. Fischbach's presentation and Council discussion focused on the implications of increased use of RFAs for Institute funding plans and the more general question of how to account for increased NINDS initiatives in setting the grant payline. For many years NINDS has paid the first 80 percent of available funds for Research Project Grants (RPGs) and centers in strict priority order. Decisions about the remaining 20 percent are based on discussions among staff and with Council about the relative merits of applications that fall below that cutoff but represent unusual opportunities or needs, or existing investments. Dr. Fischbach used a chart displaying two hypothetical FY 2000 budget levels to illustrate the effect of maintaining the 80/20 split or moving to 75/25 or 70/30. A ten percent increase would allow NINDS to use the 80/20 or 75/25 cutoff with minimal impact on the payline, but the payline would drop to the 22^nd percentile if a 70/30 funding plan were adopted.

In response to a question, Dr. Fischbach stated that the clusters are expected to generate RFAs, but also to use other mechanisms such as workshops to encourage applications in areas of special interest. He also reminded the Council of the Institute's commitment in its strategic plan to increase support for infrastructure, if necessary at the expense of investigator-initiated grants. Other Council comments focused on the appeal of RFAs as a balance to conservatism on the part of study sections, the need for NINDS to balance leadership against the value of investigator-initiated research, and the role of core grants in providing support for infrastructure. Dr. Fischbach emphasized the importance of partnership with the outside community.

Parkinson's Disease Centers.

NINDS Website

Council Subcommittees

Copies of the slides used in Dr. Fischbach's presentation are attached as Appendix 1.

VIII. Stem Cells: Biology, Therapy, and Ethics

Dr. Fischbach noted that NINDS could be the poster child for stem cell research-for no area of medicine is the need and potential greater than for disorders of the nervous system. However, the potential ethical concerns are very important, and stem cells are likely to be a subject of many Council discussions in the future. The first two parts of the Council presentation were designed to present scientific background, and the third to update ethics and regulatory matters from the previous Council discussion.

Dr. Arlene Chiu, Program Director, Repair and Plasticity Program, NINDS, noted that stroke, traumatic injury, and neurodegenerative disorders all result in the loss of nerve and glia cells. The intense interest in stem cells arises because this emerging science offers the potential to restore lost cells, the holy grail of treating these diseases. She presented an overview of stem cell biology and discussed highlights and recommendations from the NINDS workshop, "Neural Stem Cells: Promoting Repair and Plasticity of the Nervous System," held July 20^th and 21^st this year. She noted that NINDS also recently sponsored a very successful workshop for postdoctoral students focused on stem cells that included a useful exercise of grant writing skills.

The defining properties of stem cells are the capacity for self-renewal and the ability to generate many types of mature specialized cells, but the term has been used loosely to include cells that vary in the extent of self-renewal and in the range of cell types a "stem cell" can generate. ES (embryonic stem cells), derived from the blastocyst stage of the early embryo, are highly pluripotent, that is, they can generate most cell types of the body. Neural stem cells derived from the embryonic nervous system at a later stage of development can produce many kinds of nerve cells and glia, but-with present technology-are not as versatile as ES cells. Self-renewing neural stem cells, capable of producing neurons and glia, are also present in isolated parts of the adult nervous system. Finally, engineered or naturally occurring mutations can produce immortalized cell lines.

Stem cells can be used for cell replacement in vivo, as vehicles for gene therapy, in assays for pharmacological discovery and toxicity studies, and as research tools for studying development and cell biology. It is possible, at least in experimental animals, to obtain widespread distribution of stem cells introduced to the brain, and these cells appear to integrate well. In some experiments, such as those reported by Dr. Evan Snyder, effective enzyme replacement therapy with stem cells appears feasible. There are strong indications that the environment is the key to controlling the fate of stem cells, and many laboratories are actively engaged in understanding how that occurs. Among the other key issues in stem cell biology: How comparable are the many varieties of neural stem cells? How does each behave in vivo and in disease models? Do stem cells behave differently when introduced in mature vs. immature brains? How can we deliver cells to selected sites? and, importantly, How safe are they-for example, might uncontrolled growth ensue?

One of the most exciting areas of research is neurogenesis in the adult brain. While there had been indications for many years that stem cells might be present in the adult brain, recent research has strongly confirmed that new nerve cells can arise in even 60 year old human brains. The crucial paradox is why then does the adult brain have such an inadequate capacity for self-repair. As we learn more, we hope to enhance that intrinsic capacity. We do know that neurogenesis in the adult brain can be regulated by many external influences including: exercise, environmental enrichment, learning, seizures, stress, circulating hormones, and genetic differences. More invasive factors that modify neurogenesis include injury and intraventricular infusion of neurotrophic factors. In addition to a better understanding of where stem cells occur in the brain and what environmental cues can regulate them, it is essential to determine what the normal function of these cells might be. Again, we must consider the potential for harm as well as the potential for good.

