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National Advisory Council Meeting - February 4-5, 2009
Summary of the 120th Meeting
February 4-5, 2009
The National Advisory Council on Alcohol Abuse and Alcoholism convened for its 120th meeting at 5:30 p.m. on February 4, 2009, at the FishersLaneConferenceCenter in Rockville, Maryland, in a closed session. Dr. Abraham Bautista presided over the closed review of grant applications. The NIAAA National Advisory Council reconvened in closed session on February 5, 2009, to review a report from the Board of Scientific Counselors. Dr. Kenneth Warren, Acting Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), presided over the Council’s open session later on February 5, 2009. In accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, the session on February 4, 2009, was closed to the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds.
Council Members Present:
Michael E. Charness, M.D.
David W. Crabb, M.D.
Gen. Arthur T. Dean
Cindy L. Ehlers, Ph.D.
Scott L. Friedman, M.D.
R. Adron Harris, Ph.D.
Deborah S. Hasin, Ph.D.
Andrew C. Heath, D.Phil.
Vimal Kishore, Ph.D.
Lynell W. Klassen, M.D.
John H. Krystal, M.D.
Peter M. Monti, Ph.D.
Larry I. Palmer, LL.B.
Edward P. Riley, Ph.D.
Linda P. Spear, Ph.D.
Ex-officio: John P. Allen, Ph.D., M.P.A.
Chairperson: Kenneth R. Warren, Ph.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Vivian B. Faden, Ph.D., Ralph W. Hingson, Sc.D., M.P.H., Robin I. Kawazoe, Howard Moss, M.D., Antonio Noronha, Ph.D., Mark Willenbring, M.D., Samir Zakhari, Ph.D.
Other Attendees on February 5, 2009
Approximately 60 additional observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order of the Closed Session, February 4, 2009
Dr. Abraham Bautista, Ph.D. called the closed session of the 120th meeting of the Council to order at 5:30 p.m. on Wednesday, February 4, 2009, for consideration of grant applications. He reviewed procedures and reminded Council members of regulations pertaining to conflict of interest and confidentiality. Members absented themselves from the discussion and evaluation of applications from their own institutions and in situations involving any real, apparent, or potential conflict of interest. The closed session adjourned at 7:00 p.m.
Board of Scientific Counselors, February 5, 2009
In a session closed to the public and NIH/NIAAA staff, Dr. George Michalopoulos chaired the review of the June 2008 meeting of the Board of Scientific Counselors.
Call to Order and Introductions, February 5, 2009
Dr. Kenneth Warren, Ph.D. called the open session to order on February 5, 2009, at 9:05 a.m. and welcomed participants. He introduced the Council’s five new members: Linda Spear, Ph.D., Scott Friedman, M.D., Andrew Heath, D.Phil., John Krystal, M.D., and Edward Riley, Ph.D. Dr. Warren also welcomed Jill Carty, Psy.D., M.S.Ph., who substituted for the absent Department of Defense (DoD) ex-officio member Col. Joyce Adkins, Ph.D., and John Allen, Ph.D., new ex-officio member from the Department of Veterans Affairs. Additional Council members and NIAAA senior staff introduced themselves. George K. Michalopoulos, M.D., Ph.D., Chair of the NIAAA Board of Scientific Counselors also introduced himself.
Referring to the published “Director’s Report,” Dr. Warren highlighted the following Institute activities:
§ Legislation, budget, and policy. Dr. Warren stated that funding for the National Institutes of Health (NIH) currently is governed by a continuing resolution (CR). Under the CR, NIAAA’s budget has been prorated through March 6, 2009, from the FY 2008 base of $436.2 million. Congressional budget action for FY 2009 and 2010, preempted by deliberations over the economic stimulus package, was anticipated shortly, but possibly preceded by an additional CR.
§ Director’s activities. Dr. Warren noted the resignation of T.K.-Li, M.D., who had served as NIAAA Director from 2002 until 2008. Prior to his retirement, Dr. Li, accompanied by Drs. Howard Moss, Peggy Murray, Kenneth Warren, and several other scientists, participated in the fourth joint NIAAA/INSERM scientific symposium in Paris that focused on imaging and fetal alcohol syndrome (FAS). Drs. Murray and Warren participated in a major Fogarty Forum on strengthening the research enterprise in Sub-Saharan Africa that has proven fruitful in SIDS, AIDS, and other areas.
§ Honors. Dr. Markus Heilig, NIAAA Clinical Director and Chief of the Laboratory of Clinical and Translational Studies, received the ButlerCenter for Research’s 2008 Dan Anderson Research Award for his identification of a novel neural transmitter system involved in cravings for alcohol.
