The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 134th meeting at 5:30 p.m. on September 18, 2013, at the Fishers Lane Conference Center in Rockville, Maryland. The Council met in closed session for a review of grant applications and a Merit Award extension. The meeting recessed at 6:37 p.m. Dr. Abraham Bautista, Director, Office of Extramural Activities, NIAAA, presided over the closed session, which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. Dr. Kenneth Warren, Acting Director, NIAAA, reconvened the Council in open session on September 19, 2013, at 9:00 a.m.

 

Council Members Present:

Andrea Barthwell, M.D.
Carol A. Casey, Ph.D.
Linda L. Chezem, J.D.
Fulton T. Crews, Ph.D.
Suzanne M. de la Monte, M.P.H., M.D.
Marianne L. Fleury
Joseph Thomas Flies-Away, J.D., M.P.A.
Andres G. Gil, Ph.D.
Kathleen Grant, Ph.D.
Paul J. Gruenewald, Ph.D.
Sarah N. Mattson-Weller, Ph.D.
Craig J. McClain, M.D.
Robert O. Messing, M.D.
Patricia E. Molina, M.D., Ph.D.
Gyongyi Szabo, M.D., Ph.D.

Chairperson: Kenneth R. Warren, Ph.D.

Executive Secretary: Abraham P. Bautista, Ph.D.

Senior Staff:

Vivian B. Faden, Ph.D.; Ralph Hingson, Sc.D., M.P.H.; Keith Lamirande; Howard Moss, M.D.; Gary Murray, Ph.D.; Antonio Noronha, Ph.D.

Other Attendees at the Open Sessions:

Approximately 50 observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

 

Call to Order and Introductions

Dr. Kenneth Warren called the open session of the 134th meeting of the Council to order at 9:00 a.m. on Thursday, September 19, 2013. He welcomed participants to the meeting, and expressed appreciation to Dr. Kathleen Grant and Dr. Gyongyi Szabo, whose tenure on the Council was ending. Council members and NIAAA senior staff introduced themselves.
 

Director’s Report

Dr. Warren highlighted key recent Institute activities, referring to the written Director’s Report.

• NIAAA budget. Dr. Warren reported that NIAAA’s Fiscal Year (FY) 2013 budget is smaller than the FY2012 budget due to an across-the-board reduction in federal spending. NIAAA’s FY2013 operating budget of $432.9 million represented a 0.6% decrease from the prior year. The legislative process for the FY2014 budget had not yet produced a budget, though the Senate appropriations subcommittee had marked up a bill with a proposed NIAAA budget of $460.8 million. A continuing resolution was anticipated.

• Dr. Warren observed that following a doubling of the National Institutes of Health (NIH) budget during the period 1998–2003, the budget since FY2003 has declined annually by a small amount. Dr. Warren also highlighted an article published in Cell (vol. 154) on July 3, 2013, describing the declining percentage of U.S. research and development in comparison with other countries, such as China, Germany, Japan and South Korea.

• NIAAA staff additions. Ms. Kathleen Tepas-Wise has joined the Office of Science Policy as NIAAA’s Legislative Coordinator, and Ms. LaToya S. Sewell joins NIAAA as a Family Nurse Practitioner for the Laboratory of Clinical and Translational Studies.

• Director’s activities. Dr. Warren’s recent activities included a visit with investigators at long-time NIAAA collaborators Rivne Diagnostic Center and Danylo Halytsky Lviv National Medical University in Lviv, Ukraine.

• Public announcements. NIAAA participates in the multi-Institute initiatives Interventions for Health Promotion and Disease Prevention in Native American Populations, and Chronic Inflammation and Age-Related Diseases.

• Communications. Dr. Warren stated that NIAAA observed International Fetal Alcohol Spectrum Disorders Awareness Day with a website post that supported the event, and a video that ran on National Organization on Fetal Alcohol Syndrome (NOFAS) and NIAAA websites. He also noted installation of a new permanent NIAAA exhibit in NIH Building 31. To discourage drinking and driving, NIAAA ran a series of billboard ads in the mid-Atlantic region that complemented NIAAA’s summer safety fact sheet.

• Media and press releases. NIAAA issued press releases on findings that endocannabinoids trigger inflammation leading to diabetes.  A separate study found that chronic alcohol exposure leads to brain adaptations that shift behavior control away from an area of the brain involved in complex decision-making and toward a region associated with habit formation.