The Workshop participants agreed on several recommendations and needs, including:

• A need for markers that reliably identify stem cells.
• Support for research on all types of neural stem cells.
• Standardized procedures and a database available via the Web.
• Making cells easily available to the research community, perhaps via a cell bank.
• Greater interaction between NINDS and FDA in preparation for clinical trials.

Dr. Ron McKay, Chief, Laboratory of Molecular Biology, Division of Intramural Research, NINDS, has been a leader in stem cell research for many years. He discussed the biology of neural stem cells and their potential therapeutic uses, with several illustrations from the work of his laboratory.

Dr. McKay noted that experiments by Dr. Seymour Benzer in the mid 1970's laid the conceptual groundwork for mammalian neural stem cell work. Dr. Benzer showed, using genetic methods, that a single uncommitted cell gives rise to all the cell types of the drosophila (fruitfly) retina. Subsequent work supports the idea that in mammals it is not simply lineage, but rather interactions among neighboring cells that direct the development of the complex organization of the brain.

Nestin, a cytoskeletal protein, is transiently expressed in early precursor cells of the mammalian nervous system and turned off in mature neurons and glia. Nestin, thus, can serve as a useful marker to investigate the origins of cell types in the brain. Under proper conditions, single nestin-positive cells can propagate in culture and can give rise to neurons, astrocytes, and oligodendrocytes. This fulfills both criteria for multipotent stem cells. The neurons generated are "real neurons," with characteristic neuronal morphology, biochemistry and physiology, including excitatory and inhibitory synaptic connections. The specific developmental path of a neural stem cell, including even the proportion of excitatory and inhibitory connections, can be directed by exposing it to specific chemical signaling factors.

Adult-derived neural stem cells share a common biology with fetal-derived stem cells in many respects, but they are not identical. Adult neural stem cells, compared with fetal cells, can yield similar proportions of neurons, astrocytes, and oligodendrocytes, and single factors can direct the fate of adult and fetal stem cells along the similar paths. However, adult cells, while similar, are not identical. Responses to BMP factors, (bone morphogenetic proteins, a family of signaling molecules) presents one example of a difference. Thus, at this stage of our knowledge, it is important to avoid any sweeping conclusions about the adequacy of adult stem cells for any particular therapeutic application, but it is also too early to be negative about what adult cells might be coaxed to do in the future, with appropriate knowledge of their basic biology.

Two examples of work by Dr. McKay's laboratory and collaborators illustrate the therapeutic potential of stem cells. In the first instance, stem cells were expanded in culture and directed to differentiate into dopamine neurons by using appropriate signaling factors and culture conditions. When these cells were transplanted into a rat model of Parkinson's disease, they significantly corrected abnormal motor behaviors. Similarly, stem cell therapy showed considerable promise in a rat model of the human myelin deficiency disorder Pelizaeus-Merzbacher disease. Knowledge about how defined factors control embryonic stem cell fate allowed efficient generation of oligodendrocyte precursor cells. After transplantation, these cells spread widely and robustly myelinated axons in these rats.

In concluding, Dr. McKay emphasized that his enthusiasm for the therapeutic potential of stem cells for neurological disorders has continued to grow as we learn more about the biology of these cells. He felt it was crucial to convey his optimism to those who are weighing the ethical aspects of stem cell research.

Ms. Lorraine Fitzsimmons, Senior Policy Advisor, Science Policy and Analysis Branch, NINDS, reviewed the continuing moratorium on NIH funding of research using human pluripotent stem cells derived from human fetal tissue or human embryos. This moratorium was issued by Dr. Varmus on January 25, 1999, and was reaffirmed and updated on April 19; it had been discussed at the February and May meetings of the NANDS Council. The Council was reminded that while the NIH still proposes to support research utilizing these human pluripotent stem cells, it will not do so until guidelines are issued, and an oversight committee is in place to review each project and ensure that it is in accord with these guidelines. Ms. Fitzsimmons advised the Council that a subcommittee of the Advisory Council to the Director had drafted proposed guidelines after receiving public input, and briefly discussed aspects of the subcommittee's public deliberations. The draft guidelines are in the process of being reviewed prior to their being published in the Federal Register. There will be a 60-day public comment period before the guidelines would be finalized; however, there is no known anticipated date of publication and, therefore, no projected timeframe for the possible lifting of the funding moratorium. In response to questions, there was a brief discussion of research which can continue to be funded under existing policies and procedures, i.e., involving other than human pluripotent stem cells or involving human stem cells derived from sources other than human embryos or fetal tissue, and of the recently issued Executive Summary for the Report of the National Bioethics Advisory Commission with regard to stem cell research.

