RESEARCH ON ALCOHOL-RELATED HIV/AIDS IN WOMEN RELEASE DATE: October 30, 2002 RFA: AA-03-004 National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov) LETTER OF INTENT RECEIPT DATE: December 13, 2002 APPLICATION RECEIPT DATE: January 13, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute on Alcohol Abuse and Alcoholism (NIAAA) seeks applications to support research to identify and characterize the role of alcohol, drinking behaviors, and drinking environments in the epidemiology and natural history, pathogenesis, prevention, treatment and control of HIV/AIDS among women. The number of women with HIV infection and AIDS has been increasing steadily worldwide. According to the World Health Organization (WHO), approximately 16 million women are living with HIV/AIDS worldwide, accounting for 46 percent of the 32.4 million adults living with HIV/AIDS. As HIV/AIDS research becomes more focused, there is growing evidence that alcohol consumption may play an important role in sexual transmission, susceptibility to infection, and progression of HIV disease among women. In addition, alcohol use, abuse, and dependence among women may have a significant impact on the occurrence and course of comorbid conditions such as HCV, oral and esophageal candidiasis and TB, pregnancy and birth outcomes, adherence to medications and provider advice, provider and patient attitudes towards treatment, and survival. The goal of this Program Announcement is to encourage multidisciplinary, interdisciplinary, and collaborative studies that focus on a range of epidemiologic and intervention issues within HIV and alcohol among women. It advances research goals set forth in the NIH Fiscal Year 2003 Plan for HIV-Related Research. Relevant objectives identified in the plan include: - Characterize the relative importance of alcohol use in the acquisition and subsequent transmission of HIV in order to identify and apply appropriate alcohol use interventions as public health measures. - Investigate the social and environmental factors that contribute to HIV infection, behaviors after infection, and co-occurring conditions (e.g., substance use, mental illness, homelessness, hepatitis, STDs, tuberculosis), including the causes and implications of stigma. Special emphasis will be given to research which examines the effectiveness of interventions that extend beyond the level of the individual woman, with the aim of bringing all of the resources of a given community to bear on the twin epidemics of alcohol and other substance abuse and HIV/AIDS. Such research will encompass secondary analysis of existing data sets from studies of HIV/AIDS among women. The community-level focus of this RFA is, in turn, consistent with goals articulated by the international AIDS research community in its attempt to stem the spread of HIV/AIDS in resource poor areas of the world. With increasing knowledge of the dimensions of the HIV epidemic in parts of Asia and Africa has come heightened awareness of the critical importance of involving community members as equal partners in every aspect of the research process. This Request for Applications is intended to appeal to a broad audience of alcohol and HIV/AIDS researchers, including alcohol researchers with no prior experience in HIV/AIDS research, but with a keen appreciation for the relationship between problem drinking and HIV/AIDS and a strong interest in acquiring such experience; HIV/AIDS researchers with no prior alcohol research experience who realize the importance of more intensive alcohol interventions to improving clinical outcomes among HIV+ women; and those with prior research experience in the area of co- occurring HIV/AIDS and alcohol and other substance abuse. Given the breadth of research objectives included in this announcement, potential applicants are encouraged to carefully review all sections of the announcement for research opportunities. RESEARCH OBJECTIVES Background Information In the United States, the proportion of reported U.S. AIDS cases occurring among women increased from 7 percent to 23 percent from 1985 to 1998. The proportion remained at 23 percent in 1999, possibly reflecting the success of antiretroviral therapies in preventing the development of AIDS. Nonetheless, in 1999 more than 8,000 new cases of AIDS were reported among adolescent and adult women between 13 and 24 years of age and nearly 7,000 new cases were reported in women between the ages of 24 and 29. According the U.S. Surgeon General, "The epidemic has evolved from one centered on white gay men to one increasingly impacting people of color, women and the young." Women aged 45-64 and 65 and older are also increasingly being diagnosed with HIV infection. As of December 1999, women in these age groups accounted for 10 percent of the female cases. HIV infection disproportionately affects African American and Hispanic women. Together they represent less than 25 percent of all U.S. women, yet they account for more than 77 percent of AIDS cases in women. HIV/AIDS is now the third leading cause of death among women ages 25 to 44 and the leading cause of death among African American women in this age group. There is a strong association between the abuse of alcohol and other substances and the acquisition and progression of HIV/AIDS among