NINDS Advisory Council Meeting Minutes, February 12-13, 2004

1. Call to Order and Opening Remarks
2. Report of the Associate Director for Extramural Research
3. Report of the Director, NINDS
4. Setting Priorities at NIMH
5. Council Feedback on Other Institute/Center Initiatives
6. Concept Approval for Fiscal Year 2005 Proposed Initiatives
7. Council Subcommittee Reports
8. Continuation of Report of the Director, NINDS
9. Overview, Division of Intramural Research
10. Scientific Presentation: "Imaging Early Events in Human Stroke: The Discovery of Novel Therapeutic Targets"
11. Scientific Presentation: "Effects of GDNF in Animal Models of Parkinson's Disease"
12. Review of the Division of Intramural Research Board of Scientific Counselors' Reports
13. Council Review of Pending Applications
14. Adjounment

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

Summary of Meeting¹
February 12-13, 2004

The National Advisory Neurological Disorders and Stroke (NANDS) Council was convened for its 159th meeting on February 12-13, 2004, at Building 1, Wilson Hall, Bethesda, Maryland. Dr. Story Landis, Director of the National Institute of Neurological Disorders and Stroke (NINDS), served as Chairperson.

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

Open:		February 12, 2004 --10:30 a.m. to 4:20 p.m.
for the review and discussion of program development, needs, and policy; and
Closed:		February 12, 2004 - 4:20 p.m. to 5:10 p.m.
		February 13, 2004 - 8:00 a.m. to 10:15 a.m.

for the review of the Board of Scientific Counselors' Reports and discussion and consideration of individual grant applications.

Council members present were:

Mr. Ronald Bartek
Dr. Bruce Bean
Dr. Keith Black
Dr. Alicia Conill
Dr. Raymond Dingledine
Dr. J. Donald Easton (2/12 only)
Dr. Daniel Lowenstein
Mr. Bradley Margus
Mr. Jeffrey Martin
Dr. William Mobley
Ms. Ellyn Phillips
Dr. Patrick Pullicino
Dr. Sally Shaywitz
Dr. Lydia Villa-Komaroff
Dr. Ira Shoulson
Dr. Huda Zoghbi

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Council Roster (Attachment 1)

Council members absent were:

Dr. Susan Hockfield
Mr. Robert Waterman

Ex Officio Members present:

Dr. Paul Hoffman, Department of Veterans Affairs
Dr. Geoffrey Ling, Department of Defense

¹For the record, it is noted that members absent themselves from the meeting when the Council is discussing applications (a) from their respective institutions or (b) in which a real or apparent conflict of interest might occur.

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

Dr. Greg Gerhardt, University of Kentucky
Mr. Jonathan Radow , The Blue Sheet
Ms. Michelle Rodrigues, SRI
Mr. Robert Balkam, Restless Leg Syndrome Foundation
Ms. Barbara Stahl, Constella Health Sciences
Ms. Nichelle Schoultz , Epilepsy Foundation
Ms. Patricia Smith, MasiMax Resources, Inc.
Ms. Pamela Moore, Capital Publications
Ms. Kimberly Symonds, Families of Spinal Muscular Atrophy
Dr. Judy Small, National Neurofibromatosis Foundation
Ms. Patricia Wood, NBIA Disorders Association
Mr. Jeremy Scott, Tourette Syndrome Association
Mr. Michael Manganiello, Christopher Reeve Paralysis Foundation
Ms. Tricia Brooks, Christopher Reeve Paralysis Foundation

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NINDS employees present for portions of the meeting included:

Dr. Constance Atwell
Ms. Ruth Linn
Dr. John Marler
Dr. Scott Janis
Dr. Mary Ellen Michel
Dr. Joanne Odenkirchen
Dr. Barbara Radziszewska
Dr. Frances Yee
Dr. Merrill Mitler
Dr. Claudia Moy
Dr. Robin Conwit
Mr. Michael Loewe
Dr. Melinda Kelley
Dr. Meena Hiremath
Dr. Bernard Ravina
Mr. Peter Gilbert
Dr. Raul Saavedra
Dr. Katrina Gwinn-Hardy
Ms. Nena Wells
Dr. Story Landis
Dr. Brandy Fureman
Dr. Linda Porter
Ms. Marian Emr
Dr. Dan Tagle
Dr. Paul Sheehy
Dr. Tom Jacobs
Mr. Gahan Breithaupt
Dr. Ronnie Horner
Dr. Yuan Liu
Dr. Alfred Gordon
Dr. Emmeline Edwards
Dr. Ernie Lyons
Dr. Eugene Oliver
Dr. Diane Murphy
Ms. Lorraine Fitzsimmons
Ms. Quandra Scudder
Mr. Jim Stables
Dr. Laura Mamounas
Dr. Robert Baughman
Ms. Margaret Jacobs
Dr. Arlene Chiu
Dr. Maureen Beanan
Dr. Andrea Sawczuk
Dr. JoAnn McConnell
Dr. Henry Khachaturian
Dr. David Jett
Dr. Michael Nunn
Ms. Marvene Horwitz
Dr. Tom Miller
Dr. Naomi Kleitman
Dr. Audrey Penn
Dr. Yejun He
Dr. Christina Vert
Ms. Maureen Hambrecht
Dr. Ursula Utz
Ms. Karen Dunlap
Ms. Kim Mott
Dr. Daofen Chen
Dr. Paul Scott
Ms. Sylvia Parsons
Dr. Jill Heemskerk
Dr. Joe Pancrazio
Ms. Shannon Garnett
Ms. Stephanie Clipper
Ms. Nancy Hart
Mr. Paul Girolami
Dr. Gabrielle LeBlanc
Ms. Robin Latham
Mr. Paul Myers
Mr. Andy Baldus
Mr. George Bramhall
Ms. Margo Warren
Dr. Karen Bateman
Dr. Alan Willard
Dr. Richard Crosland
Dr. Randall Stewart
Ms. Renee Crouse

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Other Federal employees present for portions of the meeting included:

Dr. Jane Steinberg, NIMH
Dr. David Armstrong, CSR
Dr. Peter Guthrie, CSR
Dr. Larry Baizer, CSR
Dr. Toby Behar, CSR
Dr. Sherry Stuesse, CSR
Dr. Seetha Bhagavan, CSR
Dr. Yingying Li-Smerin, CSR
Dr. William Benzing, CSR

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1. Call to Order and Opening Remarks

   Dr. Story Landis, Director, NINDS, welcomed Council members, guests, and staff to the 159thCouncil meeting and introduced new member, Dr. Huda Zoghbi. Dr. Susan Hockfield and Mr. Robert Waterman were unable to attend this meeting. Dr. Sally Shaywitz was invited to speak briefly about her work with the Washington Literacy Council. The mission of the Washington Literacy Council is to reach those adults who are illiterate or low-literate and teach them to read. The Council recruits and trains volunteers to provide free one-on-one tutoring.

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2. Report of the Associate Director for Extramural Research

   Government in the Sunshine Act and the Federal Advisory Committee Act

   Dr. Constance Atwell, Associate Director for Extramural Research, NINDS, reviewed the Government in the Sunshine Act and the Federal Advisory Committee Act, which require the Department of Health and Human Services to open to public observation as many advisory committee meetings as possible, including the National Advisory Councils. The NANDS Council meeting was open to the public, except during the review of the Board of Scientific Counselors' Reports and the review of grant applications. Notice of the date and place for 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. 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 had not been involved in any conflict of interest situations during the review of grant applications. Council members were also reminded that they need to remove themselves from discussions of applications from any institution from which they have received an honorarium for one year from the time the honorarium was received. If the Council member's participation is deemed critical to the discussion, however, an authorization may be granted by the Institute.

   Confidentiality

   During the closed session, any information that is discussed and the outcome of any recommendation are considered privileged information. They may not be discussed outside of the closed session. If an applicant requests support for his or her application from a Council member, the Council member must respond that he/she is not permitted to discuss the application. Any inquiry should be referred to Dr. Constance Atwell as Council Executive Secretary, who will then refer the questions to the appropriate staff member for response.

   Consideration of Minutes of Previous Council Meeting

   The minutes of the Council meeting of September 18, 2003, were considered and accepted as written.

   Consideration of Dates for Future Council Meetings

   The following dates for future Council meetings were reconfirmed:

   May 27-28, 2004		(Thursday and Friday)
   September 9-10, 2004		(Thursday and Friday)
   February 10-11, 2005		(Thursday and Friday)
   May 26-27, 2005		(Thursday and Friday)
   September 15-16, 2005		(Thursday and Friday)

   New Dates

   February 9-10, 2006		(Thursday and Friday)
   May 25-26, 2006		(Thursday and Friday)
   September 14-15, 2006		(Thursday and Friday)

   Other Items

   Expedited Review Process--Dr. Atwell reported that 119 out of 175 expedited applications were ready to be awarded. She congratulatedthe grants management and program staff for successfully completing the large number of grants by the Council meeting date.