§ NIAAA staff and organization. NIAAA Associate Director for Administration Robin I. Kawazoe has begun a half-time detail as Acting Deputy Director, Division of Program Coordination, Planning, and Strategic Initiatives. Dr. Vivian Faden was named Acting Director, NIAAA Office of Science Policy and Communications. Dr. Abe Bautista has been named Director, Office of Extramural Activities. Dr. Ellen Witt was appointed Deputy Director, Division of Neuroscience and Behavior (DNB). Dr. Mike Hilton was named Acting Deputy Director, Division of Epidemiology and Prevention Research (DEPR). Ms. Amy Matush was selected as Chief, Ethics and Management Analysis Branch. Dr. Aaron White joined NIAAA as Health Scientist Administrator in DEPR. Dr. Hae Kook Lee joined NIAAA as a Guest Researcher in DEPR in an exchange relationship with the Republic of Korea. Dr. Changhai Cui joined NIAAA as a Program Director in DNB. Dr. Andras Orosz joined the Division of Metabolism and Health Effects (DMHE) as a Program Director. Dr. Dale Hereld from DMHE serves as NIAAA’s representative to the Interagency Coordinating Committee on Fetal Alcohol Syndrome.
NIH Scientific Management Review Board: Topics to be Discussed
NIH Acting Deputy Director Lawrence A. Tabak, D.D.S., Ph.D., presented an overview of topics slated for discussion by the NIH Scientific Management Review Board (SMRB). Dr. Tabak noted that in its 2006 NIH reauthorization, Congress unanimously reaffirmed its support for NIH’s role. The legislation established the SMRB to advise the NIH Director and to conduct continuous comprehensive organizational reviews and report findings to both the Department of Health and Human Services (HHS) and Congress. Dr. Tabak described the SMRB’s composition and enumerated its activities, which include issuing a report not less than every 7 years; evaluating the NIH research portfolio; determining scientific opportunities and public health needs relevant to NIH’s mission; assessing organizational issues; and making recommendations on resource allocation among Institutes and Centers (IC).
The SMRB is expected to consult broadly, including with IC Directors, NIH scientific leaders, IC Advisory Councils, and scientific and patient organizations. At least five meetings on any particular report are to be called by the SMRB Chair or the NIH Director, thus institutionalizing opportunities for deliberation; meeting summaries must be posted on NIH’s Web site to promote transparency; and a variety of forums are to be held, in connection with reports on organizational issues, with both the scientific community and consumer organizations.
At an April 2009 meeting, the SMRB initially will address the NIH Intramural Research Program (IRP). Following an overview, presentations will be made from both intramural and clinical perspectives. The SMRB also will address the potential merger of NIAAA and the National Institute on Drug Abuse (NIDA). Following an overview, NIDA Director Nora Volkow and NIAAA Acting Director Kenneth Warren are to be invited to speak from their respective Institutes’ perspectives. Dr. Tabak pointed out that the goal of the meeting is to decide solely whether or not to address issues related to a potential merger. If the SMRB decides to consider this issue further, next steps would be decided at the meeting.
Discussion: Dr. Michael Charness expressed concern about raising the merger issue at a time when HHS lacks a Secretary and both NIH and NIAAA lack permanent directors. He asserted that inadequate attention is paid to mergers’ enormous costs and long-lasting consequences, and that benefits are overestimated. Dr. Tabak responded that the merger issue has been discussed for years; the process is intended to be deliberative; and the timing is unrelated to lack of permanent leadership. Dr. Deborah Hasin and Dr. Peter Monti echoed concerns expressed about the timing. Dr. Monti noted that raising the issue at this time has potential to affect negatively the search process for a new NIAAA Director.
Dr. Charness addressed the unique nature of NIAAA’s research approach. He pointed out that no Institute better exemplifies the qualities of systems biology, in contradistinction to the more typical focal study of areas of biology. The agent that causes alcoholism is unique in that it is neither an illicit drug nor a drug that for the most part causes problems. Alcohol is used well by 100 million or more Americans, and epidemiological evidence has suggested that it is beneficial for people’s health. Nevertheless, abuse causes addiction and damage to almost every organ system in the body. NIAAA is the only place in NIH that integrates that understanding. A recent review of the NIAAA portfolio took a systems approach in looking at the influence of liver disease on the brain, brain disease on the liver, and the consequences of liver disease on the immune system, gut, and brain—not just in addiction, but regarding the interactions’ overall consequences for illness. Alcohol misuse represents one of the largest public health problems in the country. Dr. Charness pointed out that NIAAA uniquely studies the problem of addiction and also consequences including liver disease, FAS, and diseases of the heart, pancreas, immune system, and others. NIAAA has become a model Institute to choreograph research on all the interrelated problems of alcoholism. He expressed concern about a merger that might take NIAAA’s systems biological approach and disperse portions of its portfolio to other Institutes. Dr. Michalopoulos added that no Institute focuses specifically on hepatic diseases. However, they are also within the scope of NIDDK. He also inquired about whether five meetings would be held in addition to the initial meeting. Dr. Tabak responded that he will research the answer to that question. He stated that the topics for the meeting were chosen following discussions with outgoing NIH Director Elias Zerhouni and the chair of the SMRB.