women. National Institute on Allergy and Infectious Disease-sponsored cohort studies in the U. S. have found that factors associated with an increased risk of heterosexual HIV transmission include alcohol use, history of childhood sexual abuse, current domestic abuse, and use of crack/cocaine. As HIV/AIDS research becomes more focused, there is growing evidence that alcohol consumption may play an important role not only in sexual transmission and susceptibility to infection among women, but in the occurrence and course of comorbid conditions such as HCV, and TB, adherence to medications and provider advice, provider and patient attitudes towards treatment, and survival. Recent evidence has indicated that there are interactive effects of alcohol use and HIV infection on brain functioning and cognitive processes in both men and women which may affect judgment regarding high risk behaviors, as well as adherence to complex HIV medication regimens and to physician advice. Increased levels of alcohol consumption have also been associated with diminished immune function, as evidenced by reduced levels of CD4 and CD8 activity. However, many questions about the relationship between alcohol consumption and increased susceptibility to HIV infection, accelerated progression to AIDS, and accelerated course of the disease among women remain unanswered. For example, there is a need for more information about the extent to which these alcohol-related effects vary between women and men, and on the role of confounding factors such as HIV strain variations, varying patterns of adherence to HIV medications, and comorbid mental and somatic illnesses and environmental stresses. Of particular interest with regard to the unique physiology of women is the impact of alcohol on the course of HIV infection in pregnancy, and possible gender-based differences in the occurrence and course of liver disease, among other topics. It is therefore of continuing importance to conduct research which seeks to clarify the role of alcohol in HIV transmission and disease progression among women, and to develop and test preventive interventions which both reduce the risk of alcohol-related HIV transmission among women and improve the treatment of HIV-infected women with co-occurring alcohol abuse/dependence. The complex and global nature of unresolved questions surrounding alcohol and HIV/AIDS relationships among women indicates the need for a multidisciplinary approach to research. Investigators representing a broad array of academic disciplines and engaged in cross-cutting fields of science are encouraged to consider designing hypotheses-driven studies that utilize rigorous methodologies from epidemiological, basic, clinical, and behavioral research. Special emphasis areas include: 1. Epidemiology and Natural History of Alcohol Use and HIV/AIDS: Improved understanding of the epidemiology of alcohol use, abuse, and dependence in relationship to HIV/AIDS among women will help to identify high-risk groups and promote development of effective HIV prevention and treatment efforts, including medical management of HIV/AIDS disease among women. There is a need for basic epidemiologic research to strengthen understanding of the determinants, processes, and cultural and contextual issues influencing HIV-related risk and protective behaviors. For example, studies are needed to: - Gain insight into the alcohol – HIV/AIDS relationship among women through population-based research on alcohol consumption patterns of groups of women at risk for HIV infection, including women 65 and older. - Identify and model the impact of alcohol consumption patterns on the spread of HIV infection and associated opportunistic infections among women of all ages over time. - Develop and test models analyzing the complex interrelationships between women's sexual/physical victimization and subsequent alcohol consumption and involvement in HIV-risky sexual behaviors. - Examine the impact of alcohol use on sexual risk behaviors among women. - Examine patterns of HIV infection and variability in strains of HIV in heavy drinking women both in the U.S. and abroad to guide vaccine development. - Characterize alcohol use and alcohol use disorders in high-risk women with HIV/AIDS, including those with co-occurring medical and psychiatric conditions and those who are medically underserved and difficult to reach. - Describe more fully the role of gender in the intersection of alcohol and HIV/AIDS epidemics. - Examine the impact of alcohol-related public policies, including those affecting legal and illegal (particularly in foreign settings) alcohol production, access, taxation, etc., on the spread of HIV and other STDS among women. 