• Staff activities/awards/honors. At the upcoming 18th annual Mark Keller Award and Lecture, Dr. Edith Sullivan was slated to discuss, “Functional Compromise and Compensation in Alcoholism: Neuropsychology Meets Neuroimaging.”

• NIAAA staff chaired many sessions at the 2013 annual meeting of the Research Society on Alcoholism.

      

National Institutes of Health and the BRAIN Initiative:
Brain Research through Advancing Innovative Neurotechnologies

Dr. Warren described the President’s new BRAIN Initiative which is being undertaken to advance knowledge on brain structure and function. The entire neuroscience community will benefit in the end from this endeavor including the science associated with alcohol and addictive disorders.  The BRAIN initiative, jointly supported by NIH, National Science Foundation (NSF), Defense Advanced Research Projects Agency (DARPA) and major private organizations will develop sophisticated tools and technology.  It is anticipated that the BRAIN initiative will lead to an unprecedented augmentation of our understanding of how the parts of the brain work together to generate patterns of activity; how the patterns translate into thoughts, behaviors, and emotions; and how that experience alters the brain’s organization. The initiative aims to accelerate development, apply innovative technologies to construct dynamic pictures of brain function, then integrate neuronal and circuit activity over time and space, and build on a growing scientific foundation in neuroscience, genetics, physics, engineering, informatics, nanoscience, chemistry, mathematics, and other fields to catalyze interdisciplinary efforts on an unprecedented scope. NIH is the lead agency for this $200 million-plus initiative.

 

Collaborative Research on Addiction at National Institutes of Health (CRAN)

Dr. Warren updated Council members on Collaborative Research on Addiction at NIH (CRAN), formerly known as functional integration. CRAN is the entity created after a decision was reached that the National Institute on Drug Abuse (NIDA), NIAAA, and the National Cancer Institute’s (NCI) tobacco program would not be merged. The CRAN Steering Committee, composed of staff members of the three agencies, guides the integration of the CRAN Coordination Committee (CCC). The CCC has met to coordinate FY2014–15 notice of funding opportunities (NOFO), joint website development (addictionresearch.nih.gov), a Joint Council meeting presentation, and other short- and long-term plans for CRAN, including training programs and evaluation. CRAN’s mission is to provide a strong collaborative framework to enable NIAAA, NIDA, and NCI to integrate resources and expertise to advance substance use, abuse, and addiction science research and public health outcomes. The allocation from each of the Institutes for CRAN activities is proportional to their substance use and addiction related activities; NIDA 70%. NIAAA 25%; NCI, 4%; and all other institutes a total of 1%.

CRAN has published two NOFOs for FY2014 for administrative supplements and revision grant applications to promote collaborative research on addiction at NIH with a focus on comorbidity-related research. The administrative supplement allows for the expansion of the parent grant’s specific aim to broaden the number of drugs in the study, while the revision application allows for the addition of a new specific aim. Dr. Warren stated that CRAN will foster more effective communication among Institute staff and will improve collaboration and knowledge exchange among diverse scientific communities. The result will be a seamless and comprehensive approach to prevention and treatment of all substance use, abuse, and addiction, and comorbidities.

 

NIAAA Preclinical Medication Development Programs

Dr. Mark Egli, Program Director in NIAAA’s Division of Neuroscience and Behavior, described how three NIAAA preclinical and medications development programs meet the goals of discovering and validating molecular targets, synthesizing and screening small molecules, and evaluating efficiency in the process of developing medications that reduce drinking and relapse. Dr. Egli explained that the Integrative Neuroscience Initiative on Alcoholism (INIA), inspired by other biomedical research efforts to examine gene expression associated with the disease state, developed standardized mouse and rat models of excessive drinking, studied gene expression in response, and identified functional gene pathways associated with this alcohol-dependence phenotype. Surprising results emerged in that the systems involved might not be thought of in relationship to alcohol dependence. To validate the targets researchers performed experimental genetic and pharmacological studies to see if altering the targets influences alcohol depression phenotypes. This process identified three functional gene pathways: neuroimmune pathways, novel ion channels, and second messenger systems.