Mr. Larry Palmer observed that Congress established a policy process aimed at public perceptions of health and that alcohol and tobacco each has a different legal and political structure. He suggested the usefulness of thoughtful deliberations on not considering a merger and development of a rationale to educate Congress and the public on why a merger might not produce the best science that can be translated into health policy. Dr. Tabak acknowledged the value of Mr. Palmer’s comments in deciding whether or not to move the proposal forward to full analysis. Mr. Palmer cautioned against confusing policy making with policy analysis, pointing out that policy issues warrant much discussion.
Dr. Adron Harris concurred that the uniqueness of the science of alcohol and its effects on other organ systems ought to factor heavily into decisions about NIAAA’s continued independence in terms of science and policy. He inquired whether the Research Society on Alcoholism (RSA) will be invited to the April meeting and whether a timeline had been established to select a new NIAAA Director. Dr. Tabak responded that he does not know details on the search timeline. He stated that the April meeting likely will allot time for public comment on each agenda item. Dr. Edward Riley inquired whether the SMRB will accept written comments. Dr. Tabak responded that he anticipated that written comments would be accepted. Dr. Riley stated that he studies fetal alcohol consequences in a systems approach and that fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD) do not involve an addictive process.
Dr. Monti suggested postponing the meeting for 6 months, by which time a new NIAAA Director would be in place. Dr. Tabak noted Council members’ concerns and suggestions. In response to a question from Dr. Hasin, Dr. Tabak stated that if a decision is made to go forward, a process will be established at that meeting for next steps, informed by consultation with a broad array of stakeholders. He opined that the SMRB may establish subcommittees to deliberate on the issues and report to the committee as a whole.
National Institute of Biomedical Imaging and Bioengineering: Overview
Roderic I. Pettigrew, Ph.D., M.D., Director, National Institute of Biomedical Imaging and Bioengineering (NIBIB), presented an overview of scientific activities supported by NIBIB. The Institute focuses on emerging biotechnologies that cut across all organ systems and diseases, and is integrally involved with all NIH Institutes. NIBIB aims to integrate the physical engineering sciences with life sciences to advance understanding of basic principles in pathophysiology as related to disease and health, supports a wide array of technology development and related research and translates them to benefit health care. NIBIB and NIAAA jointly support interdisciplinary research initiatives to address biological, bioengineering, and medical research problems, along with neuroinformatics-based work.
NIBIB focuses on nanomedicine in research related to drug and gene delivery, tissue engineering, surgical technologies, and emerging technologies. Dr. Pettigrew illustrated a study of the brain’s response to organized versus random motion using an MRI image that has been inflated to expose the folds and surface areas in the brain, in particular the activated areas. Related research uses MRI images of the neurofibers in the brain that are produced by diffusion spectrum imaging, which tracks the movement of water molecules in the brain to define and map the brain’s neural wiring
Dr. Pettigrew explained that this technology applies to other areas, as well. One study demonstrates that an individual’s brain wave pattern corresponds to various intended activities such as thinking or moving. Deciphering brain waves and correlating them with intended motion enables researchers to replace missing limbs with mechanical devices, which the patients can control. The mechanical limb interfaces with a skull cap, which enables the person wearing the cap to control two-dimensional motion of the mechanical device mentally. The television program “60 Minutes” recently featured this work along with a demonstration of an algorithm that can identify a word as an individual spells it, letter by letter, in his or her mind.
Magnetic resonance elastography (MRE) is a new technique that can be used to investigate mechanobiological features of tissues. This approach is especially useful for the early identification of liver fibrosis. The concept of MRE is based on observations of fibroblasts placed in media of two different degrees of stiffness. In a stiff medium, a fibroblast develops a more fibrous, stiffer quality; this tissue stiffness can then be used to identify areas of abnormality, such as fibrosis, at an early stage. The process can identify movement in liver on the scale of tens of microns; the movement is then converted into measures of stiffness that correspond to areas of liver fibrosis, with more stiffness correlated to greater level of fibrosis. These measures correlate graphically with stage of fibrosis as confirmed by a biopsy.
Cardiac noninvasive angiography uses CTA to image coronary arteries. This technology has been used to investigate increased incidence of atherosclerotic diseases in patients with HIV. The technology can delineate three different regions in cross section. The condition’s etiology remains unclear in patients with HIV, whether due to the therapy, or the disease, or therapy by way of increasing lipids and the lipid profile.
