NINDS Advisory Council Meeting Minutes, September 14-15, 2006

1. Call to Order and Opening Remarks
2. Report of the Director, Division of Extramural Research
3. Report of the Director, NINDS
4. FY 2007 Budget Report
5. Discussion of Funding Strategies for FY 2007
6. Neuroscience at the National Institute on Aging
7. Discussion of Proposed NINDS Planning Process
8. Concept Clearance for FY2008 Proposed Initiatives
9. Council Subcommittee Reports
10. Council Review of Pending Applications
11. Adjournment

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

Summary of Meeting¹
September 14-15, 2006

The National Advisory Neurological Disorders and Stroke (NANDS) Council was convened for its 167^th meeting on September 14-15, 2006, at Building 31, Conference Room 10, 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: September 14, 2006 - 10:35 a.m. to 5:00 p.m.

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

Closed: September 15 - 8:15 a.m. to 11:15 a.m.

for the consideration of individual grant applications.

Council members present were:

Ms. Susan Axelrod
Mr. Robi Blumenstein
Dr. Lucie Bruijn
Dr. Alicia Conill (via telephone)
Dr. Ralph Dacey, Jr
Dr. Raymond Dingledine
Dr. Francisco Gonzalez-Scarano
Dr. Edgar Kenton
Dr. John Loeser
Ms. Prisca Chen Marvin
Dr. Helen Mayberg
Dr. Laura Ment
Dr. William Mobley
Dr. Caroline Tanner
Dr. David Van Essen
Mr. Robert Waterman
Dr. Gary Westbrook
Dr. Huda Zoghbi

Council Roster (Attachment 1)

Ex Officio Members present:
Dr. Robert Ruff, Department of Veterans Affairs
Dr. Geoffrey Ling, Department of Defense

Members of the public present for portions of the open meeting included:
Dr. Christopher Ross, Johns Hopkins University
Branka Sekis, Social & Scientific Systems
Julie Venners Yannes, Epilepsy Foundation
Dr. Vicky Whittemore, Tuberous Sclerosis Alliance
Bobbie Peterson, RTI
Michelle Rodrigues, SRI International

NINDS employees present for portions of the meeting included:

Dr. Alan Willard Ms. Ruth Linn Dr. John Marler Dr. Scott Janis Dr. Frances Yee Dr. Merrill Mitler Dr. Claudia Moy Dr. Robin Conwit Dr. Melinda Kelley 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. Tom Jacobs Dr. Yuan Liu Dr. Alfred Gordon Dr. Emmeline Edwards Dr. Ernie Lyons Dr. Eugene Oliver Dr. Diane Murphy Dr. Laura Mamounas Dr. Robert Baughman Dr. Robert Finkelstein Ms. Stephanie Fertig Dr. Ursula Utz Ms. Michelle Johnson Dr. John Porter Dr. Jill Heemskerk Dr. David Owens Dr. Heather Rieff Ms. Rebecca Desrocher Dr. Wendy Galpern Ms. Natalie Frazin Dr. Lauren Murphree Dr. Stephen Korn Ms. Preeti Hans Dr. Eugene Golanov Dr. Jane Fountain Ms. Joellen Harper Austin Ms. Lydia Munger Ms. Lynn Rundhaugen Ms. Dianna Jessee Ms. Maureen Hambrecht Ms. Nancy Hart Dr. Richard Benson

Ms. Margaret Jacobs Dr. JoAnn McConnell Dr. David Jett Dr. Michael Nunn Dr. Thomas Miller Dr. Naomi Kleitman Dr. Audrey Penn Dr. Yejun He Dr. Daofen Chen Dr. Paul Scott Dr. Gabrielle LeBlanc Mr. Paul Myers Dr. Richard Crosland Dr. Randall Stewart Ms. Cikena Reid Dr. Robert Zalutsky Dr. Katie Woodbury-Harris Dr. Debra Hirtz Dr. Shanta Rajaram Ms. Stacey Chambers Mr. Paul Girolami Ms. Shannon Garnett Dr. Audrey Kalehua Dr. Shai Silberberg Dr. Ned Talley Dr. Joe Pancrazio Dr. Laurie Gutmann Ms. Joanne Odenkirchen Mr. Phil Wiethorn Dr. John Lynch Dr. Michelle Jones-London Dr. Mark Scheideler Dr. Robert Riddle Ms. Daphne Robinson Dr. Ramona Hicks Ms. Donna James Dr. Debra Babcock Ms. Christina Vert Ms. Maxine Davis-Vanlue Dr. Janice Cordell Mr. Peter Gilbert Ms. Debbie Jarman Dr. Lorenzo Refolo Ms. Sylvia Parsons Dr. Rebecca Farcas Dr. Giovanna Guerreiro Dr. Nancy Neale Ms. Pamela Mayer Ms. Margo Warren Mr. Michael Banyas

Other Federal employees present for portions of the meeting included:

Dr. Stefano Bertuzzi, OD
Samuel Speciale, NIA
Dr. William Benzing, CSR
Dr. George Mchue, CSR
Dr. Brian Hoshaw, CSR
Dr. Biao Tian, CSR
Dr. Rene Etcheberrigaray, CSR

I. Call to Order and Opening Remarks

Dr. Story Landis, Director, NINDS, welcomed everyone to the 167^th meeting of the NINDS Advisory Council. She introduced six new Council members: Susan Axelrod, President and Founder, Citizens United for Research in Epilepsy, Dr. Lucie Bruijn, Science Director and Vice President, The ALS Association; Dr. Ralph Dacey, Professor and Chairman, Department of Neurological Surgery, Washington University School of Medicine; Dr. Edgar Kenton, Director, Stroke Prevention/Intervention Research Program, Morehouse School of Medicine; Dr. Caroline Tanner, Director of Clinical Research, The Parkinson's Institute; and Dr. Gary Westbrook, Co-Director, Vollum Institute, Oregon Health Science University. Dr. Landis welcomed Dr. Alicia Conill who was participating by telephone.