   Reports Book--The Reports Book consists of applications that have been designated for funding since the last Council meeting. It includes interim actions that have been taken, the status of applications that were identified for High Program Priority, Administrative Supplements, and a list of Special Initiatives that was provided to Council in a mailing prior to the meeting. It also includes the NIH-wide "Roadmap for Medical Research" initiatives.

   Council General Recommendations--These are the general guidelines for administrative actions that may be taken by program staff without prior approval by Council. There were no major changes. There is a slight wording change stating that no grant application that exceeds one million dollars in direct costs is eligible for expedited review. A motion was made and seconded to approve the changes in the Council General Recommendations. A copy of the approved Council General Recommendations is attached as Appendix 1.

   Staff Actions--Dr. Joseph Pancrazio, a new program director in the Repair and Plasticity Cluster, was introduced. He is replacing Dr. Bill Heetderks, whose specialty was neural engineering and neuroprosthesis. In other staff news, Dr. Atwell announced that Dr. Henry Khachaturian, the Training and Career Development Officer, is moving to the NIH Director's Office of Loan Repayment. Dr. Atwell expressed appreciation for his service and wished him well in his new position. Dr. Cynthia McCormick, Deputy Director for the Division of Extramural Research, has retired from federal service and has gone into private consulting. Scientific Review Branch Chief Dr. Alan Willard will be Acting Deputy Director until the position is filled.

   Dr. Jane Steinberg, Director of the Division of Extramural Research at NIMH, is attending the NANDS Council meeting for observation.

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3. Report of the Director, NINDS

   Dr. Landis announced that the director of the National Institute of Mental Health, Dr. Thomas Insel, will be speaking following the Director's report. His experience and perspective are particularly relevant to NINDS, in that NIMH and NINDS share some research interests, and Dr. Insel is also a new director but with a several months' longer experience in that position. NIMH has recently undergone a portfolio analysis and a subsequent change in priorities, which also have an impact on NINDS.

   Congressional Hearings

   There has been recent attention called to grants funded in human sexual behavior research. Over 200 grants were identified by the Traditional Values Coalition for de-funding, and five were named in an amendment to the HHS appropriations bill for de-funding. NINDS did not have any grants in either group. Dr. Zerhouni asked the awarding I/Cs to review their funding decisions for relevancy, scientific soundness, and whether the review process, funding levels and mechanisms were appropriate. After studying their reports, Dr. Zerhouni responded to Congress that the grants were scientifically sound and appropriate.

   Outside Consulting by NIH Staff

   In 1995, as a result of a GAO audit, it was found that NIH had more stringent restrictions and reporting requirements than those issued by the Federal government. Based on those conclusions, NIH's policies were loosened to be consistent with the rest of the Federal government. Recent publicity about NIH staff outside activities, however, has raised questions about NIH's policy. Dr. Zerhouni has created an Ethics Advisory Committee, which will be responsible for approving all activities over $2,500 as well as activities that generate stock options. A recent analysis showed that the outside consulting arrangements questioned by Congress were appropriate and had been approved by the appropriate body, and all but one were held by intramural scientists. A Blue Ribbon Panel named by Dr. Zerhouni will draft recommendations for changes, if needed, to the existing policy. The NIH website has been revised to display more information about NIH's mission and accomplishments. There is a list of contributions over the recent past that have had a significant impact on public health. Two of them relate to improvements in the treatment of stroke and spinal cord injuries.

   Staff Searches

   There is a search underway for the Intramural Scientific Director. Dr. Landis hopes to identify the new Scientific Director by July. The search for Dr. Atwell's replacement as Director of the Division of Extramural Research (DER) is chaired by Dr. Penn. The advertisement on the NIH website closes March 31. The Deputy Director position in DER is also open, but the search will not begin until the Director's position is filled. There are open searches for program directors in the following areas: neuromuscular diseases, neurodegeneration, training and careers, channels, stroke, and encephalopathies. Qualities that are important for these positions include broad knowledge of the scientific area, good personal relations skills, and the ability to organize an effective workshop. All NINDS grantees will be notified of these openings.