NIBIB’s molecular medicine and nanoscale research includes addressing the challenge of repairing nerve injury. One investigator has developed a nanofiber with a hydrophobic tail and a top with a pentapeptide containing five epitopes similar to those found in the protein laminin, which is known to have specifically potent stimulant capabilities in accelerating neuroprogenitor cell differentiation. The idea was to generate a nanofiber that presents a high density of this pentapeptide to stimulate the growth of nerve cells. Studies with neuron differentiation found fivefold faster neuron differentiation compared to laminin without the nanomaterial. Rat studies reveal the promise of this technology to repair nerve damage. Another investigator has produced nanoparticles that contain methylprednisolone to reduce scarring.
NIBIB has focused in recent years on nanotechnology in combination with microfluidics to develop platforms suitable for making diagnoses at the point of care. An NIBIB grantee has produced a platform able to screen a whole-blood sample and identify a single circulating tumor cell at a concentration of one tumor cell per billion total cells. A sample of whole blood processes through a platform containing microposts that are coated with an antibody for the epithelial cell adhesion molecules, which have a strong affinity for circulating tumor cells. This technology has particular applicability for preventing metastases by removing these circulating tumor cells from the bloodstream before they can form metastases.
NIBIB has a network of point-of care research and development centers, one of which focuses on sexually transmitted diseases (STDs), of interest to NIAAA because of the higher prevalence of STDs in persons with substance abuse problems. One research site is developing a point-of-care device to immediately and definitively diagnose STDs. The test involves the target DNA of the disease organism, a probe that corresponds to the target DNA sequence , and a specific signaling agent. This signaling agent matches a specific location in the DNA; when it binds to this DNA enhanced fluorescence occurs. Currently, this smart probe is under evaluation for detecting chlamydia.
Dr. Pettigrew explained that NIBIB focuses on combining diagnosis and treatment at the molecular level to be more preemptive in disease management by early diagnosis and definitive treatment at that point. One NIBIB grantee has developed a nanoprobe that can address a specific genetic target, which may be seen using a variety of imaging technologies, and can deliver a specific therapeutic agent to the target tissue. Dr. Pettigrew refers to the combined use of diagnostics and treatment as “molecular theranostics”: With technological advances such as these, he envisions a transformation in health care that emphasizes increased wellness, early diagnosis of disease, replacement of invasive processes with noninvasive ones, and care moved from a most expensive locus to one less expensive, such as at the initial point of physician contact and in the home.
Discussion: Dr. Vimal Kishore expressed appreciation for NIBIB as a potential source of support for research in targeted delivery. He noted the many technical challenges, particularly in working with human subjects. Dr. Charness inquired whether NIBIB conducts safety studies of innovative technologies. Dr. Pettigrew stated that his Institute supports an FDA lab to consider the most intelligent use of CT. The environmental impact of nanoparticles represents an area of focus and concern.
NIH Council of Councils’ Report
Victor Hesselbrock, Ph.D., University of Connecticut School of Medicine, who serves as NIAAA’s representative to the NIH Council of Councils, presented an overview of the organization. Organized under the NIH Reform Act of 2006, the Council of Councils has had two official meetings to date. Dr. Hesselbrock presented a chronology of NIH reauthorization legislation, noting that the 2006 Act created a new structure to facilitate trans-NIH research, improve program coordination across ICs, and manage oversight.
The legislation also established NIH’s Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI) which advises the Director on matters related to DPCPSI policies and activities, focuses attention on proposals from first-time applicants, and makes recommendations on the conduct and support of trans-NIH research proposals supported by the NIH Common Fund, but does not review grant applications. Dr. Hesselbrock stated that the 27-member group represents a broad range of disciplines and perspectives. Each IC Director nominates three individuals, two scientists and one from the general public and one person is selected to join the Council of Councils.
At the April 2008 meeting, then–NIH Director Elias Zerhouni stressed the importance of open, transparent, and bidirectional communication between the Council of Councils and individual IC Advisory Councils. He emphasized that the Council has the challenge to promote high-risk ideas and new areas of investigation. The Council established three subcommittees aligned with the three divisions of the former Office of Portfolio Analysis and Strategic Initiatives (OPASI): Resource Development and Analysis, Strategic Coordination, and Evaluation and Systemic Assessments.
Participants at the April 2008 meeting provided input on OPASI reports on the generation and vetting of trans-NIH initiatives; reviewed proposed FY 2010 concepts; heard presentations on interdisciplinary research, the Molecular Libraries Roadmap Initiative, new concepts and current Roadmap topics, public-private partnerships, and the Foundation for NIH; and heard working group and subcommittee reports. The November 2008 meeting’s agenda included a working group report on the Science of Science Management; discussions on the NIH Obesity Research Task Force, OPASI’s role in trans-NIH obesity and nutrition research, and the burden of disease in obesity and nutrition; a presentation on the microbiome; and concept approval of trans-NIH Roadmap Initiative concepts.