2. Prevention of HIV Risk Behaviors Related to Alcohol: Behavioral, affective, and cognitive factors affect the risk for HIV infection and the efficacy of HIV prevention and treatment among women who use and abuse alcohol. Models should be developed for interrelating these individual factors with contextual and social factors that influence alcohol misuse, sexual risk-taking, and other HIV risk behaviors. Development and testing of new interventions are needed at various levels, including: individual, dyadic, social network, organizational, and community. The following areas are suggested and not exclusive: - Target and retain the highest risk women drinkers (including those from difficult-to-reach, underserved populations) in HIV/STD prevention and treatment interventions — including trials for prophylactic vaccines. - Develop community-based interventions, e.g., bar-based server training, to alter alcohol availability among women and to improve linkage of alcohol and HIV preventive services. - Develop school-based interventions targeting young women, including middle school, high school, and college curricula focusing on the relationship between alcohol-related sexual risk behaviors and HIV/AIDS. - Assess ways in which membership in social organizations or less formal networks may reduce women's HIV/STD vulnerability, and develop and test interventions that build upon these insights. - Develop and test prevention programs that reduce young women's vulnerability to alcohol-related sexual assault and HIV/STD infection. - Motivate women drinkers—including those who perceive themselves to be at low risk for HIV infection—to decrease risky sexual and substance use behaviors. - Assess the relationship of alcohol consumption, alcohol-related sexual expectancies, social norms, and decision-making on HIV risk behaviors among women of all ages. - Develop and test preventive interventions for women based on social dynamics and environmental characteristics of high-risk alcohol-related settings and situations (e.g., bars, parties, neighborhoods with a high density of drinking outlets, etc.). - Develop and test family and peer group interventions to reduce alcohol use, unsafe behavior and exposure to co-occurring risks such as violence, poor health care and disease among women. - Improve methods for assessing and analyzing complex relationships between alcohol use and abuse, psychological, and environmental factors, including alcohol regulations and policies, and HIV-related risk behaviors among women. 3. Medical Aspects of Treatment Among HIV-Positive Individuals with Alcohol Use Disorders: Alcohol use may be a key determinant in disease transmission and progression, adherence and response to therapeutic regimens, among other effects on women. Still many questions remain unanswered with regard to how the co-occurrence of HIV/AIDS and alcohol abuse/dependence currently influences clinical decision making, and how provider practices could be modified to improve clinical outcomes among women. Research is needed to determine whether and how alcohol affects disease progression in various organ systems in HIV+ women; to develop and evaluate pharmacological interventions for the treatment of alcohol dependence in HIV+ women; to guide the development of HIV treatment regimens tailored to the needs of women with coexisting alcohol abuse/dependence; and to improve motivation for treatment and adherence to treatment among women. Specifically research efforts are needed to: - Develop and test therapeutic regimens for women which are based on a)drug-drug interactions between alcohol and antiretroviral medications; b)changes in drug metabolism in women with alcohol-related liver dysfunction and other physiologic impairments; c)results of testing for drug resistance; and d)lifestyle factors in heavy drinking women (e.g., structured treatment interruptions, salvage therapies, etc.). Examine effects of drug sequence on occurrence and course of liver and other organ dysfunction. - Compare the efficacy of various pharmacological interventions for the treatment of alcohol dependence (e.g. Naltrexone) in HIV+ women. - Advance understanding of the dynamics between alcohol use and abuse and adherence to HIV therapeutic regimens among women, and test strategies to improve compliance. - Investigate mechanisms by which alcohol consumption affects liver disease progression in women with HIV, including those coinfected with hepatitis C (HCV), to improve clinical outcomes in heavy drinking women. - Improve guidelines for prophylaxis and treatment of opportunistic infections among women by examining the relationship between alcohol- related host defense impairment and the emergence and course of disease caused by pathogens such as M. tuberculosis, S. pneumoniae, P. carinii, HCV, and candida. - Investigate impact of alcohol on HIV-specific complications among women, including neuropathogenesis and pathogenic processes involved in AIDS dementia and peripheral neuropathy; cardiomyopathy; enteropathy and wasting; oral, gastrointestinal, and genital candidiasis, among other conditions. Determine whether and how hormonal status of women affects the occurrence and course of HIV-specific complications. - Study the impact of alcohol on fat redistribution and other aspects of fat, protein, and carbohydrate metabolism and nutrition in women with HIV/AIDS. Examine influence of hormonal status on fat distribution, metabolism and nutrition in heavy drinking women with HIV/AIDS. - Enhance linkage of primary medical care and reproductive health care with alcohol prevention and treatment services for HIV-infected women with co-occurring alcohol misuse. - Improve medical technology for rapid diagnosis and determination of HIV genetic subtypes and drug resistance patterns in heavy drinking women. 