After identifying targets, researchers have synthesized and screened small molecules for activity at these targets. NIAAA fulfills this goal by participating in the NIH Roadmap Molecular Libraries Initiative, which supports high-throughput screening, assay development projects, and probe optimization. Dr. Egli noted three screening campaigns in which NIAAA staff participated: orexin-1 receptor, CRF-2 receptor binding protein, and NPS (neuropeptide S) receptor. NPS is expressed in the amygdala, the area of anxiety and emotions in the brain that also is important in acquiring alcohol dependence. NIAAA researchers have identified a brain penetrant small molecule that acts as an antagonist on the NPS-1 receptor, shown to block ethanol-induced ERK phosphorylation in the central amygdala and reduce alcohol self-administration.

NIAAA’s preclinical Medication Efficacy Testing Program encourages pharmaceutical companies’ collaboration in developing treatment for alcoholism. The program aims to provide initial efficacy testing, using blind testing under standardized conditions, to help companies decide whether or not to pursue and commit to further development of their compounds for alcohol dependence. To accommodate the pharmaceutical industry’s need for fast decisions, NIAAA has developed and validated simple mouse and rat models of excessive voluntary ethanol intake that capture the diverse range of biological influences on alcohol dependence. Companies have invested considerable funds in proprietary compounds; contracts have intellectual property protections and allow NIAAA to provide initial information on efficacy in tests related to alcohol dependence. This research has generated both positive and negative control compounds. About one third of the proprietary compounds tested were provided by NIDA’s pre-clinical development program. The ability to test compounds for multiple indications is attractive to industry partners and has permitted both NIAAA and NIDA to attract and obtain more compounds. Seven compounds have shown positive effects to date.

NIAAA-funded Integrative Neuroscience Initiative on Alcoholism (INIA)’s four projects are dedicated to efficacy testing of drugs discovered by the consortium that act on neuroimmune targets, with priority given to drugs clinically approved for humans. If positive outcomes are observed, drugs can move more quickly into human or laboratory testing. This coordinated effort permits gathering much information quickly and can accelerate decisions about future directions.

A number of NIH programs address NIAAA’s goals in preclinical medication development. These include the NIH Neuroscience Blueprint Neurotherapeutics Network (NBNN) and NIH’s National Center for the Advancing Translational Sciences (NCATS) Bridging Interventional Development Gaps (BrIDGs). NBNN deals with neuroscience projects, while BrIDGs focuses on the expensive aspect of research in which toxicity and pharmacokinetic studies are performed prior to the submission of an investigational new drug application to FDA. The new Library of Integrated Network-Based Cellular Signatures (LINCS) program aims to develop a library of molecular signatures by examining responses of a variety of human cells to a number of perturbants, including ethanol, to offer clues to important molecular targets and to serve as pharmacotherapy for alcohol dependence.

Dr. Egli noted the field’s need to develop ex vivo brain tissue platforms that would enable researchers to discriminate effective from ineffective compounds. A greater number of compounds could be tested, and more rapidly, because smaller quantities of compounds would be required. Growth of this program will generate greater need for infrastructure support to obtain and distribute compounds to labs.

Discussion. To a question from Dr. Grant, Dr. Egli responded that the contracts for this effort are solicited in traditional ways. Dr. Egli replied to Dr. Robert Messing that many compounds are at fairly late stages of development for other uses and have considerable safety data. The program focuses on the pathway to commercialization, does not preclude developing a compound that has not yet passed through the valley of death, and resists being overly prescriptive. Dr. Fulton Crews commended choosing drugs that translate easily into human use and observed value in partnering with other Institutes. Dr. Egli responded that NIAAA plans to reach out to other Institutes, including NIDA and the Aging Institute.

 

Center for Scientific Review: Update

Dr. Richard Nakamura, Director, Center for Scientific Review (CSR), NIH, explained that peer review aims to ensure that NIH grant applications receive fair, independent, expert, and timely reviews, free from inappropriate influences, to enable NIH to fund the most promising research. In 2012 CSR reviewed 40% of NIAAA’s 522 grant applications. Under the NIH review process, primary investigators initiate grant applications, in response to notice of funding opportunities. Peer review constitutes the first level of review in study sections at either CSR or within the Institutes and Centers (ICs), which derive scores and percentiles. Applications proceed to ICs for second-level review by national advisory councils before awards can be made by the appropriate ICs. Outcomes and progress of the research are documented in publications, and investigators later submit new applications to build upon their previously funded research. CSR receives 85,000 applications and reviews 58,000 annually; the rest are reviewed by ICs. Annually CSR uses 16,000 reviewers and 230 scientific review officers (SROs), and conducts 1,465 review meetings.