IX. Clinical Trials Update

In response to a request at the May 1999 NANDS Council meeting, Dr. John Marler, Associate Director for Clinical Trials, NINDS, presented proposed guidelines to be used by Council in considering clinical trials planning grant applications for approval. The guidelines were developed in conjunction with the NINDS Clinical Trials Group, and incorporated considerations from an NINDS-sponsored Clinical Trials Workshop held on the NIH campus on June 23 as well as a telephone conference with select members of Council. Dr. Marler outlined the steps leading up to the development of a Phase III randomized clinical trial application and the review process and criteria for R21 planning grant applications. Beyond the usual scientific review of applications, Dr. Marler proposed the following criteria for Council's consideration in prioritizing and approving applications:

• Scientific impact (degree to which scientific understanding is advanced; appropriate timing of question being addressed);
• Impact on the burden of the disease (proportion of patients affected by the disease; significance of therapeutic effect; potential impact on quality-of-life; economic impact; relation to similar trials);
• Available treatments for the disease (availability of approved, effective treatments, if any; uniqueness of the proposed intervention - new mechanism or delivery method; approved, available intervention, but undocumented effectiveness for the disease); and
• Ethical design (well-defined and acceptable risks and benefits).

Dr. Marler noted that the guidelines are informal, and not every factor may apply equally to each proposed trial being considered. The Council endorsed the proposed guidelines.

Dr. Marler also proposed two specific changes to the review process:

1. Creation of a new NINDS review committee for clinical trials; and
2. Review by Council of all R21 clinical trial planning grant applications (not just those being recommended for funding).

The concept of creating a single review group to evaluate all NINDS clinical trials in order to provide more complete and equitable evaluations of proposed clinical trials research was approved by the Council. The core review group is expected to be comprised of individuals with expertise in clinical trials leadership; trial design and methodology; biostatistics; neurology and neurosurgery; and human subjects protection; experts in the subject disease will be added on an ad hoc basis. The Council also agreed to the expanded review of R21 applications as a way to give members a more complete picture of the clinical questions being proposed for study in clinical trials.

X. Council Consideration of Pending Applications

This portion of the meeting, involving specific grant review, was closed to the public. The Council gave special attention to applications from foreign institutions and applications for which there were concerns about human subjects, including appropriate representation of women and minority subjects, or laboratory animals.

A. Research Training and Career Development Programs

The Council reviewed a total of 32 research career development grant applications; of this total, 24 applications had primary assignment to NINDS, and 21 of them (87.5 percent) were recommended for support in the amount of $2.1 million first-year direct costs. It is anticipated that, of the research career development grants competing at this Council, NINDS will be able to pay first-year direct costs of approximately $1.1 million.

B. Research Grant Awards

The Council reviewed a total of 1,280 research grant applications; of this total, 770 applications had primary assignment to NINDS, and 515 of them (66.9 percent) were recommended for support in the amount of $123.0 million first-year direct costs. It is anticipated that, of the research grants competing at this Council, NINDS will be able to pay first-year direct costs of approximately $45.6 million.

Senator Jacob Javits Neuroscience Investigator Awards

The Senator Jacob Javits Neuroscience Investigator Awards are made to distinguished investigators who have a record of scientific excellence and productivity, who are actively pursuing an area of research of strategic importance, and who can be expected to continue to be highly productive for a seven-year period. Candidates are now nominated and selected at each Council meeting. However, at this meeting, there were no nominations for Javits awardees.

C. Special Program Actions

The Council reviewed a total of 138 Small Business Innovation Research (SBIR) and Small Technology Transfer Award (STTR) grant applications; of this total, 77 applications had primary assignment to NINDS and 48 of them (62.3 percent) were recommended for support in the amount of $7.0 million first-year direct costs. It is anticipated that, of the SBIR and STTR applications competing at this Council, NINDS will be able to pay first-year direct costs of approximately $4.2 million.

The Council reviewed a total of 15 Academic Research Enhancement Awards (AREA) applications; of this total, 5 applications had primary assignment to NINDS, and 4 of them (80.0 percent) were recommended for support in the amount of $0.3 million direct costs. It is anticipated that NINDS will be able to pay first-year direct costs of approximately $0.2 million.

X. ADJOURNMENT

The meeting was adjourned at 11:35 a.m. on Friday, September 24, 1999.

These minutes will be formally considered by the Council at its next meeting. Corrections or notations will be incorporated in the minutes of that meeting.