NINDS Advisory Council Meeting Minutes, May 24-25, 2012

Department of Health and Human Services 
Public Health Service
National Institutes of Health
National Advisory Neurological Disorders and Stroke Council

Summary of Meeting[1]
May 24-25, 2012

The National Advisory Neurological Disorders and Stroke (NANDS) Council was convened for its 184th meeting on May 24-25, 2012, 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:

Council members present were:

Council member absent was:

Dr. Louis Ptacek

Council Roster (Attachment 1)

Ex Officio Members present:

Dr. Geoffrey Ling, Department of Defense

Ex Officio Members absent:

Dr. Robert Ruff, Department of Veterans Affairs

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

Mr. Ronald Bartek, Friedreich's Ataxia Research Alliance 
Dr. Michael Nunn, The Salk Institute

NINDS employees present for portions of the meeting included:

Other Federal employees present for portions of the meeting included:

Justin Ripley, OD
Kate Saylor, OD
Yancy Bodenstein, NIMH
Dr. Linda Brady, NIMH
Dr. Wei-Qin Zhan, CSR
Dr. Laurent Taupenot, CSR
Dr. Rene Etcheberrigaray, CSR
Dr. Kevin Walton, CSR
Dr. John Ferrell, CSR
Dr. Joe Rudolph, CSR
Dr. Yuan Luo, CSR
Dr. Suzan Nadi, CSR

I. Call to Order and Opening Remarks

Dr. Landis, Director, NINDS, welcomed Council members, visitors, and staff to the 184th meeting of the National Advisory Neurological Disorders and Stroke Council meeting.

Dr. Landis announced that this was the last meeting for Emery Brown, Robert Friedlander, Katie Hood, and Louis Ptacek, and thanked them all for their service throughout their term which ends July 31, 2012. Dr. Landis mentioned that Dr. Louis Ptacek and Dr. Robert Ruff, the NANDS representative from the Veteran’s Administration, were unable to attend this Council meeting. In addition, Dr. Landis announced that Dr. Geoffrey Ling, the NANDS representative from the Department of Defense, was retiring from the US Army after 21 years of active duty, and that Scott Prince, the NINDS web master, was leaving to assume the role of the NIH Online Information Branch Chief in the Office of Communications & Public Liaison. Lastly, Dr. Landis informed Council of the sudden death in late February of Dr. Tom Miller, a program director in the Office of Translational Research. Dr. Landis spoke of his contributions to NINDS.

II. Report of the Associate Director for Extramural Research, NINDS

Approval of Council Minutes -- Dr. Finkelstein requested, and the Council voted approval, for the February 14-15, 2012, Council meeting minutes.

The following future Council meeting dates were confirmed:

• September 20-21, 2012 - (Thursday and Friday)
• January 31-February 1, 2013 - (Thursday and Friday)
• May 23-24, 2013 - (Thursday and Friday)
• September 12-13, 2013 - (Thursday and Friday)
• January 30-31, 2014 - (Thursday and Friday)
• May 29-30, 2014 - (Thursday and Friday)
• September 11-12, 2014 - (Thursday and Friday)

Expedited Review Process - A subset of Council members, prior to the meeting, approve applications with scores within the payline for which there are no unresolved issues. Dr. Finkelstein thanked Donna Ferriero, Sharon Hesterlee, and Amita Sehgal for handling this responsibility this fiscal year. For this Council round, 154 applications were eligible to be expedited including 8 career or K applications. One hundred ten of these have already been issued and most of the others will be issued shortly after Council.

DER Announcements - Dr. Finkelstein introduced Dr. Andrey Kuzmichev, a new program analyst in the Neurodegeneration Cluster. Dr. Rajesh Ranganathan, Director, Office of Translational Research (OTR) introduced two new members of OTR: Dr. Eric Nelson and Dr. Rebecca Roof, and announced the departure of Dr. Jill Heemskerk.

III. Report of the Director, NINDS

Dr. Landis announced that September 12, 2012, had been selected as the date for the 2012 NINDS Non-Profit Forum.

National Bioeconomy Blueprint
On April 26, 2012, the White House released the The National Bioeconomy Blueprint , the goal of which is to lay out strategic objectives that will help realize the full potential of the U.S. Bioeconomy and to highlight early achievements toward those objectives. The National Bioeconomy Blueprint describes five strategic objectives for a bioeconomy with the potential to generate economic growth and address societal needs and notes that much work remains if the United States is to remain competitive in a changing world.