NIH’s grant success rate has declined from 40% in 1979 to an estimated 16% in 2013, in part due to a 25% increase in the number of applications submitted.

Recent CSR review issues include concerns about the meanings of descriptors for the 1–9 scoring chart introduced in 2009. The scoring system was adjusted in 2013; for an application to reach the highest level, reviewers must describe great strengths before they consider weaknesses. Reviewers also are reminded that “5” is a good medium-impact score, not the worst score as in the previous scoring regime, and that reviewers should use the entire range of scores to differentiate quality. CSR also studied the distribution of preliminary scores and found the general sense among scientists that applications are better than average. In looking at actual scores after discussion, it is apparent that more than 5% of all scores are “20,” meaning that a significant portion of scores are seen as tied within study sections. CSR is working with study section chairs to help them get a sense of whether or not many of the scores of 20 reflect opinion or discern which are slightly better or worse to enable staff and councils’ consideration.

Dr. Nakamura explained that Ginther and colleagues (2011, Science 333:1015-1019) found major differences between scores earned on applications by African American scientists and other scientists that have resulted in significant award disparities. Applications from African Americans were 10% less likely to receive NIH funding compared to applications from Caucasians, raising the possibility of bias in peer review and a cumulative disadvantage for African Americans. Looking at the statistics another way, African American scientists receive 55% of the awards that would be expected to be awarded to white scientists. NIH Director Francis Collins has placed a high priority on eliminating disparity. To increase diversity on study sections, CSR has doubled the number of African American members and will implement a $3–4 million series of studies to understand the causes. CSR has been advising review panels and advisory councils about the situation. CSR also has initiated an early career reviewer program by training and placing on study sections more than 1,000 new early-career independent scientists, including approximately 30% underrepresented minority scientists, under the watchful eye of SROs and study section chairs.

CSR’s efforts to recruit the best reviewers involve consideration of academic rank in seeking a mix of 70% full professors for standing members, 25% associate professors, and a lower number of assistant professors. One meeting annually takes place in a city outside the Washington, DC, area to facilitate attendance, and CSR is developing new review platforms, such as video-assisted reviews and possibly all-electronic reviews. CSR has expanded no submission deadlines for chartered members of study sections and frequent reviewers, and provided flexible time for reviewers. Despite the difficult recent economic environment and reduced success rates, virtually no resignations have been submitted to study sections.

Dr. Nakamura stated that CSR’s goals are to perform the highest-quality peer review involving a focus on developing quality measures, accuracy of referrals, and evaluations of peer review; to conduct peer review as efficiently as possible; to implement controlled experiments to improve peer review quality; and to understand award disparities.

Discussion. In response to a question from Dr. Crews, Dr. Nakamura stated that though demographic information on applicants is separated from applications prior to review, consultants often personally know the applicants and their relative prominence in the field. The gap in preparation for a research career is consistent among the nation’s research institutions. He commented on the disturbing finding that African American scientists get worse impact scores than white scientists when controlling for criterion scores. Dr. Nakamura asserted that NIH is determined to understand the causal relationships.

Dr. Nakamura responded to Dr. Patricia Molina’s question that CSR has encouraged out-of-range scoring in pre-review discussions to avoid the harm of over-compression of scores and that CSR also is working to proselytize this approach across ICs. CSR proposes to conduct ranking studies following initial scoring to learn if that strategy helps reviewers get a better sense of better and worse applications. The SRO and chair would need to convince reviewers that they have permission to vote a bit out of range.

Dr. Crews pointed out the difficulty in recognizing good quality when reviewers read only a small number of applications. Dr. Nakamura responded that the goal is 9.5 applications per reviewer, and that chairs and SROs offer feedback before and after the review meeting. CSR may start providing feedback to individual reviewers about their scoring patterns. Low success rates make it difficult to enable reviewers to feel that they select the top half of the top third of applications.