4. Strategies to Interrupt Mother-to-Child transmission applicable to resource-rich and –poor countries: Although rates of vertical transmission of HIV in the U.S. and other resource rich areas of the world have declined dramatically since the introduction of antiretroviral regimens which prevent mother-to-child transmission, vertical transmission remains a very serious problem in resource-poor nations and among poor populations in resource-rich nations. Much remains to be learned about the role of alcohol in vertical transmission of HIV and about the role of interventions targeting women who misuse alcohol in preventing vertical transmission. Such interventions, given their relative affordability, would have particular relevance in resource-poor areas where access to effective medications may be extremely limited. Areas which require further investigation include: - Effect of alcohol on the mechanisms and timing of mother-to-child HIV transmission (in utero, intrapartum, and postpartum via breast milk), including impact of alcohol on mechanisms of protective immunity to HIV in newborns and infants. - Impact of alcohol use among pregnant women on adherence to antiretroviral regimens to prevent mother-to-child transmission. - Interactions between HIV therapeutics, alcohol, and medications used for the treatment of alcohol dependence in pregnant women. Impact of these interactions on the efficacy of antiretroviral regimens to prevent vertical transmission and implications of these interactions for the maintenance of alcohol pharmacotherapy or antiretroviral therapy. - Role of integrated alcohol prevention and treatment services, reproductive health, family planning, social services, mental health services, and pediatric health services in improving health outcomes in HIV-infected mothers and their children. 5. Multi-level Behavioral and Psychosocial Approaches to the Prevention of HIV Transmission Among Individuals Who Misuse Alcohol and to the Treatment of Individuals with Co-occurring HIV/AIDS and Alcohol Abuse/Dependence: The implementation of research-based behavioral/psychosocial interventions which will complement state-of- the-art pharmacologic interventions for the treatment of alcohol dependence in HIV+ women will be critically important to the achievement of improved clinical outcomes. Research is needed to better characterize and address the impact of behavioral and psychosocial factors on access to treatment and on drinking and HIV/AIDS outcomes among women, and to ameliorate negative behavioral, affective, physical, cognitive and social consequences of HIV infection in alcohol-using and -abusing women through multilevel interventions. Such interventions may target, separately or in combination, individual women, couples, families, treatment programs and networks of programs, and communities. Specifically, research efforts are needed to: - Integrate alcohol risk reduction goals into HIV/AIDS treatment programs which serve women, including behavioral, psychosocial, and pharmacological interventions. Evaluate effectiveness of behavioral/psychosocial interventions to help women stop drinking and avoid relapse. Develop tailored treatments as needed for special populations such as underserved minority women, pregnant women, and women with comorbid psychiatric diagnoses. - Integrate HIV risk reduction goals into alcohol abuse treatment programs which serve women, including behavioral, psychosocial, and educational interventions. Evaluate the effectiveness of HIV risk reduction strategies for women in alcohol treatment settings. Develop tailored treatments as needed for special populations such as underserved minority women, pregnant women, and women with comorbid psychiatric diagnoses. - Develop and test interventions to improve the quality of life of women with coexisting HIV/AIDS and alcohol use disorders (e.g., strategies to reduce the impact of alcohol-related consequences on social, family, vocational functioning and well-being, and on the course of AIDS-related illnesses.) - Increase knowledge of effective collaborative approaches to the organization and management of services for HIV-positive women, including adolescents, with alcohol use disorders, including analyses of barriers to access and utilization of services, and strategies to overcome them (e.g., mobile vans as a means for improving health care access by women who abuse alcohol). - Improve understanding of the relationship between alcohol use and abuse, access to care, and delivery and cost of services for infected women. 6. Biological Research on Alcohol and HIV/AIDS: Lack of knowledge on the influence of alcohol on HIV infectivity and viral replication among women is a major impediment to understanding HIV-related morbidity and mortality. Therefore, research that provides detailed knowledge of possible gender-based differences in how alcohol and HIV, each in its own way or acting in concert, usurp host defense mechanisms and enhance viral replication is urgently needed. Biological research that delineates the multiple effects of alcohol and HIV on host defense mechanisms and disease progression among women will provide a rational basis for the development of new methods of therapeutic intervention. The following topics serve to illustrate the types of research that would be responsive to this RFA: - Effects of alcohol on viral burden, immune