Dr. Warren stated that the Office of the Director will name a replacement for Dr. Hesselbrock, whose term on the NIAAA Council has ended, to represent NIAAA on the Council of Councils.
Compliance with Inclusion Guidelines
Bridget Williams-Simmons, Ph.D., Health Science Administrator, Office of Science Policy and Communications, NIAAA, presented data for incorporation in NIAAA’s 2009 Biennial Advisory Council Report on Inclusion of Women and Minorities as Subjects in Clinical Research. Dr. Williams-Simmons explained that the congressionally mandated report is based on the principle that all members of society should share in the burdens and benefits of biomedical and behavioral research. The NIH Revitalization Act of 1993 requires that women and minorities and their subpopulations be included in all NIH-supported clinical research; NIH must support outreach efforts to recruit and retain those populations in clinical studies; exclusions may be made only by the NIH Director or IC Director based on a clear and compelling rationale; cost is not an acceptable reason to exclude these populations; and Phase III trials should be designed to allow for analyses of differences and similarities in intervention effects between gender groups and racial/ethnic groups. Each IC Advisory Council prepares a biennial report describing the manner in which the Institute has complied with the policy, with reports included in the NIH Director’s report to Congress.
Dr. Williams-Simmons enumerated NIAAA’s procedures to ensure compliance: All funding opportunity announcements that involve human subjects include a section on the NIH inclusion policy; program officials answer questions from potential applicants; special attention is given to identification of Phase III clinical trials to ensure compliance; scientific review officers (SRO) inform peer review group members about the inclusion policy before and during review; review groups evaluate proposals to ensure adequate representation in relevant projects; SROs summarize reviewer comments and code summary statements to reflect review committees’ comments and concerns; applications with unacceptable inclusion plans are barred from funding; program officials discuss issues of noncompliance with applicants, who may modify their plans and/or provide additional information to address reviewer concerns and thus become eligible for funding; program officials monitor target enrollment data; and NIAAA provides staff training on the inclusion policy.
Data for 2007 and 2008 show that women constituted more than 50% of the enrollment population in clinical studies, while minorities represented 16 and 19% of the enrollment population, respectively, for 2007 and 2008. Each year NIAAA funded only one Phase III study, on alcohol-related problems more prevalent in men; female participation was low and minority participation relatively high. The racial/ethnic populations that had the greatest representation in 2007 and 2008 extramural clinical studies were White, Black/African-American, and Hispanic/Latino – in that order. The enrollment for American Indian/Alaska Native, Asian and Hawaiian/Pacific Islander populations increased significantly from 2007-2008 (~2-fold, ~2-fold and ~4-fold, respectively). Minority group enrollment in Phase III studies were Black and Hispanic.
Certification: Members of the NIAAA National Advisory Council voted to accept the presentation, with one abstention.
Discussion: Mr. Palmer suggested that NIAAA staff distribute inclusion data to Council members prior to meetings at which the inclusion policy is discussed. Dr. Friedman inquired about provisions related to studies that target a single gender or ethnic group. Dr. Warren responded that assessments for funding eligibility are made by the IRG, the National Advisory Council, and the Institute. Dr. Simmons-Williams responded to a question from Gen. Arthur Dean that the full report enables comparisons between Institutes, which may not be meaningful, depending on prevalence and the scientific questions asked.
Progress on Alcohol Biomarkers
Dr. M. Katherine Jung, Program Director, Immunology and Cancer, Division of Metabolism and Health Effects, NIAAA, serves as chair of the NIAAA (Transdivision) Biomarkers Working Group, which focuses on advancing the discovery and development of alcohol biomarkers. She explained that biomarkers enable early detection of situations amenable to early intervention, better prognosis, and reduction of complications. The biomarker development pipeline, focused on bringing a product to market that will benefit patients, involves discovery, validation, prioritization, development, regulatory improvement, and implementation. The question arises as to the steps on which NIAAA should focus.
Alcohol biomarkers are needed to measure long-term, cumulative alcohol consumption; distinguish among binge, acute, moderate, and chronic drinking; measure compliance after withdrawal (to detect relapse); assess organ damage, including alcohol-induced damage; and identify alcohol risk factors (genetic screen). Good biomarkers should have sensitivity, specificity, overall accuracy, and easily obtainable source tissue, and should be cost-effective, easy to use, portable, robust, and simple. Currently used biomarkers can distinguish between alcohol users and nonusers, but cannot classify individual patients.