NINDS periodically invites, as guests of the Council, the chairpersons of review committees and study sections as part of the Institute's continuing effort to strengthen the liaison between initial review groups and the Council. Dr. Landis introduced Dr. Christopher Ross, who is Chair of the Cell Death in Neurodegenerative Study Section in CSR. Dr. Ross is Professor, Department of Psychiatry, Division of Neurobiology, Johns Hopkins University.

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II. Report of the Director, Division of Extramural Research

Dr. Finkelstein, Associate Director for Extramural Research, reminded Council that they are in open session and will go into closed session to discuss individual grant applications tomorrow.

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. Robert Finkelstein as the 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 May 25-26, 2006, were considered and accepted as written.

Consideration of Dates for Future Council Meetings

The following dates for future Council meetings were reconfirmed:

February 15-16, 2007 (Thursday and Friday)
May 24-25, 2007 (Thursday and Friday)
September 20-21, 2007 (Thursday and Friday)
February 7-8, 2008 (Thursday and Friday)
May 29-30, 2008 (Thursday and Friday)
September 18-19, 2008 (Thursday and Friday)

Dr. Finkelstein reminded Council that their terms end on July 31 of the year printed next to their names on the Council roster.

Other Items

Expedited Review Process-A subset of Council members approve applications within the payline that have no issues or that are controversial prior to the Council meeting. Robi Blumenstein, David Van Essen, and Laura Ment are serving in this capacity for FY 2007. This round 11 K award applications were approved through the early concurrence process. Since applications from this Council round are funded from FY 07 funds and the payline is uncertain at this time, no research project grant applications were presented for early concurrence.

Loan Repayment Program-The Loan Repayment Program began about five years ago for the purpose of encouraging MDs, MD/PhDs and clinically oriented PhD to go into research careers. There were 157 loan repayment applications this Council round that focused on clinical research and pediatric research. We were able to fund 37 of the clinical research and 24 of the pediatric research applications with the $2.6 million allocated for this program. The applicants included 34 MDs, 11 MD/PhDs, 8 PhDs, and individuals in a few other degree categories.

In terms of specialty, 20 were in neurology, 20 in pediatric neurology, 5 in neurosurgery, and the rest in various other specialties.

Staff Actions-The following new DER staff were introduced: Dr. Nancy Neale, a program analyst in the Technology Development Cluster and three new grants management specialists: Stephanie Mitchell, Melissa Hanborough, and Yvonne Talley. Among departures from DER are Dr. Barbara Radziszewska, who has taken a position with the National Heart, Lung, and Blood Institute, and Dr. Andrea Sawczuk, who has taken a position with the National Center for Research Resources. It was announced that Dr. Katie Woodbury Harris, a Scientific Review Administrator in the Scientific Review Branch, will be retiring in February 2007 after 30 years of public service.

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III. Report of the Director, NINDS

Dr. Landis reported on the following topics:

Budget status: The NIH does not yet have a budget for FY 2007; however, the Appropriations Committees have completed the markups of the bills. The proposed House budget is closer to the President's Budget, but the proposed Senate Budget included an increase for the NIH. However, due to the possibility of taps and rescissions, it is not possible to predict a final appropriation at this time. The expectation is that the budget will not be finalized until early in 2007 due to mid-term elections; this somewhat complicates planning for future initiatives.

Recruitments: Dr. Landis announced that the Institute has hired Dr. Alan Koretsky as its new intramural research director; he will begin his official duties on October 1st. The individual in this position must engage in a broad range of activities; the greatest challenge was identifying a qualified candidate with a broad background and range of interests. Dr. Koretsky has a B.S. in chemistry, a Ph.D. in physical chemistry, spent two years in the intramural program at NHLBI, and served on the faculty at Carnegie Mellon University and MIT. In 1999 he moved to the NINDS, and is well-known for applying novel imaging techniques to neuroscience questions. One of the immediate challenges facing Dr. Koretsky will be reorganizing the intramural program to maximize its productivity and developing a plan for the program which will be reviewed by a blue-ribbon panel prior to the next Council meeting in February 2007.

Dr. Landis also noted that the recruitment for a Deputy Director is ongoing, and interviews have been conducted. She indicated that the name of the new hire may be made public at the February 2007 Council meeting.