   NINDS Budget

   A pie chart showing total NIH spending on neuroscience research by institute estimates $4.9 billion in spending in FY 04. NINDS holds the largest share, at 30.9 percent. Nine NIH institutes are major contributors to neuroscience research and constitute a neuroscience consortium. These institutes strive to collaborate to share common interests and promote neuroscience research. NINDS has had a policy of sharing resources and interests for the last several years. A survey showed that in the last 4 years, NINDS has participated in 23 Requests for Applications, 7 Program Announcements with Set-Asides, and 30 Program Announcements, with other institutes. NINDS has also led or participated in several major collaborative programs with other institutes: joint predoctoral training, mouse mutagenesis and phenotyping, autism centers, a pediatric brain imaging database, a bioactive compound collection, and the NIH Porter Neuroscience Building. These collaborations have been successful; however, the neuroscience institute directors would like to focus on prospective efforts to guide neuroscience research. They have been asked by Dr. Zerhouni to draft a neuroscience roadmap, a "blueprint for the brain." The blueprint draft includes focusing on infrastructure, research tools and technology development, neurodegeneration and repair, circuits, and behavior. The institute directors will also engage the research community in their plans, in their effort to propose programs that maximize the benefit for dollars spent.

   Council members asked questions about staffing for the Roadmap initiatives and overall NIH staffing. Council members also reaffirmed the importance of working with voluntary organizations to promote the neuroscience roadmap goals.

   The budget presentation was suspended at this point to allow for the NIMH Director to make his presentation.

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4. Setting Priorities at NIMH

   Dr. Thomas Insel, Director, NIMH, prefaced his remarks by reaffirming his commitment to working with NINDS and other neuroscience I/Cs to advance neuroscience research.

   NIMH's mission is to reduce the burden of mental illness and behavioral disorders through research on mind, brain and behavior. The need for research in mental illness is great: the highest cause of disability in the U.S. is mental illness. There are 30,000 deaths from suicide each year in the U.S., and it is the third leading cause of death in adolescence. The total cost of mental health care was $71 billion for treatment and $79 billion in indirect, social costs in FY 03. NIMH's budget in FY 03 was $1.3 billion, which was a 7.7 percent increase over FY02. The Institute's budget increased by 3 percent in FY 04, and the President's budget proposes an increase of 2.8 percent for FY 05. Regarding funded applications, the number of applications NIMH received from 1998 - 2003 increased by 40 percent; therefore, the success rate of new applications did not increase during the doubling period. The cost of non-competing grants has gone up, as well, which results in less available for new grants. In light of the reduced budget and at the same time broad research portfolio, how does the Institute set priorities? They decided on three major themes, which will guide future decisions: 1. Relevance (what is needed?), 2. Traction (what can be done?), and 3. Innovation (what is new?). Relevance includes supporting new or refined diagnostic tests, new treatments, new strategies for prevention, and new strategies for disseminating discoveries. The question of "what can be done" was applied to the six leading types of mental illness, evaluated in terms of whether the following apply: genes known, cells/circuits, behavior/cognition, whether there are animal models, and the status of drug treatment. In the area of innovation, NIMH looked at genetic research; gene expression and cells; systems, such as rodent/primate imaging, real-time information processing, and informatics; and clinical trials.

   Dr. Insel gave an overview of NIMH's organizational structure. Extramural research is divided into three areas: Neuroscience and Basic Behavioral Science, Mental Disorders and AIDS, and Services and Interventions. Dr. Insel has created Council member working groups to make any recommendations necessary to address NIMH research support in terms of relevance, traction, and innovation. Once their reports are issued, the Institute will evaluate their recommendations within the budget and other limits. NIMH will make more use of co-funding with other I/Cs as a way to further its objectives. Some of the future challenges to focusing research funding are the limited budget for new initiatives and the fact that most applications are not reviewed by NIMH and so may not receive the same consideration the Institute would give the applications. The Institute is committed to making its decisions as transparent as possible and meeting the urgent needs in mental health research.

   Following Dr. Insel's presentation, Jeff Martin asked if the cost figures for mental illness included lost wages and other indirect expenses related to the burden of disease. Dr. Insel believed it was an underestimate and suggested that NIMH may undertake its own cost data collection. He also said he will look into co-funding opportunities by affected agencies, such as Medicare. Brad Margus asked for the process for setting funding priorities on collaborative projects. Dr. Landis responded that generally, the Institute with the most interest in the project makes the largest commitment. Dr. Insel found thatNIMH and NIDA were funding closely similar clinical studies on many of the same patients, and that it was his goal to avoid funding parallel studies and work toward greater collaboration with institutes studying the same disorder or patients. There was further discussion about dividing research portfolios among institutes versus collaboration among two or more I/Cs on the same project. The Porter Building was cited as an example of collaboration of researchers from many of the neuroscience I/Cs on projects of similar interest. The future lies in a blending of disciplines into a general neuro-psychiatric area. Dr. Zoghbi raised a question about creating a different payline based on a high priority area as a means to channel research into a particular area. There are problems with funding applications that don't score within the Institute's payline. Dr. Insel replied that the pitfalls have not all been worked out, and that he would like to avoid the negative consequence of redirecting valuable research in one area to a high program priority area. Dr. Landis pointed out the need to inform the public about the successes NIH funding has produced and the need for funding to build on those successes. Dr. Black expressed the need to translate basic research findings into new treatments and therapeutics and to make the process efficient.