Leadership in Decline
On May 17, 2012, United for Medical Research (UMR) released the report, Leadership in Decline: Assessing US International Competitiveness in Biomedical Research.  The report examines a number of key indicators in the life sciences industry, concluding that:  U.S. leadership in global life sciences industry is under threat.  Moreover, the report notes that while the U.S. Federal investment in biomedical research is declining, global competition is increasing as China, India, Singapore, and the U.K. have increased their research funding.  The UMR report recommends that Congress should expand NIH funding to a level that represents at least 0.25% of GDP.

NSTC Neuroscience Working Group
In November 2011, the Neuroscience Working Group was established in the National Science and Technology Council (NSTC) as an interagency working group to coordinate activities in neuroscience research across the Federal government with a focus on the fundamental understanding of learning, brain development and plasticity, and brain health and recovery.  Established in response to P.L. 112-55, the Consolidated and Further Continuing Appropriations Act of 2012, the working group’s charter states that it “will enhance Federal efforts related to: improving our understanding of learning and cognition and applying that to improvements in education and other areas; improving our understanding of a variety of neurological conditions and injuries; and developing appropriate resources, tools, techniques, interventions, and therapies to assist in research, treatment, and recovery.”

Patient-centered Outcomes Research Institute
The Patient-Centered Outcomes Research Institute (PCORI) was established in the Affordable Care Act, signed into law by President Obama on March 23, 2010.  The mission of PCORI is to help people make informed health care decisions and improve health care delivery and outcomes by producing and promoting high integrity, evidence-based information that comes from research guided by patients, caregivers and the broader health care community.  The research priorities and research agenda were approved at a public meeting on May 21, 2012.  In FY12, PCORI is supporting 50 two year pilot projects focused on the methodologies of conducting Comparative Effectiveness Research (CER).  It is currently unclear how NIH and the Agency for Healthcare Research and Quality (AHRQ) efforts in CER will be impacted by the formation of PCORI.

NCATS: Therapeutics Discovery Pilot
On May 3, 2012, the NIH launched the Discovering New Therapeutic Uses for Existing Molecules program, a collaborative pilot program designed to develop partnerships between pharmaceutical companies and the biomedical research community to advance therapeutic development.  This program will match researchers with a selection of molecular compounds from industry to test ideas for new therapeutic uses, with the ultimate goal of identifying promising new treatments for patients.  NCATS has collaborated with eight companies who have agreed to make 58 compounds available for the pilot program.  The available compounds have undergone significant research and development by industry, including safety testing in humans and therefore provide a strong foundation for moving forward.  NCATS is anticipating contributing $20M in FY13 towards advancing this program.

National Alzheimer’s Project Act
The National Alzheimer’s Project Act (P.L. 111-375) was signed into law by President Obama on January 4, 2011.  This law tasked the Department of Health and Human Services (DHHS) with developing a national strategic plan for Alzheimer’s disease (AD), including research, care, and services.  A draft plan was released on March 8, 2012, and the final plan was released on May 15, 2012, at the Alzheimer’s Disease Research Summit.  In addition, a national research plan for Alzheimer’s disease was developed at the Summit, which was presented to the National Institute on Aging (NIA) Council and will be sent to DHHS.  A second meeting on related dementias including vascular dementia, frontotemporal dementia (FTD), Parkinson’s disease (PD) dementia and others organized by NIA and NINDS will be held in 2013.

On February 7, 2012, the Obama Administration announced an initiative for NIH to dedicate an additional $50M in the FY12 budget for AD research.  Of the $50M, $25M will be used to sequence the genomes and exomes of people with AD to identify both risk factors and protective genetic variants.  This work will be done by the National Human Genome Research Institute (NHGRI) sequencing centers.  The remaining $25M will be spent on two clinical trials, iPSC research and a supplement to the Atherosclerosis Risk in Communities epidemiology project.  The President’s FY13 budget includes an additional $80M for AD research, which the President proposes to add to the NIH budget.  Currently, NIA funds about 70% of AD research and NINDS funds about 10%.

NINDS Stroke Planning
In 2001, the NINDS launched the Stroke Progress Review Group (PRG) effort which was established to assist in assessing the state of knowledge and identifying scientific opportunities and needs the stroke field.  Specifically, Stroke PRG members were asked to: take a broad view in identifying and prioritizing unmet scientific needs and opportunities that are critical to the advancement of the research field; identify and prioritize scientific research opportunities and needs, and the scientific resources needed to address them, to advance medical progress; compare and contrast these priorities with an NINDS-prepared analysis of its Stroke research portfolio; and to develop a research plan of action that addresses unmet opportunities and needs.  Over the 10 year period since the SPRG was convened, three reports reviewing the landscape of stroke research have been completed.  The final report of the SPRG was completed in January 2012.