Congressional Update: Two Congressional committees have had oversight over the NIH during the past ten years; the appropriations committee has had the most significant impact. However, reauthorization (last completed in 1993) also influences the NIH, and is conducted by the House Energy and Commerce Committee and the Senate Committee on Health, Education, Labor and Pensions. The NIH reauthorization has attracted the interest of Representative Barton, who chairs the full House Energy and Commerce Committee, and he has initiated legislation to reauthorize the NIH in both the 2004 and 2005 Congresses. The NIH Reform Act of 2006 is now in Committee and could have a significant impact on the management of science and budgetary control at the NIH. Specific areas of impact include the allowable number of NIH Institutes and Centers (ICs), the decision-making capacity of IC directors with respect to their organizations, a review of the NIH structure, the development of a common fund and the use of budget increases as a source for supporting this fund, trans-IC collaborations, and the establishment of a division under Dr. Zerhouni's direction that would oversee cross-institute projects. Dr. Zerhouni has already established the latter office (the Office of Portfolio Analysis and Strategic Initiatives, or OPASI) and is currently undertaking a search for a Director of this Office. OPASI will oversee both Roadmap projects and the "common fund," thus the leadership of this office is critical to the NIH. Roadmap efforts continue with "version 1.5," acknowledging that the original Roadmap was intended as a 5-10 year incubator space for projects rather than a permanent home for research initiatives. In theory, funding for the current Roadmap initiatives will be released at the end of this period for other projects. The NIH is now looking for new candidate projects for Roadmap and the common fund, and is gathering input from a variety of sources, including panels of outside scientists from a range of disciplines, IC staff, and the public. A "Council of Councils" will be assembled which will advise Dr. Zerhouni on these recommendations.

Dr. Landis's report was followed by a discussion in which a Council member described her experience in serving on one of these outside committees. She indicated that it was an interesting exercise in identifying transforming research endeavors; however she noted that the participants at this meeting tended to focus on their own areas of research interest. She encouraged other Council members to comment when the suggestions are posted publicly.

Additional Council discussion focused on the links between Blueprint and the collaborative IC initiatives discussed in the legislation. Dr. Landis noted that while Blueprint activities are transformative and synergistic, they are not likely to qualify for Roadmap or cross-cutting funds from the NIH.

Genes and the Environment: When the Secretary of HHS arrived at his current position, he brought an interest in both genealogy and environmental factors. He subsequently brought these interests together in an NIH research effort on genes and the environment, which was originally designed to spend a set-aside of $40 million in FY 2007 funds. Whole genome association studies and the development of methods of measuring environmental exposures are included under this effort, and funding will be distributed to the IC base budgets for carrying out projects in each Institute's areas of interest: the National Human Genome Research Institute will be involved in genetic studies, the National Institute of Environmental Health Sciences will explore the influence of environmental exposures, and the National Institute of Mental Health will examine psychosocial stress issues.

Resource Sharing: Since the development of the Genetic Association Identification Network project, the NIH has struggled to ensure that genetic data collected using NIH funds is shared across the research community. To facilitate this sharing, the NIH has developed a proposed policy and is now collected feedback on this draft. Provision of the draft policy include nine months of exclusive access to genetic data for the researchers who collected the data and the development of a database to collect genotype and phenotype data from participants who cannot be individually identified.

New Investigator Funding Rate: The research community has often expressed concern about the ability of new investigators to obtain funding in challenging budget climates. The Office of Extramural Research (OER) has collected data across the NIH ICs, and these data indicate that in FY 2004, the funding rates were lower for new investigators (16 percent) vs. experienced investigators (19 percent). Although NINDS and other Institutes have developed policies to assist new investigators, the OER data suggests that the situation continues to be challenging for new investigators and for PIs trying to renew their first R01s.

Council discussed other issues including the selection of projects that will be funded under the common fund, and the generation of funds for Roadmap 1.5. These funds will be generated through the identification of residual resources available from Roadmap 1.0 initiatives that may not move forward. Additionally, Council discussed the "Council of Councils" that will help to distribute these funds, and Dr. Landis indicated that this group will include members from all of the IC Advisory Councils, including public members, clinicians and basic scientists. Terms will be staggered, but term length has not been finalized. Dr. Landis inquired as to the Council members' interest in serving on this committee. Council members emphasized that it was critical that the Council of Councils identify truly "transformative" cross-cutting initiatives that are not necessarily linked to the personal interest of the members. Council commented on the need to make these projects milestone-driven and of varying lengths in addition to being transformative, to ensure that we are responsive to Congress and the public with accountability and some "early wins." Council also asked about the trends in research proposal that account for the current perception that NIH has little money to fund research; Dr. Landis indicated that with the NIH doubling, the number of grant applications doubled, the grant size increased by 40 percent and more new people are applying than ever before.

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IV. FY 2007 Budget Report

Dr. Finkelstein presented the budget outlook for FY 2007. While Congress has not yet finalized the NIH budget for FY 2007, it is likely that funding for NIH and NINDS will be limited. Dr. Finkelstein described the FY 2007 budget timeline, which began in late 2005 with NINDS submitting the initial budget request, continued through February 2006, with the release of the President's budget, and, in theory, should end in the fall of 2006, with Congress announcing the final conference budget. However, due to the November mid-term elections, it is likely that a final budget will not be released until January 2007.

Dr. Finkelstein also noted that while the doubling of the NIH budget gave NIH many important opportunities, it has created an even more challenging situation given the current budget climate. During the budget doubling, many academic institutions expanded their research efforts, including hiring more investigators. This means that NIH is now faced with more grant applications and more requests for money, making planning for the projected lower budgets in the coming years even more difficult.