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5. Council Feedback on Other Institute/Center Initiatives

   Dr. Atwell discussed the results of the Council survey of the list of other I/Cs' initiatives in which NINDS chose to participate. There was generally high enthusiasm for the initiatives NINDS staff chose to co-fund, with 84 percent scoring 3 or above (on a scale of 1 - 5, 5 being best). Support for autism and disease-specific initiatives was high. There was less enthusiasm for the two diabetes-related initiatives and the cognitive/behavioral projects. The greatest number of co-funded initiatives were with NIMH (20 percent). The Fogarty International Center came in second at 16 percent. The third highest was NIAMS, with 12 percent. The rest were distributed among NCCAM, NCI, NHLBI, NIA, NIDDK, NICHD, and the NIH Director's office. Dr. Pullicino asked how NINDS views global initiatives. There are restrictions applied to funding foreign institutions, and all foreign grants must be approved by Council individually. The projects NINDS collaborates on are either for training or for infrastructure development.

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6. Concept Approval for Fiscal Year 2005 Proposed Initiatives

   Dr. Atwell asked the Council to review for concurrence two initiative concepts submitted by staff for FY 2005. Under the Federal Advisory Committee Act, an outside review group must clear all initiatives that involve funding by the Federal Government. Beginning with the 156th Council, the Institute asked that Council conduct the outside review for all new initiatives. Concurrence does not guarantee that these will go forward, as the final decision on the initiatives depends on the availability of funds. The first is an Administrative Supplement for Sharing and Distribution of Mouse Genetic Models. A question was raised about the rationale for making the supplements available to NINDS grantees only. Dr. Landis responded that the National Center for Research Resources funds mouse-sharing to all grantees. The second initiative concept is Genetics, Pathobiology, and Treatment of Vascular Dementia. A motion was made and passed by Council approving the concepts.

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7. Council Subcommittee Reports

   Training and Career Development Subcommittee

   Dr. Bruce Bean, Chair of the Training and Career Development Subcommittee, announced that Margaret Jacobs, Program Director in Channels, Synapses and Circuits, will be the Acting Training and Career Development Officer until a replacement for Henry Khachaturian is found. The subcommittee discussed the following issues:

   1. Training Opportunities for Scientists with Disabilities (K01). The K01 is already used to support underrepresented minorities, for scientists re-entering the workforce, and for translational research. The subcommittee recommends adding scientists with disabilities as a group eligible for a K01 award. The subcommittee also recommends that staff look into what other mechanisms can be made available to scientists with disabilities.
   2. The K24 Mechanism. This program is targeted to mid-career scientists who can serve as mentors to other K awardees. There is a concern that some eligible candidates may not be getting these awards; the NST review committee is conservative with the review of these applications, perhaps due to how the eligibility criteria are written. This problem needs to be addressed. NIH will be releasing an updated K24 program announcement shortly, and staff should scrutinize this document carefully for eligibility criteria.
   3. Develop Training Programs for Community-Based Physicians Participating in Clinical Trials. Several recommendations were discussed to address this need, such as training in their residencies or supporting a summer program for practicing neurologists which would result in a certificate. The Subcommittee recommended that Margaret Jacobs look into how best to implement this goal.
   4. K Awards in General. The Subcommittee believes that more resources need to be devoted to training. NINDS is on the low end of the spectrum relative to other I/Cs. The Subcommittee recommended an increase in the K award budget, with the goal of increasing the success rate of K awards. Dr. Landis responded that NINDS had a significant dip in the number of K08 and K23 applications because NINDS's program was for three years and other I/Cs had five-year programs. The temporary decrease in funded applications is most likely due to the change in policy. Since FY 03, the Institute has changed its policy and the success rate should reflect that. The Subcommittee's suggestions were based on the goal to increase the success rate for a training grant: 1) Commit new funds, with a minimum of $1 million to maintain success rates for the fellowship program at a minimum of 25 percent for F31s and F32s and a minimum of 30 percent for the F30 awards. 2) Commit a minimum of $2 million to maintain success rates for the career development programs at 25 percent for the K01 and K02, K24, K25, and a minimum of 30 percent for the K08 and K23 award. Currently 2.2 percent is spent on K awards by the Institute. Many of the other institutes devote 4 percent of their budgets to training grants. 3) Increase the K awards by .5 percent per year for the next four years.