In 2006 NIAAA funded 13 grants to use genomics, proteomics, or metabolomics in easily obtainable tissues to identify either biomarkers of alcohol consumption or alcohol-induced tissue damage, many of which looked at tissue damage and most complied with the notion of looking at fingerprints. At a June 2008 NIAAA Workshop on Alcohol Biomarkers, grantees discussed their results, problems, and proposals for improved progress in a closed session. In an open session, presentations were given on regulatory and intellectual property issues; infrastructure supporting biomarker development (Foundation for NIH and the National Cancer Institute); success stories using genomics, proteomics, and metabolomics; and systems biology approaches to correlating ‘omic data. The conference closed with a panel of NIAAA researchers who listened to participants’ opinions and recommendations for NIAAA consideration.
Dr. Jung pointed out that the notion of using a signature is promising. Work in signature identification using male monkeys has found that nine proteins identified individuals with alcohol abuse versus no alcohol abuse with 98% accuracy. When monkeys self-administer alcohol, seven proteins can predict usage group with 94% accuracy.
A number of informal recommendations from grantees and other participants focused on goals and strategies: Continue encouragement of the discovery and development of signatures as biomarkers of classification using ‘omics approaches; promote better quantification of time and dose dependence of currently used biomarkers; expand validation of mechanistic studies in both animal models and well-characterized patient populations; support a Web site and brief annual meetings of a working group of investigators (perhaps at RSA) to keep current on tools, approaches, and research progress; support a central repository of well-characterized, well-annotated human specimens for validation, with three potential versions—supported by NIAAA, curated at NIAAA, or a central core laboratory at NIAAA to perform analyses for clinical and translational studies; clearly define the clinical or research questions at the outset and encourage collaboration between clinicians and bench scientists; and encourage industry involvement via the SBIR mechanism. Overall strategy questions included: Should NIAAA emphasize discovery or development? Can NIAAA interests be maximized by interactions with other infrastructures that support biomarker development? And, what is the role of industry in alcohol biomarker development? Dr. Jung explained that industry, well represented at the June 2008 open meeting, wants NIAAA to set priorities, and big pharmaceutical companies are likely to develop them.
Discussion: Dr. David Crabb noted the insurance industry’s interest in biomarkers: biomarkers must be approved for reimbursement by insurers before they will be used in practice. He suggested that another arrow be added to the biomarker-development pipeline model. Dr. Lynell Klassen inquired about the distinction between a proprietary approach and openness in development. Dr. Jung responded that since the Bayh-Dole Act of 1980, university investigators are encouraged to seek patent protection for potentially useful developments; once the patent has been applied for, information can be released. Dr. Warren expressed discomfort about withholding information from the public and pondered whether a standard governs how long data may be kept private. Dr. Klassen stated his concern about big pharmaceutical companies’ buy-and-bury tactics to protect their interests, which may impede development of new, competitive technologies. Dr. Jung responded that when the Foundation for NIH is involved, all parties relinquish intellectual property rights. Dr. Kishore inquired about the group’s view on the balance between discovery and development. Dr. Jung replied that sentiments were divided, but that consideration must be given to what is most realistic and what can NIAAA afford. Dr. Kishore asserted that discovery or development should be aligned with NIAAA’s mission to improve health. He added that discovery is essential to have something to develop, but that translation of discoveries to benefit the public has lagged significantly and that funding has not supported development.
Dr. John Krystal concurred with the value of establishing a repository to facilitate replication and recognizability. He suggested that the Council discuss possible mechanisms in the future. He also suggested the need for an examination of issues related to the management of complicated withdrawal. Dr. Hasin stated that DSM-V Work Groups are encouraged to learn if any practical biomarkers are ready to aid in the diagnostic process. Dr. Jung noted that no new information was developed at the meeting. Dr. Krystal suggested partnership with DoD, for which alcohol consumption among returning service members and functional status are major concerns. Dr. Moss responded that NIAAA has written an SBIR contract solicitation for bids to develop a repository. To determine whether to emphasize discovery or development, NIAAA is examining the National Cancer Institute program model. NIAAA also has written a contract proposal to develop point-of-care biomarkers. Dr. Scott Friedman noted the particular value of biomarkers in detecting recent alcohol use prior to liver transplantation. NIAAA’s Dr. Peter Silverman confirmed that NIAAA can discover a biomarker and then license it to the biotech industry for development.
Consideration of the September 2008 Minutes and Future Meeting Dates
Council members voted unanimously to approve the minutes of the Council meeting of September 17–18, 2008. Dr. Abraham Bautista announced that upcoming Council meetings will take place on June 10–11, 2009, September 16–17, 2009; February 3–4, 2010, June 9–10, 2010, September 15–16, 2010 (tentative); February 16–17, 2011; June 8–9, 2011; and September 14–15, 2011.