Dr. Finkelstein presented a line item budget chart which outlined NINDS's commitments for FY 2006 and projected spending for FY 2007. Within the category of research project grants, most of the money (approximately 75 percent) is obligated for non-competing awards, while 25 percent of the funds are available for new awards. Other funding categories include Centers, Contracts, Training, Intramural, Research Management and Support (RMS), and Roadmap. He noted that for FY 2006, 0.9 percent of the NINDS budget went to the NIH Roadmap. Given these commitments, the payline for FY 2006 was the 12th percentile, while for FY 2007 it is projected to be the 9th percentile. He expressed concern that this lower payline will discourage young/new investigators, and noted that NINDS is taking a number of steps to try to raise the payline. These include proposed cuts to competing grants (12.5 percent modular/17.5 percent non-modular), and utilizing unspent committed dollars (e.g., balances from clinical trials that may have extra money due to problems with patient recruitment). Other strategies to save money include budgeting less funds for P01s and cutting the money available for High Program Priority (HPP) grants from $12 million to $6 million. He also noted that NINDS is being more vigilant about looking at overlap between grants. He noted that to raise the payline by 1 percent, approximately $17 million needs to be freed up from other categories. He asked for Council's feedback on this lower payline and on the strategies NINDS was proposing to raise it.

Council members were concerned that utilizing unspent committed dollars would set the Institute up for even tougher fiscal times down the road, since it means even further out year commitments. Dr. Landis acknowledged that this makes it challenging to budget since you are in theory just extending the time period for these commitments, but stressed that NINDS is taking this into consideration in budgeting for future years.

Council members felt that there should be cuts to non-competing grants. Dr. Landis and Dr. Finkelstein explained that this is an NIH-wide issue where individual Institutes do not have the flexibility to put in place their own policies. Council believed that the Institutes should have the flexibility to make cuts to grants in this category and recommended that Dr. Landis communicate to Dr. Zerhouni and the Steering Committee that this issue be carefully examined. In addition, some Council members felt that the money set aside for HPPs should not be cut, noting that this category was even more important in financially challenging times.

V. Discussion of Funding Strategies for FY 2007

Council members expressed strong concerns about setting the payline in the single digits. Fierce competitions for grants may drive excellent senior neuroscientists out of academic research and discourage new scientists from entering the field. A low payline also stresses the grant review system. It is difficult for study sections to differentiate among outstanding grants, and applications that score just above the payline will come re-review, keeping the payline low and wasting the time and resources of applicants and reviewers. Council members argued that the ultimate goal should be a pay line in the 12-15th percentile range.

The Council discussed the pros and cons of various strategies to raise the payline. Cuts to the intramural budget and to the Roadmap set-aside were proposed, but these are not options that the NINDS can consider. Grants could be cut if they are not meeting their milestones, but very few grants are written with milestones incorporated, and milestones are inconsistent with the goals of highly innovative basic research. New grants could be cut beyond the proposed 12-17 percent, but deeper cuts could make it impossible to achieve the scientific aims

Some Council members argued that basic and clinical research should receive comparable cuts, but others contended that budget cuts to clinical trials could harm recruitment to the point that the trial would not be worth conducting at all. Although the details were not resolved; the Council voted 12 to 4 (with two abstentions) to recommend that NIH enact equitable cuts to non-competing grants in order to enable NINDS to raise its pay line. Dr. Landis agreed to forward the Council's recommendation to Dr. Zerhouni's Steering Committee.

Several Council members warned that NINDS should not restrict its focus to the payline to the point that it loses sight of its mission. The NINDS would not want the payline to rise because neuroscientists are leaving research in droves. Cutting the HPP budget could raise the payline, but it puts most of the Institute's funding decisions in the hands of extramural reviewers who may not be aware of the Institute's research priorities and existing investments. In trying to support as many scientists as possible, the NINDS may make it impossible for some scientists to do truly great work. The Institute must sustain excellent senior and junior researchers and superb science, not as an end in and of itself, but to cure disease.

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VI. Neuroscience at the National Institute on Aging

Dr. Richard Hodes, Director, National Institute on Aging (NIA) presented an overview of neuroscience research at the NIA. The NIA's mission is to improve the health and well-being of older Americans through research. Half of the NIA's budget is devoted to neuroscience research, reflecting the importance of the nervous system in aging.

The NIA extramural program focuses on many aspects of neuroscience in aging, including the biology of normal aging, normal cognitive and emotional aging, and the many forms of dementia, such as that associated with Alzheimer's disease (AD), Huntington's disease and Lewy body dementia. The NIA funds a continuum of studies, from research on the cellular and molecular mechanisms of aging to clinical intervention studies, including early detection of pathologies, and age related change in various functions, such as motor, sleep and neuroimmune function.

Dr. Hodes presented in more details the following major NIA neuroscience initiatives:

The Alzheimer's Disease Centers (ADC) program aims to promote research and training on AD. The centers consist of core centers with or without a specific research component (P50 or P30). In order to facilitate collaboration among the ADCs, a National Alzheimer's Coordinating Center (NACC) was established in 1999. Using a minimum data set, the NACC maintains a database of patient information collected by the ADCs can be used for various types of studies.