   Dr. Bean concluded by thanking Dr. Khachaturian for his years of service as Training and Career Development Officer.

   Dr. Landis thanked Dr. Bean for his report and informed the Council that since the last Council meeting, the Institute has begun to increase the K award rate consistent with the Subcommittee's recommendations.

   Clinical Trials Subcommittee

   Dr. Daniel Lowenstein, Chair of the Clinical Trials Subcommittee, gave an overview of the clinical trials currently being funded: There are 4,060 grants in the NINDS portfolio, and 960 of them involve human subjects. One hundred and ten of the grants are Phase I, II, or III trials, with 27 of them Phase III trials. These clinical research grants span 150 neurological diseases. The Subcommittee discussed a proposal to do an analysis of previously-funded NINDS-funded clinical trials. The goal is to investigate the broad, societal impact that these studies have had. Staff have invited outside investigators to conduct analysis, in partnership with NINDS staff. The analysis will look at the impact of trial results on health and health care costs in the U.S. and which segments of society or components of the health care industry have benefited from the Phase III trials. It will identify characteristics of the trials that are associated with a greater ultimate impact on clinical care in society, and then compare the subjects in target populations in NINDS-sponsored trials to those of industry-sponsored trials. The Subcommittee then went into closed session to review individual grant applications. The Subcommittee has a much more sophisticated database from which they can get a good view of the portfolio and compare incoming trials in terms of disease focus and cost with those already funded. They have also instituted an electronic pre-evaluation process that worked quite well. Last, the subcommittee discussed ways to improve patient recruitment. They recommended that PIs be required to include data regarding the number of potentially available subjects for their trials, with their applications.

   Infrastructure and Neuroinformatics Subcommittee

   Mr. Brad Margus reported that the Subcommittee reviewed the funding strategies for the P01 and P50 mechanisms and compared NINDS policies with other I/Cs. Currently, P01s and P50s are treated identically by our institute. Should that be changed? In FY03, NINDS was funding 81 P01s and 36 P50s. The amount spent on these mechanisms has dropped over the last ten years, but the number of grants has remained level. The Subcommittee noted that the success rates were better than for R01s, and NINDS is approximately in the middle range as compared with other I/Cs on amount spent per grant. Some of the options considered were proposing a different payline for multicomponent grants or new funding caps. There was a suggestion to analyze the results of the center grants that have been funded. An Institute of Medicine report will be issued soon making recommendations for multicomponent grants, which will be studied by the Subcommittee. Questions about how to handle program projects with one weak project were discussed, as was changing the Institute policy of accepting unsolicited P01s or making an across-the-board cut of the 10 percent lowest-scoring applications each year. They decided to make sure large grants were not being discouraged by the reviewers and consider other mechanisms, to avoid the typical review process. They also considered applying the same pre-review process to large multicomponent applications as the Clinical Trials Subcommittee does for large clinical trial applications. The Subcommittee's recommendations were as follows:

   • Maintain same payline as R01s
   • Only 20-25 competing P01/P50 awards are made per year; lowering the payline would have a small effect
   • Continue to accept unsolicited P01s for the present
   • The percent of total budget is low; there are many important investigator-initiated, multicomponent projects
   • Begin shift of patient-oriented research projects to P50s
   • Maintain tight control of the P50 $1.5M cap for patient-oriented research by requiring an announcement for eligibility
   • Maintain $1M cap for other all other P01/P50 applications
   • No sunset provision
   • The P30 Center Core grants with a $500K cap and P50 grants with a $1.5M cap are recently implemented; continue to monitor the impact of these new programs

   Due to time limitations, Dr. Landis said that the discussion regarding caps on multicomponent grants will be placed on the next Council meeting's agenda, in order to ensure adequate time will be available for a full discussion. Dr. Zoghbi suggested that the Genome Center be engaged in functional studies to co-fund those studies.