function, and organ system dysfunction in HIV-infected women of all ages or in appropriate animal models. - Organ system changes (e.g., changes in endothelial cell permeability to HIV proteins, etc.) at the tissue, cellular, and molecular levels that may influence infectivity, viral load, disease progression and/or therapeutic response among women. - Animal models of alcohol consumption and AIDS to explore effects on HIV infectivity, cellular metabolism and immune state dynamics among women and to explore the influence of age/hormonal status on these effects. How may these effects vary pre- and post-puberty; pre- and post-menopause? - New in vitro models to characterize the effects of alcohol on the response of cellular systems to HIV among women (e.g., blood brain interface, placental interface, vaginal mucosa, etc.) - Drug-drug interactions between alcohol and antiretroviral drugs among women, including altered pharmacokinetics, metabolism and toxicity due to chronic or acute alcohol consumption. 7. Community-Based Participatory Research: Community-based participatory research in public health is a partnership approach to research that equitably involves, for example, community members, organizational representatives, and researchers in all aspects of the research process. The partners contribute their expertise and share responsibilities and ownership to enhance understanding of a given phenomenon, and to integrate the knowledge gained with action to improve the health and well-being of community members. Such research recognizes the community as a social and cultural entity with the active engagement and influence of community members in all aspects of the research process. Within the area of community-based participatory research, suggested special emphasis areas include: - Research on the characteristics of community-based organizations and coalitions most likely to be successful in implementing effective science-based interventions targeting high-risk women drinkers. - Studies which identify and evaluate outcome measures and data collection systems appropriate to the evaluation of research-based HIV prevention interventions for women in community settings. - Research on models for facilitating cooperation among research and service professionals. - Studies of the mechanisms by which institutions which serve women network with other community agents and other community institutions. When and how do such connections and collaborations improve HIV and AOD prevention efforts? When and how do they fail to do so? - Multi-level collaborative research to study patterns of communication between various sectors of society (e.g., Federal, state, and local governments, community-based service organizations, and the business community, etc.) and their impact on the delivery of prevention, intervention, and treatment services to women with coexisting HIV/AIDS and alcohol use disorders. - Programs of community-based participatory research involving U.S.- supported researchers and researchers in other nations to evaluate community-level strategies to arrest the global spread of HIV infection and its consequences among women. 8. Dissemination and Diffusion of Research Findings: Despite advances in our knowledge of effective approaches to preventing HIV infection, it is clear that information, strategies, and models for HIV prevention have not always reached community program levels. Likewise, information developed by community programs has frequently not reached or influenced HIV prevention researchers. It is extremely important that more effective collaborative relationships between the research community and the community of public organizations delivering prevention programs to high-risk women be developed in such a way that a sustainable research infrastructure is established and/or enhanced at the level of local communities. Models of technology transfer need to be developed and validated in large-scale community settings. These models must include effective training for community providers as well as ongoing assessment of what happens to research-based interventions when they are put into practice. Critical to the success of these efforts will be an awareness of the cultures in which the interventions were undertaken and ways in which existing interventions may have to be modified to be successful. Interventions which leave in place infrastructures capable of complex problem solving, program evaluation, and ongoing two-way communication with the research community should facilitate future technology transfer. Suggested areas of research include but are not limited to: - Studies that develop and test different models for transferring effective research-based HIV prevention interventions for women into relatively resource poor communities. - Studies of mechanisms that would enable community-based organizations to advise and communicate with the research community on needed research to improve responses to ongoing or emerging HIV-related issues among women. - Collaborative programs to train minority investigators to conduct clinical, biomedical, and prevention research which explores the impact of alcohol abuse on HIV transmission, disease progression, and clinical outcomes among women. MECHANISMS OF SUPPORT This RFA will use the following