The AD Genetics Initiative aims to identify genetics risk factors for AD. The initiative is structured so that all the data collected is stored in a database with extensive sharing. This facilitates the identification of new pathways and targets for interventions, as well as these individuals at high genetic risk.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to identify biomarkers and imaging modalities which could be used for earlier and more accurate diagnosis and measurement of AD progress. Any surrogate marker found could be used to shorten clinical trials and decrease the number of participants required. The ADNI includes 54 enrollment sites and has implemented an unprecedented rapid sharing of the data. It is funded through a public-private partnership at $12 million per year for 5 years. The participation of the FDA as a federal partner has been essential to clarify the quality of data necessary to identify valid biomarkers. The private partners from the pharmaceutical and biotech industries have received no preferential treatment. Indeed, their main concern was to have equal rights and the same access to the data as the other partners. The information in the database can be used freely for the development of new intellectual property. The National Institute of Biomedical Imaging and Bioengineering contributed to the development of protocols for the standardization and sharing of the data. All the clinical and imaging data are de-identified and centralized. The data are freely open to the public immediately following a quality control phase. Distribution of cerebrospinal and blood samples are reviewed by a committee and any analysis of these samples must be included in the database.

The Alzheimer's Disease Cooperative Study, initiated in 1991, is an ongoing program of clinical trials testing promising therapeutic agents. The program also funds the development of new instruments and novel approaches to clinical trials. This program coordinates patient recruitment over a large number of sites to facilitate enrollment in trials. A recent publication issued from that program showed that vitamin E did not prevent the progression of AD. Recent studies are evaluating interventions for preventing the onset of AD in an amnestic subset of patients with mild cognitive impairment and a home-based assessment of cognitive decline.

The NIA also supports many translation research initiatives, from target and lead discovery and validation to a toxicology contract, preclinical and clinical studies. A large number of agents are being developed that target several elements of the pathophysiology of AD. Similarly, many clinical trials are underway, testing a variety of compounds including vitamins, gingko biloba, homocysteine lowering, simavastin, fish oil and raloxifene.

The Cognitive and Emotional Health Project focuses on the healthy brain, and seeks to assess the demographic, social and biological determinants of cognitive and emotional health in aging adults, and the ways in which they influence each other. A critical evaluation study committee issued a report in February 2006 identifying about 40 factors. The NIH toolbox (part of the NIH Neuroscience Blueprint) is developing standard neurological and behavioral assessment protocols, which will facilitate further studies.

The NIA and NINDS collaborate extensively on all of these initiatives as well as within coordinating efforts including the Blueprint, the AD Coordinating Committee and the Parkinson's Disease Coordinating Committee. Both institutes participate in joint projects such as the Udall centers, as well as numerous workshops and even intramural projects.

In conclusion, Dr. Hodes highlighted several recent research findings from NIA-supported projects. NIA-funded researchers identified a second gene for frontotemporal dementia; this gene encodes progranulin, a growth factor influencing cell division and mobility. A recent neuroeconomics study showed that limbic areas are involved in deciding on immediate gratification, whereas lateral prefrontal cortical areas were active during the decision to delay rewards. Donzepil was shown to delay AD onset only during the first 12 months, with no long term effects. Finally, NIA-funded investigators have developed a biological "barcode" which can measure amyloid levels derived from skin cells, potentially distinguishing AD from other dementias at early stages.

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VII. Discussion of Proposed NINDS Planning Process

At a previous Council meeting, Dr. Landis spoke briefly about the concept of strategic planning and said that NINDS would embark on a Strategic Planning Process. She explained that the NINDS has had a fruitful history of utilizing plans to guide its research goals in specific research areas and in fulfilling its mission. Plans have been developed for diseases such as Parkinson's disease, stroke, epilepsy, multiple sclerosis, and others, as well as for goals such as reducing health disparities. However, the last effort providing a similar document for the Institute as a whole was in 1999 with the Neuroscience at the New Millennium plan. This broad-based plan, undertaken at a time when funds were more available, was organized around unifying scientific themes. Some of the goals from this document are still being implemented. However, the significant budgetary and scientific changes that have occurred in the last few years warrant a new planning effort. This new strategic plan should enable the NINDS to pursue its mission more efficiently and effectively by ensuring balance across the scientific portfolio and by prioritizing the Institute's research agenda for financially tough times. The Institute also has the responsibility to demonstrate due diligence to the public and Congress with respect to its mission and stakeholders. Increasingly, Congress has been demanding more transparency and accountability from the NIH. Recently, both the House and Senate expressed difficulty relating the Congressional Justification to the Institutes' plans. They would like to see increased transparency in the implementation of the NIH strategic plans.

To be effective, the planning process will have to be based on data about what the NINDS and other ICs are doing. This data will provide insight about processes that might need change, or areas where there is unneeded overlap. The process will include input at different levels, from Council, external consultants, scientists, and the public. It is expected that the planning process will ultimately help us identify areas of opportunity and will provide concrete recommendations that we can act on at a program level. For Congress and the public, the planning process will produce a broad description of the activities and programs the NINDS will carry out over the next five years. For the Institute's operation, the crucial output will be guidance for what the NINDS could and should do differently. It is expected that a new plan will have practical implications on issues such as: how to use P01s, Centers, and other mechanisms; how to balance payline and high program priority funding; which grants should be in the NINDS portfolio versus the National Institute of Mental Health, the National Institute on Drug Abuse, and other ICs.