Dr. Andrea Barthwell offered observations on addressing bias gained from her personal experience on a study section. Dr. Barthwell explained that a scientist at an HBCU (Historically Black College or University) who lacks institutional support is at a disadvantage compared to someone from a majority university. An HBCU scientist with a heavy teaching load typically has neither experience with study groups nor support from anyone in that culture to help write for a grant application. Individuals at HBCUs may be willing to sacrifice their careers for the greater good of the African American community.  Dr. Barthwell asserted that HBCUs often lack the necessary resources, and as a result, applicants from these institutions are penalized. However, if people do not begin doing research at those institutions, no culture of research will grow there. Dr. Barthwell also saw bias against the narrow focus that African Americans might bring to the research experience. Reviewers may not understand the motivation or a topic may not interest them. She also cautioned CSR that people brought in under special status may have a lesser voice, and that strategy may not have the desired impact.

 

Consideration of the June 12–13, 2013, Meeting Minutes and Future Meeting Dates

Council members unanimously approved the minutes of the NIAAA Council meeting held June 12–13, 2013. NIAAA plans future Council meetings for February 4–6, 2014, including a Joint NIAAA/NIDA (and possibly NCI) meeting on February 5, 2014; June 4–5, 2014; September 10–11, 2014; February 4–5, 2015 (NIAAA and Joint NIAAA/NIDA); June 10–11, 2015, and September 16–17, 2015; February 3–4, 2016 (NIAAA and Joint NIAAA/NIDA), June 8–9, 2016 and September 14–15, 2016.

NIH AIDS Research: Planning, Priority Setting, and Budget Development

Dr. Robert Eisinger, Director, Scientific and Program Operations, Office of AIDS Research (OAR), NIH, explained that the NIH AIDS Research Program incorporates biomedical, behavioral, and social science research on HIV and its complications. All NIH ICs sponsor AIDS research, coordinated by OAR since 1988 under a legislative mandate to develop an annual strategic plan and trans-NIH budget linked to that plan. OAR conducts trans-NIH coordination, management, and evaluation activities.

In OAR’s strategic planning process, a trans-NIH coordinating committee, NIH IC personnel, and a diverse group of stakeholders update the prior year’s plan to reflect new scientific findings, gaps, scientific needs, opportunities in the field, and priorities specific to each IC, and the OAR Advisory Council identifies overarching scientific priorities. The plan informs the scientific community, public, and AIDS-affected communities about the trans-NIH research agenda, frames development of the budget, and determines the use of dollars. The plan also serves as the basis for tracking and monitoring expenditures. Aligned with the President’s national HIV/AIDS research strategy, the plan covers basic research, reducing new infections, improving disease outcomes for HIV-infected individuals, reducing HIV-related disparities, and translating research from bench to bedside to community. Overarching priorities in the FY2013 plan focus on strong basic science; prevention research, including development of vaccines, microbicides, and behavioral interventions; and research toward a cure for HIV and AIDS. Objectives in behavioral and social science research include preventive intervention research, basic behavioral and social science research, consequences of HIV infection, and research methodology. The behavioral and social science research portfolio includes adherence/‌‌compliance/retention in care; stigma, discrimination, poverty, and criminal justice; neurocognitive complications; and drug and alcohol use and drug interactions.

To formulate the annual budget, all ICs submit their new and expanded program initiatives for each area of the scientific plan. OAR scientific staff review these initiatives, working closely with ICs, and the budget is developed in consultation between the OAR and NIH Directors. Upon budget approval or a continuing resolution, OAR allocates budget levels to each IC based on program initiatives. The President’s budget request for FY2014 is approximately $3.1 billion, or approximately 10% of the total NIH budget. The NIAAA budget is approximately $28-29 million. Development of microbicides, vaccines, and behavioral and social service research are priorities of the NIH AIDS Program, but the current economy necessitates holding funding constant for therapeutics and reducing funding to investigate natural history and epidemiology.

OAR manages and coordinates the NIH AIDS program across ICs, including trans-Institute programs, managing multi-Institute research, fostering research through designated funds and targeted workshops, and supporting domestic and international initiatives as pilot funding or seed money. Guided by the strategic plan to track all AIDS dollars, ICs code all NIH-funded projects, contracts, and grants to the plan’s objectives, and an OAR database makes data available internally and to the public, searchable by project.