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8. Continuation of Report of the Director, NINDS

   Dr. Landis presented the FY99 - FY05 NINDS and NIH total budgets and the percentage increase of each year. NINDS's budget increased an average of 13.3 percent until FY 04, at which time the increase fell to 3.1 percent, and is projected at 3 percent in FY 05. The total budget is projected to be $1.5B in FY 05. A graph illustrated the percentage of the total budget spent on noncompeting grants (56 percent), competing grants (16 percent), the Intramural program (9 percent), Centers and Contracts (5 percent each), RMS (3 percent), and Other (2 percent). A graph illustrating the changes in proportion of spending among the same categories over FY93 - FY05 showed that the Intramural and RMS budgets have decreased, and the Contracts budget has increased slightly due to the use of contracts to provide a number of resources to investigators. It also showed an increase in the competing grants budget every four years, as the non-competing grants came to an end and were resubmitted as competing continuation grants. There was a discussion about the role of the RMS budget and how the Institute was managing more projects without a proportional increase in management costs. There was also a discussion about the use of contracts to relieve staff of administrative duties and whether management could find other ways to use contracts to support the staff. Dr. Atwell explained that NINDS contracts out its logistical support for conferences, workshops, and teleconferences, and that NIH was mandated to contract out its extramural support staff, with NIH having the opportunity to bid on the contract. NIH won the bid, and the result will be a leaner staff.

   Dr.Landis next presented the totals awarded and related data for competing research grants from FY 98 - FY 04. She noted that the payline percentile was 19.0 in FY 98, rose to 26.0 in FY 00 and FY 01, dropped to 21.0 in FY 02, and dropped to 19.0 again in FY 04. The number of applications went from 1,650 in FY 98 to 2,950 in FY 04. The President's FY 05 budget requests a 2.6 percent increase in the NIH budget overall, and a 3 percent increase for NINDS, totaling $1.546 billion. NIH has given the institutes rules to follow in putting together their budgets. One of the rules has been to fund the largest possible number of grants. One way NINDS has achieved this goal is to only allow a 1 percent average increase in the budgets of competing continuation grants.

   Following the budget presentation, Dr. Hoffman suggested that the partnership that has been achieved between NINDS and voluntaries to support research funding be extended to supporting training as well. A copy of the slides that Dr. Landis used in this presentation are attached as Appendix 2.

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9. Overview, Division of Intramural Research

   Dr. Landis reported that the foremost issue for the Division was the recruitment of a new Scientific Director. Currently, Dr. Landis is overseeing the direction of DIR, assisted by Dr. Henry McFarland, who is the Clinical Director and Dr. Gene Major as the Basic Neuroscience Director. The other important issue is the progress of the Porter Building. NINDS PIs will move into the Porter Building in June, where investigators will be placed according to research themes. The only hiring in Intramural is for positions that were previously committed. The increases in the Intramural budget have been less than the increases that the Institute has received as a whole, and the increase in the FY 04 budget was less than the average of all of the other institutes.

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10. Scientific Presentation: "Imaging Early Events in Human Stroke: The Discovery of Novel Therapeutic Targets"

    Dr. Steven Warach, Chief, Stroke Diagnostics and Therapeutics Branch, reported that the overall goal of the section is to build on the success of the NINDS rt-PA trials to expand the indications for acute stroke therapies. Their strategy is to (1) investigate the early events in patients with evolving ischemic brain injury using advanced MRI methods, (2) develop novel imaging markers of ischemic events, whose modification would be hypothesized to improve clinical outcome and (3) perform Phase I and II clinical trials of novel stroke therapies using these markers. The study centers at Suburban Hospital in Bethesda and the Washington Hospital Center in the District of Columbia permit them to perform early, serial MRI exams in large samples of acute stroke patients.

    Three examples were discussed. Reperfusion of stroke. They have determined that reperfusion of at least 30 percent of the ischemic brain region two hours following rt-PA treatment predicts complete clinical recovery. These and additional observations about reperfusion have served as the basis for design of the Reperfusion Of Stroke - Imaging Evaluation (ROSIE) clinical trials, which are imaging based dose finding clinical trials of the combination of thrombolytics and glycoprotein IIbIIIa inhibitors up to 24 hours from onset. Early blood brain barrier (BBB) disruption. A novel imaging marker of BBB disruption in the first several hours after stroke onset, termed Hyperintense Acute Reperfusion Marker (HARM), was discovered. This appears as gadolinium enhancement of sulcal CSF on FLAIR MRI. HARM is associated with reperfusion, with risk of hemorrhagic transformation, and with poor clinical outcome. The occurrence of HARM is greater in the presence of thrombolytic drugs. This marker is being used to develop trials aimed at protecting BBB integrity and making thrombolytic therapy safer. Recurrent silent stroke. They observed a high frequency (35-50 percent) of patients with silent recurrent ischemic lesions on MRI in the first week after a clinical stroke. These early recurrent silent strokes predicted further silent stroke up to 90 days, and silent recurrence predicted 2-year clinical stroke incidence. They hypothesize that silent recurrent ischemic lesions up to 90 days from clinical stroke onset may be a surrogate for long term secondary stroke risk in stroke prevention trials. They are testing this hypothesis as a sub-study in a large international secondary stroke prevention trial.