Phase two of stroke planning will help NINDS identify priorities for advancing prevention, treatment and recovery/rehabilitation research.  A steering committee has been established as a working group of Council, and an RFI has been posted soliciting community input on Stroke Research Priorities that if completed over the next 5-10 years would lead to major advances in stroke science.  Workgroups will come to consensus on 2-3 research priorities for each area based on RFI responses and SPRG priority topics.  Additionally, an evaluation of the Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) Network will occur in parallel to the stroke planning effort.

Effects of the A2 policy on R01 funding
In response to the NIH effort on Enhancing Peer Review, the NIH announced in October 2008, that beginning with original new applications (i.e., never submitted) and competing renewal applications submitted for the January 25, 2009, due dates and beyond, only a single resubmission (A1) to an original application would be accepted (see NOT-OD-09-003 and NOT-OD-09-016).  This policy was implemented, in response to the trend that very few grants were awarded on the first submission and that more than 30% were not funded until the third submission.  Since this change in policy, almost 50% of grants are funded on the first submission (up from 28% in 2007), the average number of applications required to receive funding has dropped, and the time to award for an unsolicited, new R01 has dropped from 93 weeks to 56 weeks for both new and experienced investigators. 

Additional possible intervention points to improve peer review outcomes are being discussed at the NIH level, including: providing applicants with more useful scientific review group (SRG) information (e.g., technology approaches for identifying the most appropriate study section), enhancing the accuracy of SRG assignments, identifying better reviewers, evaluating SRG output (e.g., does study section A review grants of comparable quality to study section B?), and providing Institutes/Centers with more information on application quality in context.  Dr. Landis noted that the output of SRGs significantly impacts an Institute’s portfolio in addition to a number of other factors including: the Institute to which a grant is assigned (applies to grants < 500K direct costs), whether an Institute accepts a grant > 500K direct costs for review, whether the grant is reviewed in CSR or in the Institute, whether the grant is percentiled or not, and the complement of CSR study sections that review grants for an Institute. 

IV. Overview of the NINDS Clinical Trials Program

Dr. Petra Kaufmann, Director of the NINDS Office of Clinical Research, provided Council members with an update on NINDS-funded clinical research, including: highlights from recently completed clinical trials, a description of the current NINDS clinical trials portfolio, and strategies for increasing the efficiency of the clinical research enterprise at NINDS.

Dr. Kaufmann described the WARCEF trial (Homma et al., 2012), which was designed to determine whether heart-failure patients, who are at an increased risk for death and stroke caused by thromboembolic events, would benefit more from treatment with Warfarin or from treatment with aspirin.  Results from WARCEF show that there was no overall difference in the risk of a composite of ischemic stroke, intracerebral hemorrhage, or death from any cause with treatment with warfarin vs. aspirin.  Dr. Kaufmann also reported on the completion of the Rapid Anticonvulsant Medication Prior to ARrival (RAMPRT) Trial. RAMPART was a double-blind randomized clinical trial to investigate whether intramuscular delivery of midazolam (an anti-epileptic drug) is as effective as IV-delivered lorazepam, the current standard of care.  The RAMPART study demonstrated that IM midazolam was the optimal initial pre-hospital treatment for status epilepticus by paramedics.

Dr. Kaufmann provided Council members with a description of the other major activities in the NINDS clinical research portfolio.  Updates were provided for Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), Interventional Management of Stroke III Trial (IMS III), the Silent Infarct Transfusion Trial, and for Systolic Blood Pressure Intervention Trial (SPRINT).  Additionally, Dr. Kaufmann described the NINDS processes for accepting clinical trials, and detailed some of the factors considered by NINDS when determining whether or not to accept a trial for review.  Lastly, Dr. Kaufmann discussed strategies that NINDS is employing to increase clinical trial efficiency, specifically to support the successful implementation of trials and to obtain answers earlier.