Dr. Eisinger reported that OAR shifts AIDS research program priorities and resources to meet the changing epidemic and scientific opportunities. The investment in AIDS research has produced critical scientific advances and also has assisted in the prevention and treatment of other important diseases.

Discussion. Dr. Eisinger replied to questions from Dr. Warren that several sites managed by the Centers for AIDS Research (CFAR) include alcohol investigators. While Clinical Trials Networks focus on evaluation of prevention or treatment strategies, CFARs serve as infrastructure for administrative and core services when a number of NIH-funded AIDS researchers work at the same university or groups of centers. Research on medications compliance/adherence, alcoholism, and binge drinking will continue as significant priorities.

Dr. Craig McClain noted that alcohol-related issues affect HIV/AIDS in a number of ways and advocated for research funding. Dr. Eisinger stated that each Institute submits its initiatives, and OAR makes funding decisions based on the priorities of the scientific plan.

Dr. Molina asserted that since HIV has become a chronic disease, the impact of chronic alcohol use will be more significant than intravenous drug use in overall longevity, quality of life, and cost of health care. Judge Linda Chezem added that chronic alcohol use and adherence to anti-retroviral therapy are serious problems in rural areas that lack intervention services. Dr. Eisinger stated that the Centers for Disease Control and Prevention’s (CDC) finding of an increasing HIV epidemic in the rural South and other rural communities indicates the need to develop and implement prevention and treatment strategies. OAR is working with the Institutes to develop, test, and implement rural approaches. Dr. Grant added that chronic alcohol consumption will affect the efficacy of any vaccine development funded or planned.

 

Initiative to Enhance Reproducibility and Transparency of Research Findings

Dr. Howard Moss, Associate Director for Clinical and Translational Research, NIAAA, described the NIH-wide Initiative to Enhance Reproducibility and Transparency of Research Findings, an effort to address the problem of lack of untrue findings, particularly in preclinical research. In a controversial 2005 paper written by Ioannides, JPA entitled “Why Most Published Research Findings are False” (Public Library of Science (PLoS) Medicine, 2(8); e124), analysis of mathematical models shows that failure to take into account such factors as prior probability, a finding being true or not. This diminishes the likelihood that published findings are correct. Corollaries of the main premise are that the probability of untrue findings rises with the smaller studies conducted; the smaller the effect sizes; the greater the number and lesser selection of tested relationships in a scientific field; the greater the flexibility in design definition, outcomes, and analytical modes in a scientific field; the greater the financial and other interests and biases; and the hotter the scientific field.

Following up on Ioannides article, Moonsinghe and colleagues (2007, PLoS Medicine 4(2);e28) demonstrated that the replication of research findings enhances the positive predictive value of original research findings and thereby bolsters inferences of the original finding being true. This issue has received considerable attention in the press recognizing that scientists publish findings from large epidemiological studies about safety and health that sometimes conflict with each other. NIH believes this problem undermines its credibility as a major scientific biomedical influence. Another paper from the Bayer Health Care (Prinz, Schlange, & Asadullah, 2011 Nature Reviews-Drug Discovery 10; 712) raised concerns from many NIH science administrators. The Bayer Health Care tried to replicate 67 published studies identifying druggable molecular targets for a variety of diseases. The company’s in-house researchers could replicate only one third of them and could not confirm they were valid targets.

Some ICs have mounted internal efforts to increase the quality of the science, and an ad hoc group of Institute directors has addressed the issue and brought their consensus concepts to the NIH Director. IC directors have devised next steps to enhance reproducibility through a formal initiative that involves three trans-NIH activities. All ICs and Office of the Director’s (OD) offices will discuss reproducibility and transparency in research findings with their stakeholder communities to alert them and solicit feedback. Office of Intramural Research (OIR-OD) will create and pilot a new module on research integrity related to experimental bias and study designs as part of required ethics training for all intramural fellows. Once tested, OIR will post the module on the web and encourage adoption or equivalent by extramural training programs and fellow trainees.