Planning will be guided by a steering committee made up of staff from the Office of Science Policy and Planning, the Division of Extramural Research-, intramural scientists, and Council members of different professional backgrounds. The steering committee will give input on the overall planning structure and process. It has been initially proposed that the planning process should be divided into four modules, each of which will examine a segment of our portfolio. The basic, translational, and clinical modules will be integrated at the end of the process through a final disease-focused module. This final module will examine the findings of the basic, translation, and clinical modules in light of the burden of disease, the needs of the community, and the opportunities for progress. The intramural division will undertake its own planning process in parallel, with oversight from a blue ribbon panel. The intramural process will examine ways in which it is uniquely poised to contribute to the NINDS mission. The final phase of the process will involve integration of the extramural and intramural plans.

Dr. Paul Scott, director of the Office of Science Policy and Planning, continued the presentation by explaining that planning has been proposed to begin with the translational research module. Translational research is critical to the NINDS mission, and is an area of increasing interest to Congress and patient groups. There has also been significant progress in translation research techniques and opportunities from 1999 to the present. Since the New Millennium plan, the NINDS extramural program has put into operation multiple translational research mechanisms, mainly in therapeutic development. Because both the scientific and programmatic landscape have changed significantly since 1999, translational research might profit significantly from strategic planning.

The translational research module will include any research aimed at developing a therapy or diagnostic (including biomarkers), up to the stage of an Investigational New Drug (IND) or Investigational Device Exemption (IDE). This module will not include early clinical trials of interventions because these will be covered in the clinical module. However, the translational research module has been designed to be broad and inclusive in terms of the preclinical research modalities considered to enable full discussion of any potential approach and technique.

The analysis of translational research for the purposes of planning will be subdivided into three "big picture" questions: 1) What translational research should the NINDS support? 2) How should the NINDS support this research? and 3) Who do we engage in this research and how? Institute planning groups will be expected to come up with questions that cover these three aspects of translational research and pose them to an expert panel for advice. Framing the right questions will be important to obtain direct recommendations that we can act upon.

Dr. Scott encouraged the members of Council to provide comments on the strategic planning process design and specifics. It is expected that Council will be intimately involved in the process at several stages. Selected members of Council will serve on the steering committee, which will give input on the proposed overall planning structure and process and will provide early input into types of questions that each module should consider. Council members will also be part of consultant groups. NINDS staff will also give periodic updates to Council as planning progresses.

This presentation elicited a number of comments from Council. One Council member indicated that undertaking a disease-focused analysis at the beginning rather than at the end would allow us to identify diseases where it would be most beneficial and productive to invest in translational research. Dr. Landis assured him that the disease integration module would provide that fine-tuning for the basic, translational, and clinical modules at the end of the process. However, a solely disease-focused analysis of translational research, or any other module, might limit the opportunity to identify non-disease specific areas of interest to the Institute.

Council also asked whether issues such as developing the science and research of performance indicators, for pay-for-performance insurance initiatives, would be included in the clinical module. Dr. Landis indicated that because there is a need for scientific studies to validate the indicators, this is an NIH issue. It will be something to consider for the clinical module. NINDS staff commented that clinicians who had received NINDS K23 awards, designed to encourage this type of patient-oriented research, were having trouble getting funding after their K23s ran out and that this might be due in part to the NIH culture, which doesn't recognize this type of research. Council also asked how issues of training would be integrated into the planning process, since training or lack thereof might be a big determinant for research areas that are currently neglected. One approach could be to include training in each module as part of the overall analysis, rather than as an independent, broad goal.

Council also asked about ways in which reassessing the role of the intramural division could complement strategic planning for NINDS. Dr. Landis agreed that intellectual integration between the intramural and extramural divisions was a high priority of the planning process and mentioned that at least one intramural researcher will serve on the steering committee for the extramural process.

Lastly, Council commented that perhaps a strategic plan might be too big of an undertaking for the whole institute and, in addition, we might be left with a document that becomes obsolete in a couple of years. One Council member suggested that perhaps we should be guided by a strategic process, where an infrastructure is set up to periodically evaluate and prioritize NINDS issues. High-priority problems would be tackled one at a time, such that the strategic process would result in easy to implement goals, as well as in a mechanism for regular reevaluation.

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VIII. Concept Clearance for FY2008 Proposed Initiatives

Contract/RFP: Facilities of Research Excellence in Spinal Cord Injury (FORE-SCI) Program director: Naomi Kleitman, PhD

Dr. Kleitman provided an overview of the proposal to continue NINDS support of three out of the five original centers; one provides hands-on training in spinal cord injury (SCI) research techniques, and two attempt replication of studies that report promising preclinical data indicating efficacy in SCI repair or protection. Dr. Kleitman stated that the spinal cord injury field continues to be limited by the fact that therapies that appear to show efficacy in animal models are not moving to human clinical trials. In the past, those agents that have moved to clinical trials have been negative, partly because of limitations of the animal models and, in hindsight, failure to recognize some warning signs in the animal data. The contracts specify that the results of replication studies be made available in peer-reviewed journals. The field is also developing standards of evidence required before moving to a clinical trial.

Of the four studies that have been completed under the current contract, none have successfully reproduced the original behavioral and anatomical results. In one case, the replication study revealed that a staining artifact was responsible for the results; this finding is being published in the same high-profile journal that published the original observation.