V. Special Council Review Process for PIs Exceeding $1.5M in NIH Support (Discussion)

Dr. Alan Willard, Deputy Director, Division of Extramural Research, NINDS, reported on a new policy announced by NIH to conduct an additional review of proposed awards to any PI who already has NIH funding of $1.5 million or more in total annual costs.  The policy emerged following a number of NIH-wide discussions regarding the best way to manage limited resources in austere times, and was announced publically on May 18, 2012, in the NIH Guide (NOT-OD-12-110).  The Guide Notice states that “During May 2012 NIH Institute and Center (IC) Advisory Council meetings, Councils will discuss and pilot-test procedures for the additional review of grant and cooperative agreement applications from Program Director(s)/Principal Investigator(s) [PD(s)/PI(s)] who already receive in excess of $1.5 million per year in total costs to determine if additional funds should be provided to already well-supported investigators.”  Moreover, “NIH will be piloting procedures whereby Council members will be asked to provide additional consideration of new and renewal applications from well-supported investigators who currently receive more than $1.5 million in Research Project Grants (RPGs)...Council members will be asked to recommend consideration of funding for applications that afford a unique opportunity to advance research which is both highly promising and distinct from the other funded projects from the PD/PI.”  In preparation for this pilot, NANDS Council members were provided with the application’s summary statement; staff recommendations for funding; and a list of the PD/PIs other support, including % effort, project end date, and whether a renewal will be requested.   Other questions that were addressed in the materials provided by NINDS staff include:  How is the current application distinct from the PI’s other funded projects and what are the highly-promising unique opportunities that this additional grant will support.

VI. Follow up to Analysis Working Group Report

Dr. Finkelstein recapped a series of presentations from the February 2012 Council that analyzed past NINDS expenditures and described potential core principles to guide future spending. As previously discussed, NINDS has begun to analyze past and current expenditures to facilitate discussion of this issue, and many of these findings were presented to the NANDS Council in February.   First, Dr. Finkelstein showed data analyzing NINDS expenditures by funding mechanism.  These findings indicate that the percentage of the NINDS extramural grants budget supporting R01s has varied significantly both positively and negatively since 1995. He also showed that funding for P01 grants has steadily decreased, and that funding for Phase III clinical trials and preclinical therapy development grants increased. The increase in support for Phase III clinical trials was shown to be largely due to increased funding for ongoing trials.  Dr. Finkelstein next recapped the results of a pilot analysis designed to address the question of whether the balance of Basic and Applied research has changed over time. Competing grants in the NINDS research portfolio were analyzed in two years (2002 and 2010) and assigned a percent effort to the following categories: Basic/Basic, Basic/Disease-Related, Applied/Translational, and Applied/Clinical. Preliminary data from this analysis suggests that the percentage of competing funds supporting investigator-initiated disease-focused research (Basic; Disease-Related, Applied; Translational; and Applied; Clinical) was increased in 2010 compared with 2002. The results obtained when analyzing Investigator-initiated R01s were similar to the overall NINDS portfolio.

Dr. Finkelstein reported that since the February Council meeting, the NINDS Analysis Working Group extended this analysis to include 8 time points between 1997 and 2011.  These data show that total basic expenditures declined from 87% to 66% of the competing budget, while total applied funding increased from 13% to 34%.  Moreover, these data indicate that basic/basic research declined from 52% to 21% during this time period.  A number of potential confounding factors (e.g. inclusion of two year grants, greater inflationary rate in the conduct of clinical vs. basic research) were analyzed and shown to have a negligible effect on the outcomes demonstrated in this analysis.

VII. Presentations by the Division of Intramural Research, NINDS

Overview, Division of Intramural Research
Dr. Alan Koretsky, Scientific Director, NINDS, provided NINDS Council members with an overview of the NINDS Intramural Training Program.  The Intramural Research Program (IRP) training program spans all levels of career development, including: a summer program targeting college students, several partnership programs with other neuroscience programs to train graduate students, and postdoctoral and clinical fellows.

NINDS Intramural Neurosurgical Training Opportunities
Dr. Russell Lonser, Chief, Surgical Neurology Branch, NINDS, reported that over the last decade, work-hour limitations and socioeconomic constraints have limited research training opportunities for resident and early career neurosurgeon-scientists nationally.  To combat these difficulties and to enhance research training opportunities, the NINDS Surgical Neurology Branch (SNB) developed 2 new intramural research training programs, including a Neurological Surgery Residency Training Program and an Assistant Clinical Investigator position within the SNB.

In 2010, the NINDS SNB received Accreditation Council for Graduate Medical Education approval to be the Sponsoring Site for a Neurological Surgery Residency Training Program (7 year training program that accepts 1 resident/year).  The residency is a collaborative effort with the University of Virginia, which functions as a Participating Site.  Since that time, the residency training program has recruited outstanding medical students from around the country.  Current residents include David Weintraub, M.D., Gautam Mehta, M.D., and Winson Ho, M.D. 

To enhance the research training opportunities for neurosurgeons that have finished residency training, an Assistant Clinical Investigator position within SNB was developed in 2009.  This position is designed to train early career neurosurgeons-investigators on the NINDS intramural campus.  These positions begin with a 2- to 3-year mentored phase.  Following the mentored phase, the Assistant Clinical Investigator can receive independent resources for a 3-year period with Board of Scientific Counselors approval. 