Every IC has been asked to develop a pilot program to address the lack-of-reproducibility issue. NIAAA intends to issue a new NOFO soliciting U01 cooperative agreement grant applications to conduct replication studies of key single-site, proof-of-concept clinical trials of a behavioral or pharmacological nature. Targets include alcohol use disorders and alcohol-associated organ damage. The initiative sets forth specific definitions and standards of replication. Interesting problems are anticipated at the review level, since innovation typically is important in scoring grants but in this instance investigators are asked to copy. Dr. Moss stated that the NIH Director is interested in each Council’s response to this initiative.

Discussion. Dr. Suzanne de la Monte cautioned against assuming lack of ethics on the issue, noting that considerable variability exists across platforms. She stated that studies often use multiple validation methods that enable confidence in the results and observed the need for a better way to quantify animal studies. Dr. Warren responded that broaching this topic during the ethics segment of training sessions does not imply deliberate lack of ethics, and he emphasized the importance of awareness of bias.

Responding to Dr. McClain’s question, Dr. Moss stated that NIAAA will request high-impact, investigator-initiated applications.

Dr. Crews observed that researchers may use different methods, but call them by the same name and consequently generate different results. His institution plans to write standard operating procedures for methods previously thought to be standardized. He added that large site effects may influence results, that replication should be implemented across sites, and that NIAAA might investigate a database related to multisite trials. Dr. Crews commented that unknown factors also may influence results and whether or not results are reproduced, the field is making progress. Dr. Mattson stated that differences in site and standard operating procedures are important, and it is important to understand why they are different.

Dr. Messing volunteered to participate in a discussion group on this topic. He suggested that applicants describe not just limitations in designing a replication, but also parameters for flexibility. Dr. Grant asserted the need to understand the underlying factors in failure to replicate.

 

FDA-NIH Partnership on Tobacco Regulatory Science

Dr. Cathy L. Backinger, Deputy Director for Research, Office of Science, Center for Tobacco Products (CTP), Food and Drug Administration (FDA), described the FDA-NIH partnership on tobacco regulatory science. FDA has authority over the manufacture, marketing, and distribution of tobacco products intended for human consumption, including cigarettes and roll-your-own and smokeless tobacco products. FDA plans to propose a rule to bring e-cigarettes, cigars, pipe tobacco, and tobacco for hookah smoking also under its jurisdiction. Funded by user fees from tobacco company assessments, CTP has a $513 million budget for FY2013.

Dr. Backinger explained that CTP aims to prevent Americans, especially youth, from initiating tobacco use; to encourage current users to quit; and to decrease the harms of tobacco product use. The Tobacco Control Act mandates regulation using a population health standard that reflects impact for both users and nonusers of tobacco products. CTP reviews pre-market applications for new and modified risk tobacco products, requires companies to test and report levels of harmful and potentially harmful constituents by brand and sub-brand, sets tobacco product standards, implements health warnings on cigarettes and smokeless tobacco products and ads, implements advertising and promotion restrictions, requires the industry to provide a list of all ingredients in all tobacco products, and conducts research to support FDA authorities. CTP cannot set tax rates for tobacco products, regulate therapeutic products, set clean indoor air policies, regulate tobacco growing, require reduction of nicotine yields to zero, or provide cessation services. FDA uses its regulatory authority to understand the regulated products, control product changes that affect public health, prohibit false and misleading claims that state or imply reduced risk, decrease the harms of tobacco products, expand the science base, restrict marketing and distribution to protect public health, ensure industry compliance, and educate public about FDA’s regulatory actions and harms caused by tobacco products.

The FDA Office of Science’s more than 150 employees work in a wide range of scientific areas related to tobacco products, tobacco users, and populations, and each contributes knowledge in the evaluation of product applications or regulations. Dr. Backinger explained that tobacco regulatory science ensures that scientifically valid techniques, tools, and models are available to evaluate products and to inform regulatory actions. CTP’s regulatory authorities include preventing youth access, advertising restrictions, information dissemination/health warnings, public education campaigns, product standards, and new and modified-risk tobacco products.