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11. Scientific Presentation: "Effects of GDNF in Animal Models of Parkinson's Disease"

    Dr. Greg Gerhardt, Professor, Department of Anatomy and Neurobiology, University of Kentucky, reported that glial cell line-derived neurotrophic factor (GDNF) has been shown in preclinical studies to be both neuroprotective and neurorestorative for the substantia nigra dopamine neurons that degenerate in Parkinson's disease (PD). Due to the progressive nature of PD, sustained delivery of GDNF may be necessary for optimal, long-term neuronal effects. In addition, GDNF does not cross the blood-brain barrier, necessitating direct intraparenchymal infusion. Accordingly, their objective was to evaluate the effects of continuous GDNF administration to either the dopamine neurons in the substantia nigra or into the putamen, which is innervated by affected dopamine neurons in PD.

    GDNF was administered via computer-controlled infusion pumps connected to intraparenchymal catheters implanted to rhesus monkeys with neurotoxin-induced neural deficits modeling the advanced stages of PD. Evaluations included quantitative morphological analyses of the nigrostriatal dopamine system and standardized parkinsonism ratings of the animals before and during chronic infusions of GDNF or vehicle. Post-mortem neurochemical measurements of dopamine and related metabolites were also carried out in the basal ganglia. Chronic infusions of GDNF (7.5 - 22.5 µg/day) into either the putamen or the substantia nigra significantly increased dopamine levels in the striatum and globus pallidus, along with an increase in dopamine fiber density, indicating dopamine neuron regeneration. GDNF-treated parkinsonian monkeys also demonstrated significant improvements in motor movements, which were maintained for months without evident side effects.

    Based on these studies and prior data, it is apparent that continuous, dose-controlled infusion of exogenous GDNF via programmable pumps offers a promising new therapeutic approach for treating patients with PD. They are currently carrying out a Phase-I FDA approved trial in 10 patients with advanced PD. A similar study is also being conducted in England by Dr. Steven Gill and his colleagues. While the preclinical data and the early clinical data are encouraging, it must be emphasized that the safety and efficacy of targeted trophic factor delivery remains to be determined in double-blinded clinical trials. (Supported by USPHS grants P50 NS39787, P01 AG13494 and K02 MH01245)

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12. Review of the Division of Intramural Research Board of Scientific Counselors' Reports

    In closed session, Dr. Landis presented the findings and recommendations of the Board of Scientific Counselors based on their review of specific DIR laboratories/units during 2003. The Council discussed the reports of the Board and accepted them.

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13. Council Review 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 other applications, which needed specific discussion.

    Research Training and Career Development Programs

    The Council reviewed a total of 141 research career development and institutional training grant applications; of this total, 93 applications had primary assignment to NINDS, and 78 of them (83.9 percent) were recommended for support in the amount of $13.6 million first-year direct costs. It is anticipated that, of the research career development and institutional training grant applications competing at this Council, NINDS will be able to pay first-year direct costs of approximately $5.5 million.

    Research Grant Awards

    The Council reviewed a total of 1,760 research grant applications; of this total, 1,039 applications had primary assignment to NINDS, and 657 of them (63.2 percent) were recommended for support in the amount of $178.8 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 $56.2 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 nominated and selected at each Council meeting. At this meeting, the Council recommended six investigators as Javits awardees.

    Small Business Innovation Research and Small Technology Transfer Award Programs

    The Council reviewed a total of 167 Small Business Innovation Research (SBIR) and Small Technology Transfer Award (STTR) grant applications; of this total, 96 applications had primary assignment to NINDS and 54 of them (56.3 percent) were recommended for support in the amount of $7.5 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 $4.9 million.

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14. Adjournment

    The meeting was adjourned at 10:20 a.m. on Friday, February 13.

We certify that, to the best of our knowledge, the foregoing minutes and attachments are accurate and complete.

Alan Willard, Ph.D.
Acting Executive Secretary
National Advisory Neurological Disorders and Stroke Council
Acting Director, Division of Extramural Research, NINDS
National Institute of Neurological Disorders and Stroke

Story C. Landis, Ph.D.
Chairperson
National Advisory Neurological Disorders and Stroke Council
Director
National Institute of Neurological Disorders and Stroke

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.

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