Several Council members expressed support for the initiative. During the discussion, it was noted that the idea of replication before trials is essential, that pharmaceutical companies routinely conduct these studies, and that the publication of negative results is a very important feature of this initiative. A suggestion was made to consider including a larger animal model of spinal cord injury, which would also provide a replication of the observation but in a system that may be more relevant to the human condition.

Dr. Finkelstein noted that because this is a contract initiative, the formal concept clearance has been completed but NINDS would like Council approval of the concept. The group voted unanimously to endorse the initiative concept.

NINDS ImPACT Program (Immediate Practice-Altering Clinical Trials) Program Director: Deborah Hirtz, MD

Dr. Hirtz introduced the proposed initiative, which is envisioned as a mechanism to identify high impact clinical trials that are not submitted to the Institute through other mechanisms. The intent is to supplement existing clinical trial mechanisms, not to replace them. The program is designed in four stages, but at this point Council is being asked for concept clearance of the first stage, only. Council approval will be sought before each of the subsequent stages is initiated.

Dr. Hirtz noted that the goal of the first stage of the NINDS ImPACT Program is to identify high priority questions about best clinical care for patients with neurological conditions, and to develop a model to predict potential public health impact of providing answers to those questions. Later stages of the program will attempt to rapidly facilitate practice-altering research that will answer selected questions and improve care. Dr. Hirtz said that this approach could help to identify many potentially answerable questions that would have a large impact on clinical care that are not addressed through the current process. In this FY08 initiative, NINDS will proactively assemble clinical practice questions from groups that we don't currently solicit input from (including federal partners, practicing clinicians, professional societies, etc.). Another important part of this stage is the development of a theoretical model to predict the potential public health impact of a range of outcomes from a particular trial - this could be broadly useful and is not something that NINDS or applicants routinely do now.

Many Council members expressed strong support for the concept. Among the reasons that Council members gave for their support were that they believed it addresses important questions, it would strengthen the evidence-base in neurological/neurosurgical practice, it incorporates estimates of savings that will result from changes in practice, it is responsive to the needs of practicing neurologists in terms of practice guidelines and quality measures, it is collaborative, and that it presents an opportunity for very creative approaches. There was a suggestion to help contain costs of these trials by "bootstrapping" onto the practitioners to help answer the questions, such as through the NINDS Clinical Research Collaboration (CRC). A Council member suggested narrowing the scope of who is asked about clinical questions so that good ideas don't get overlooked, and noted that it will be a challenge to evaluate how trials drawn from this pool have changed practice. Council members also noted that the Institute's strategic planning process could collect useful information that would be related to this proposal. Dr. Landis agreed, saying that when this proposal was presented at the extramural retreat it became obvious that there's an intersection with strategic planning. She noted that the pre-trial cost-benefit analysis would be interesting data for all trials, not just those done through this process. Council members agreed that the greatest challenges would be in prioritizing the ideas and in making sure that a balance is maintained between ImPACT-developed trials and investigator-initiated trials testing new approaches.

Dr. Landis noted that pilot studies would be useful before embarking on a huge effort. The motion to approve the initiative concept was approved unanimously.

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IX. Council Subcommittee Reports

Training, Career Development, and Special Programs, Dr. Huda Zoghbi, Chair

Dr. Zogbhi presented the results of an overview of the status of training at NINDS. Only 16 percent of fellowships (F31s and F32s) were funded by NINDS in FY06. A total of 15 K08 and 4 K99 were awarded up to August 2006. She said the Subcommittee was concerned that the lowered success rates were due to the increasingly large number of F31 applications received (over 400). Because some of the applications NINDS receives are not relevant to our mission, the staff is determined to review these more rigorously. The NINDS is currently one of few ICs that fund F31s. The NINDS is encouraging other ICs to start supporting them.

The Subcommittee also discussed several ideas for retaining bright young principal investigators, and decreasing the age of grantees receiving their first R01. The first idea proposed the creation of a funding mechanism to award highly-successful, and experienced recent Ph.D. graduates with financial support for independent research. This idea is based on the "fellows programs" of several universities. It would be expected that the academic institution would provide lab space and other costs. This mechanism would prevent a "brain drain" to the more lucrative, secure jobs of industry. Because of the high criteria to qualify, it was expected that only a handful of awards would be made a year. Some Council members expressed caution in the selection of the fellows and in the design of the award. Some bright graduates might still benefit from training and some institutions might take advantage of award to "vet" potential faculty members. We should engage in dialogue with universities that currently have these awards to get a better idea about what their experience has been. Others suggested that the K99/R00 awards could be modified to include graduate students straight out of a postdoc.

A second idea was the development of an RFA like the NIEHS Outstanding New Environmental Scientist (ONES). This special R01 mechanism establishes a study section to review applications from outstanding young investigators nominated by their institution. This mechanism prevents the evaluation of young PI R01s against those of more senior investigators. The program awards $400,000 a year for two years, and $275,000 for the next three years. The Subcommittee decided this idea would be too costly for the NINDS and it might be detrimental to pit the talented NINDS young investigators against each other for a small number of awards. Dr. Landis commented that it might be something to consider if we identify any NINDS areas lacking in outstanding young PIs during the planning process. Some members of Council expressed support for the idea of all young investigators to be judged against their own cohort to improve their success rate. Others commented that an easier way to ensure consideration for young PI status would be to set aside a time at the beginning or end of review to focus on young PI proposals.