FDA/CTP’s large research program collaborates with NIH, CDC, FDA’s National Center for Toxicological Research, and outside organizations with needed expertise. The Joint NIH-FDA Leadership Council for Regulatory Science was established in 2010, and the Tobacco Regulatory Science Program (TRSP) was established in 2013, capitalizing on FDA’s expertise and resources, and NIH’s expertise in tobacco research and infrastructure for receipt, review, and administration. TRSP allows research implemented in tobacco regulatory science and provides new funding opportunities. Located within the Office of the Director (OD, NIH, TRSP coordinates trans-NIH extra- and intramural collaboration activities with CTP; serves as a resource for IC program, review, budget, and grants management; with input from FDA and NIH staff, prepares NOFOs, screens applications for responsiveness, arranges for scientific review, ensures special terms are met, monitors progress, schedules meetings, and monitors CTP-related expenditures. NIH ICs serve as TRSP’s face to the extramural community, to participate in the development of notice of funding opportunities (NOFO), plan and organize grantee meetings, respond directly to investigator inquiries and communicate with TRSP staff for clarification.

Highlights of the partnership include 44 projects, eight intramural projects, and an NOFO for P30 revision applications. This includes, the Population Assessment of Tobacco and Health (PATH) Study contract, which is a large, national, longitudinal cohort study of tobacco use and health in the United States. PATH will collect data from adults, youth, and parents, and biospecimens from adults. One of its aims is to identify and explain differences and changes in tobacco use patterns and risk perceptions with changing regulatory actions. The PATH Study will characterize the natural history of tobacco dependence, cessation, and relapse, and assess health conditions related to tobacco use; assess associations between CTP-specific actions and tobacco product use, risk perceptions, attitudes, use patterns, and cessation outcomes; assess changes over time; compare former and newer users for changes in relapse, uptake, risk perceptions, and indicators of tobacco exposure and disease processes. CTP will use data to launch small-scale research studies that focus on new and emerging tobacco-related behavior, attitudes, and health issues. Baseline data collection began in September, 2013. Dr. Backinger announced that NIH awarded $54 million in September, 2013 for TCORS-supported grants for multidisciplinary research. The 14 P50 grants will fund developmental and pilot research and research training, and will require collaboration across grantees and data harmonization. CTP’s website address is prevention.nih.gov/tobacco.

Discussion. Dr. Backinger noted that the FDA’s authorities place certain constraints on the types of research CTP can fund. Dr. Backinger responded to Dr. de la Monte that though FDA’s tobacco authorities do not extend to other countries, the science developed in the United States is expected to have ramifications elsewhere. To Dr. McClain’s question about future plans, Dr. Backinger replied that CTP will evaluate the research process prior to issuing more NOFOs.

 

Council Member Round Table

In response to a question from Dr. Grant, Dr. Warren stated that the extent of Institutes’ financial involvement in CRAN is based on past history of activities funded for addictions. CRAN currently is not a mechanism for research of comorbidities with mental disorders, though it might in the future. NIAAA and NIDA currently have significant interests in the addictive aspects of obesity research, and the opportunity exists in CRAN to invite NIMH’s or National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)’s obesity program, or both, to collaborate.

Council members joined Dr. Barthwell in thanking Dr. Warren for his service and leadership during his tenure as Acting Director of NIAAA.

 

Public Comment

Ms. Pamela Walters, Al-Anon Family Groups, explained that Al-Anon provides help to friends and families of alcoholics through peer support meetings worldwide. She drew attention to Al-Anon’s public outreach magazine, which includes stories from members about how Al-Anon help and articles from professionals about Al-Anon’s compatibility with counseling.

Dr. Kenneth Litwak, Physicians Committee for Responsible Medicine, urged NIAAA to rethink the role of animals in research and to focus instead on human-based prevention, education, and treatment paradigms. Examples include exploring the link between combat-acquired traumatic brain injury and drinking behaviors to inform future intervention practices, or development of innovative, computer-based alcohol prevention curricula for middle-school students.

Mr. Clay Rittenhouse, Alcoholics Anonymous, described new CDs and DVDs for alcoholics with special needs that present stories of how members of that population have been accepted into AA membership. AA has also added new stories to its pamphlets targeted to the armed services and correctional treatment facilities.

 

Adjournment The meeting adjourned at 12:45 p.m.

 

CERTIFICATION

I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.

/s/

Kenneth R Warren, Ph.D.
Acting Director, National Institute on Alcohol Abuse and Alcoholism
and
Chairperson, National Advisory Council on Alcohol Abuse and Alcoholism

/s/

Abraham P. Bautista, Ph.D.
Director, Office of Extramural Activities
and
Executive Secretary, National Advisory Council on Alcohol Abuse and Alcoholism