Enhancing Peer Review
Dr. Abe Bautista presented highlights of changes to NIH’s peer review process, effective for applications to be reviewed beginning in May 2009. Page limits will be implemented for the January 2010 submissions. Dr. Bautista urged reading all Funding Opportunity Announcements (FOA) for specific details prior to submitting a new application. Enhanced review criteria for all applications for research grants and cooperative agreements for FY2010 funding apply to applications submitted after January 2009. The enhanced criteria aim to improve the quality and transparency of review and to modify the rating system so reviewers focus less on methodological details and more on potential scientific impact. Dr. Bautista noted that in some CSR study sessions, reviewers are asked to evaluate significance prior to discussing the application; if the application has no significance, reviewers can stop at that point, score it, or unscore it.
The regulations state that the “scientific peer review group shall assess the overall impact that the project could have on the research field involved, taking into account: significance, approach, innovation, investigator(s), environment, inclusion plans, budget, and protection for humans, animals, and environment.” Reviewers with concerns about these factors, with the exception of budget, are asked to “ding” an application, and to indicate that it is unacceptable for human subject inclusion. The new order of consideration of core criteria is: significance, investigator(s), innovation, approach, and environment, each of which receives individual criterion scores; applicants will see the criterion scores in their summary statements. The summary statement will include an overall impact score. Additional criteria include protections for human subjects, women, animals, resubmission applications, renewal applications, revision applications, and biohazards. A side-by-side comparison of enhanced and former review criteria is available at http://grants.nih.gov/grants/peer_review_process.htm .
The new scoring system will be subjected to periodic evaluation and review. Highly rated applications will receive a “1,” while a poor application will receive a score of “9”; the old scoring system does not equate with the new, and emphasis should be placed on the overall impact of the application on the scientific field. In spite of problems with its approach, the significance alone of a novel application may yield an exceptional rating. Applications that are not discussed are no longer deemed “unscored,” but rather “not discussed”; some applications may be “not recommended for further consideration.” The changes aim to better quantify applications’ scientific merit, reduce possible rating discriminations to a potentially more reliable number, provide rating descriptors to improve reliability, and encourage reviewers to use the entire scale range. Reviewers will provide an impact priority score to be discussed at the review meeting. Criterion scores also will be reported at the meeting, but reviewers will vote only on the application’s final score. Summary statements will highlight only strengths and weaknesses, and reviewers will be asked to limit summaries to one-quarter page for each criterion. This format will present better advice to applicants on how to proceed with their applications. Reviewers will enter a code to characterize inclusion of women, minorities, and children.
Dr. Bautista described the timeline for implementing the structured critique templates. SROs will train reviewers beginning in February and March 2009, and will use the new template for May 2009 and later. Newly structured summary statements will be available for the September 2009 meeting.
A2 resubmissions will be phased out both to ensure that the largest number of high-quality and meritorious applications receive funding earlier and to improve system efficiency. Reviewers must evaluate whether an application is worth resubmitting for an amendment or deem a first-time submission unworthy of further consideration. This provision applies to all new, renewal, and revision applications submitted for funding in FY 2010 and to all activity codes. Dr. Bautista offered specific details on the new policy in the transition period: A0 applications submitted after January 25, 2009, were allowed one resubmission—A1 only. Applications submitted for due dates prior to January 25, 2009, may have a resubmission to the A2 by January 7, 2011. Because many FOAs remain to be modified, potential applicants must attend to details such as page limits for P50 and other mechanisms. A CSR committee will evaluate the virtual A2. When an applicant submits an application, it flags the submission’s history.
Policy regarding early-stage investigators (ESI) encourages the transition to independent investigator. ESIs have fewer than 10 years of research experience following a terminal research degree. “New investigators” are those who have never received an R01 grant from NIH. During review, R01applications from new investigators and/or ESIs are to be discussed first, prior to other applications. The new investigator distinction applies only for R01 applications. Expectations of preliminary data for ESIs should not be the same as for established investigators; the focus should be on individuals’ ability to conduct research. The eRA Commons now has fields for applicants to enter and update their dates of degrees and medical residency.
Discussion: Dr. Bautista responded to questions from Dr. Andrew Heath that foreign investigators are eligible to be new investigators and that although a Nobel laureate who may never have received an R01 may be eligible as a new investigator, reviewers can evaluate level of experience for comparison. Dr. Harris pointed to the need for SRO leadership in helping reviewers to think differently. Dr. Cindy Ehlers identified a problem during the transition period that some rounds will be overloaded with last-chance A2s. Dr. Bautista replied that A1 and A2 reviewers will be instructed to ignore previous scores, to compare applications only with others in the current group, and to score applications appropriately, however revised. He noted that the queuing effect is not new. Although CSR sends resubmissions to different reviewers, NIAAA intends to provide continual review to the degree possible. Dr. Klassen inquired about screening resubmissions changes. Dr. Bautista responded that the application tracking system will help to identify substantially unchanged applications.