A final idea was the development of a K08 and K02 award for biomedical researchers. The current postdoctoral National Research Service Award offers only three years of funding, a period of time which is usually insufficient for a post-doctoral fellow to achieve independence. An alternative strategy would be to increase the number of K99s awarded. Dr. Landis commented that because the K99 mechanism is so new, we still do not know how many K99 applications to expect. If the number of applications increases in the future, increasing the number of K99s awarded might be a possibility. Otherwise, another approach would be to recommend successful F32s for a K99. Dr. Finkelstein pointed out that if we increase the number of K99s awarded we might also increase the number of foreign applications. The citizenship status is not currently being tracked.

In conclusion, the training Subcommittee expressed interest in both the first and last mechanisms to retain young investigators doing neuroscience research.

Clinical Trials Subcommittee, Dr. Laura Ment, Chair

The Clinical Trials Subcommittee did not hold an open session this round, so there was no discussion of issues in the open session of Council.

Basic and Preclinical Programs Subcommittee, Dr. Raymond Dingledine, Chair

Dr. Raymond Dingledine reported to Council on the Basic and Preclinical Programs Subcommittee meeting. The closed session of that meeting discussed the CounterACT, which develops countermeasures for chemical threats, and the open session discussed translational research resource centers and the lifetimes of program project grants.

Although Dr. Dingledine could not discus specific grants considered by the Subcommittee in closed session, he reminded Council about the basic features of the CounterACT program. The NINDS worked closely with several other NIH Institutes, other federal agencies and outside experts to develop this program on countermeasures against chemical threats. The funding does not come from the NINDS budget, but from the Department of Homeland Security via the Department of Heath and Human Services. The Subcommittee's closed session discussed funding for single investigator and multi-investigator center-like cooperative agreements and for SBIR grants to develop diagnostics and therapies.

The Subcommittee next discussed U24 resource centers, which are a new aspect of the NINDS cooperative program for translation research. These centers will provide to the community resources for preclinical development of therapies, either on a subsidized fee for service basic or through collaborations with sharing of intellectual property. The question before the Subcommittee was whether the NINDS should limit submissions of proposals for these centers to once per year. The main argument in favor of this is that a single receipt date would facilitate comparisons of the proposals with one another. The major argument against is that this limitation might slow the funding process of these critical resources, particularly if resubmission of an amended application was required for funding. The Subcommittee did not make a recommendation on resolving this issue.

The third topic discussed by the Subcommittee was whether program project grants should be limited to a single five-year term, without renewal. This proposal had been raised at the previous Council meeting. The arguments presented in favor of eliminating renewal included: Five years should be long enough for the research to get underway effectively, after which R01's should take over if continuing is appropriate. With renewals, study sections may place less emphasis on synergy among the investigators, which is the key value of program projects. Some PIs and groups develop a sense of entitlement, and there may be an aspect (at least perceived) that an "old boy network" comes into play in renewals. The arguments against eliminating renewal of program projects included: If there is no competing renewal, accountability is eliminated. Some types of research, such as natural history studies, require ten years or more to complete. Limiting the duration of program projects could discourage team science. The quality of the science should take precedence other considerations. A compromise recommendation offered by the Subcommittee was to allow renewal but with stringent pre-application screening.

Council discussed several points related to the renewal of program projects. The high cost of these grants, whose fate may be controlled by a few reviewers, led to discussion of the recently increased attention by NINDS staff to overlap with other funding. A progress assessment after the first three years, before rewarding the final two, might increase accountability. The imminence of the end of the grant might also motivate investigators to be productive enough to compete for an R01. There was considerable discussion about the rigor of review of the individual projects compared to R01 proposals and about whether weak subprojects were funded on the backs of the strong. Comparing scores of projects submitted in parallel as R01's and P01 subprojects might provide useful data on these points. Council members also stressed that for some problems team approaches and durations greater than five years are critical.

Dr. Landis noted that the discussion fit well with the Institute's practices with regard to program project grants. NINDS recently stopped percentiling these grants, because of issues regarding the comparability of the different types of research in the study sections. The Institute has also increased attention to pre-submission screening for mission relevance and to overlap. The Council discussion, in general, supported this trend of the Institute taking increased responsibility toward these grants, which may also extend to post-review assessment of the proposed projects within the context of the Institute priorities. The Institute will share with Council data on the review issues and about proposals not accepted for review.

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X. 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 165 research career development and institutional training grant applications; of this total, 100 applications had primary assignment to NINDS, and 65 of them (65.0 percent) were recommended for support in the amount of $8.1 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 $2.4 million.

Research Grant Awards

The Council reviewed a total of 2,204 research grant applications; of this total, 1,363 applications had primary assignment to NINDS, and 793 of them (58.2 percent) were recommended for support in the amount of $344.0 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 $37.1 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 one investigator as a Javits awardee.

Small Business Innovation Research and Small Technology Transfer Award Programs

The Council reviewed a total of 235 Small Business Innovation Research (SBIR) and Small Technology Transfer Award (STTR) grant applications; of this total, 124 applications had primary assignment to NINDS and 63 of them (50.8 percent) were recommended for support in the amount of $18.0 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 $6.4 million.

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XI. Adjournment

The meeting was adjourned at 11:15 a.m. on Friday, September 15.

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

Robert Finkelstein, Ph.D.
Executive Secretary
National Advisory Neurological Disorders and Stroke Council
Director, Division of Extramural Research
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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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.