NIH award mechanisms: - Research projects (R 01); - Small grants (R03); - Exploratory/developmental grants (R 21); - Education projects (R 25); Applications for R01s may request support for up to 5 years. Facilities and Administrative (F&A) costs will be awarded based on the negotiated rate at the time of the award. Under the NIAAA Small Grant mechanism (R03) applicants may request either $25,000 or $50,000 in direct costs per year for up to two years. These awards are not renewable; however, a no-cost extension of up to one year may be granted to the grantee institution prior to expiration of the project period. Before completion of the R03, investigators are encouraged to seek continuing support for research through a research project grant (R01). (See Program Announcement PA-99-098, "NIAAA Small Grant Program," http://grants.nih.gov/grants/guide/pa-files/PAR- 99-098.html, for a complete description of the R03 mechanism.) NIAAA Exploratory/developmental grants (R21) are limited to 3 years for up to $100,000/year for direct costs. (See Program Announcement PA-99-131, "NIAAA Exploratory/Developmental Grant Program," http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete description of the R21 mechanism.) Exploratory/Developmental Grants and Small Grants cannot be renewed: however, a no-cost extension of up to one year may be granted prior to expiration of the project period. Investigators are encouraged to seek continued support after completing an Exploratory/Developmental Grant project or a Small Grant project through a Research Project Grant (R01). Information about NIAAA Alcohol Education Project Grants may be found at http://grants.nih.gov/grants/guide/pa-files/PAS-99-165.html As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats. (See http://grants.nih.gov/grants/funding/modular/modular.htm.) Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. FUNDS AVAILABLE NIAAA intends to commit up to 3 million dollars in FY 2003 to fund eight to twelve new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and, if applying for an R01 award, a budget for direct costs of up to $500,000 per year. If applying for a small grant (R03) or developmental exploratory grant (R21), please see the budget limitations described under the "Mechanisms of Support" section, above. Applications for exploratory/developmental research (R21) involving innovative concepts and methodologies are also strongly encouraged. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIAAA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues. Direct your questions about behavioral and social science research issues to: Kendall Bryant, Ph.D. Scientific Director Alcohol and HIV/AIDS Research Chief, Collaborative and Special Health Programs Office of Collaborative Research Suite 302 National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 402-9389 FAX: (301) 480-2358 Email: kbryant@niaaa.nih.gov Direct your questions about epidemological research issues to: Vivian Faden, Ph.D. Chief, Division of Biometry and Epidemiology Suite 514 National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard Bethesda, MD 20892-7003. Telephone: (301) 594-6232 Direct your questions about clinical and prevention research issues to: Robert C. Freeman, Ph.D. Health Scientist Administrator National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 505 Bethesda, MD 20892-7003 e-mail: rfreeman@mail.nih.gov phone: 301-443-8820 fax: 301-443-8774 Direct your questions about basic research issues to: Denise Russo, Ph.D. Chief, Division of Basic Research Suite 402 National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard Bethesda, MD 20892-7003 Telephone: (301) 402-9403 Fax: (301) 594-0673 E mail: drusso@niaaa.nih.gov Direct your questions about review matters to: Eugene G. Hayunga, Ph.D. Chief, Extramural Project Review Branch Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 Direct your questions about financial or grants management matters to: Judy Fox Chief, Grants Management Branch Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 504 6000 Executive Boulevard, MSC 7003 Bethesda, MD 20892-7003 (301) 443-4704 (telephone) (301) 443-3891 (fax) email: jsimons@willco.niaaa.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: RFA-AA-03-004 Extramural Project Review Branch Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 409, MSC 7003 Bethesda, MD 20892-7003 (use Rockville, MD 20852 for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: RFA-AA-03-004 Extramural Project Review Branch Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 409, MSC 7003 Bethesda, MD 20892-7003 (use Rockville, MD 20852 for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIAAA. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIAAA in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Institute on Alcohol Abuse and Alcoholism National Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below.) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: December 13, 2002 Application Receipt Date: January 13, 2003 Peer Review Date: March-April 2003 Council Review: June 4, 2003 Earliest Anticipated Start Date: July 1, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.273 and 93.279, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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