Council Member Round Table
Dr. Krystal asserted the importance for NIAAA to create novel mechanisms to enable testing of new pharmacological agents on an ongoing basis. Dr. Warren responded that NIAAA’s discussions with drug companies over the past several years have generated access to a number of test compounds. NIAAA is working to determine the best mechanisms to move toward public-private partnerships and will learn about this approach from other Institutes. Dr. Mark Willenbring stated that drug development is one of the most important areas to advance treatment efficacy. NIAAA has consulted with many pharmaceutical companies that currently are developing novel compounds and has helped many to design Phase I and II trials. NIAAA has developed an enduring contract mechanism to implement Phase II proof-of-concept trials rapidly. If compounds show promise, developers would move ahead with larger Phase II and then Phase III trials. NIAAA also is exploring development of a practice-based network of community physicians who are addictions specialists. The network would serve as a low-cost, enduring infrastructure to conduct simple, community-based trials with real patient populations. This infrastructure would enable learning how physicians currently use medications and could serve as a resource for researchers who wish to use that infrastructure to conduct a trial. Dr. Moss stated that although few R01 applicants propose to develop novel compounds, NIAAA-supported research has enjoyed success in identifying promising targets; pharmaceutical companies have volumes of compounds in their molecular libraries, which facilitate identification of promising molecular targets.
Dr. Willenbring stated that NIAAA is working closely with the FDA, pharmaceutical companies, and the extramural research community to clarify outcome criteria of interest. Consensus in the field is growing toward full remission, best defined as absence of heavy drinking days but that may include some drinking as well as abstinence. Dr. Moss noted that FDA’s willingness to accept reductions of hazardous levels of alcohol consumption has changed the paradigm for thinking about alcohol dependence. In addition, it distinguishes NIAAA from NIDA’s medication-development program, which accepts only abstinence as a political-scientific clinical benchmark. Dr. Willenbring observed that people who maintain light drinking over time typically have the same outcomes as people who are abstinent and asserted that recovery is the goal of NIAAA’s pharmaceutical program. Dr. Krystal commended NIAAA staff for their work with FDA and the pharmaceutical companies. He suggested identifying opportunities regarding novel drugs that are under development for other indications and that might be brought productively into the alcoholism field. Dr. Warren concurred with the need to continue efforts in this area.
Gen. Dean commended NIAAA for its innovative, in-depth efforts to disseminate and translate research into communities across America, and for its increased interest in community-based participatory research, which brings research to the community level and also increases the number of advocates who have a positive effect by educating their elected officials.
Dr. John Allen inquired about NIAAA’s participation in research that focuses on the needs of veterans and returning active-duty service members. Dr. Warren responded that NIAAA has engaged in dialogue with both NIDA and DoD and is currently contemplating whether to partner with NIDA in its forthcoming initiative or to develop a separate alcohol-specific announcement, or both. While alcohol is not a problem in theater, it becomes a major problem upon a service member’s return. NIAAA couples this issue with the issue of traumatic brain injury and posttraumatic stress disorder (PTSD). Dr. Willenbring added that NIAAA also has been talking with the VA about possible collaboration in recognition of the nonexistent evidence base for treating the problems of brain injury, PTSD, physical disability, chronic pain, and depression, all of which commonly coexist with alcohol. The need for a long-term, basic research effort is evident on how alcohol may affect an injured brain differently from how it affects a healthy brain, as well as clinical and services research. NIAAA anticipates meeting with representatives of the Center of Excellence and working with the VA on surveillance for substance-use problems in the military. Dr. Willenbring highlighted the striking differences in the science between alcohol and drug use. In the military, one positive drug screen generates discharge. Alcohol is legal, but it is associated with traffic crashes, domestic violence, and suicide. NIAAA is engaging with potential partners to create a long-term program. In addition, NIAAA is responding to DoD’s request for immediate help to create a system to evaluate their current efforts and a strategy to implement evidence-based practices.
Ex-officio Member Reports
Dr. Allen explained that the VA has established the position of Substance Abuse Specialist on PTSD teams in every facility and stated that the VA will support NIAAA’s efforts. Dr. Warren expressed strong interest in addressing the issues with the VA. Dr. Jill Carty also expressed interest in NIAAA’s focus on veterans’ issues and stated that she will report at the next meeting on DoD activities regarding alcohol issues.
Time was allocated for public comment, but no one came forward to speak.
Dr. Warren adjourned the meeting at 2:05 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.