Neurofibromatosis Type 2
Dr. Ashok Asthagiri, Assistant Clinical Investigator, Surgical Neurology Branch, NINDS, reported that neurofibromatosis type 2 (NF2) is a multiple neoplasia syndrome caused by a mutation in the tumor suppressor gene located on chromosome 22. Ongoing findings of basic science and clinical research studies in NF2 conducted at the intramural NIH campus were presented. A retrospective analysis demonstrated that NF2–associated intracranial tumors most frequently demonstrated a saltatory growth pattern. Because new tumors can develop in NF2 patients over their lifetime and because radiographic progression and symptom formation are unpredictable, resection may be best reserved for symptom-producing tumors. Moreover, establishing the efficacy of nonsurgical therapeutic interventions must be based on long-term follow-up (several years). A prospective cross-sectional study performed on NF2 natural history study participants identified a model in which hearing loss develops as a result of cochlear aperture obstruction and accumulation of intralabyrinthine protein.  MRI based identification of elevated intralabyrinthine protein may help identify the ear at-risk for developing hearing loss. Finally, the findings of a laboratory investigation were presented which indicate that amino acid substitutions in mutant merlin result in quantitative reductions in protein expression, rather than intrinsic functional changes. This suggests that NF2 missense mutations result in altered protein stability and implicates a protein quality control pathway through which such mutant merlin is detected and degraded within cells. Because manipulation of protein quality control pathways using proteostasis regulators results in increased expression of functional mutant tumor suppressor protein, specific molecular mediators involved in these pathways may provide a unique treatment paradigm for NF2 and other similar disorders.

Exploring the Neural Correlates of Cognitive Function through Neurosurgery
Dr. Kareem Zaghloul, Staff Clinician, Surgical Neurology Branch, NINDS, reported that epilepsy surgery and deep brain stimulation surgery, two major surgical techniques used within functional neurosurgery, rely on recording neural activity directly from and direct stimulation of the human brain to in order to best address neurologic dysfunction.  Because of this, it is clear that the future of neurosurgery is intimately related to the establishing a more comprehensive understanding of basic neural circuits that lies at the heart of neuroscience.  Research in the Surgical Neurology Branch is aimed at demonstrating that this relationship can be reciprocal, that just as neuroscience informs neurosurgery, neurosurgery can also be used as a vehicle to inform neuroscience.  Research was presented demonstrating how direct recordings during deep brain stimulation surgery are used to explore the neural mechanisms that underlie human reinforcement learning and human decision making within the structures of the basal ganglia.  In addition, studies were presented demonstrating how neurophysiologic recordings captured after implantation of intracranial electrodes for seizure localization in epilepsy surgery are used to explore the neural and network mechanisms that underlie human episodic memory formation.

VIII. Review of the Division of Intramural Research Board of Scientific Counselors’ Reports

In closed session, Dr. Koretsky presented the findings and recommendations of the Board of Scientific Counselors based on their review of specific DIR laboratories/units during 2011.  The Council discussed the reports of the Board and accepted them.

IX. Council Consideration of Pending Applications

This portion of the meeting, involving specific grant review, was closed to the public.  The Council gave special attention to applications from foreign institutions and other applications which needed specific discussion.  Prior to the discussion of the grants, Dr. Finkelstein reminded Council regarding conflict of interest and confidentiality as follows:

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.

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, the Council Executive Secretary, who will then refer the questions to the appropriate staff member for response. 

Research Training and Career Development Programs
The Council reviewed a total of 85 research career development and institutional training grant applications; of this total, 71 applications had primary assignment to NINDS, and 45 of them (63.4 percent) were (scored/percentiled) in the amount of $6.9 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 $2.7 million (17 grants).

Research Project and Center Awards
The Council reviewed a total of 1,673 research project and center applications; of this total, 1,348 applications had primary assignment to NINDS, and 754 of them (56.0 percent) were (scored/percentiled) in the amount of $222.9 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 $61.3 million (233 grants).

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, three Javits awards were recommended.

Small Business Innovation Research and Small Technology Transfer Award Programs
The Council reviewed a total of 125 Small Business Innovation Research (SBIR) and Small Technology Transfer Award (STTR) grant applications; of this total, 100 applications had primary assignment to NINDS and 63 of them (63.0 percent) (scored/percentiled) in the amount of $14.7 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 $4.7 million (17 grants).

X. Adjournment

The meeting was adjourned at 11:05 a.m. on Friday, May 25.

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.