PRENATAL ALCOHOL EXPOSURE AMONG HIGH-RISK POPULATIONS: RELATIONSHIP TO SUDDEN INFANT DEATH SYNDROME RELEASE DATE: November 18, 2002 RFA: HD-03-004 National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov) National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov) LETTER OF INTENT RECEIPT DATE: February 17,2003 APPLICATION RECEIPT DATE: March 17,2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements 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 of Child Health and Human Development (NICHD) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) invite cooperative agreement applications for the development of community-linked studies to investigate the role of prenatal alcohol exposure in the risk for sudden infant death syndrome (SIDS) and adverse pregnancy outcomes such as stillbirth and fetal alcohol syndrome (FAS), and how they may be inter- related. The investigators will work collaboratively under cooperative agreements with NICHD and NIAAA over a three-year period to plan and pilot multidisciplinary investigations using common protocols, within communities at high risk for prenatal maternal alcohol consumption. The long-term goals of this initiative are to decrease fetal and infant mortality and improve child health in these communities. RESEARCH OBJECTIVES Background, Nature, and Scope of the Research Problem Sudden infant death syndrome (SIDS) and adverse alcohol-related birth outcomes such as fetal alcohol syndrome (FAS) affect all human cultures and ethnic groups. Rates for SIDS and FAS vary across populations and each is influenced by unique factors. Epidemiological evidence increasingly suggests, however, that elevated rates of SIDS and FAS may co-occur among populations in which excessive alcohol consumption by pregnant women is common. Studies in some American Indian communities provide an example of the co-risk for FAS and SIDS. Epidemiological data indicate that in the U.S., the rates for FAS appear to be the highest for American Indian and Alaskan Native populations. Excessive alcohol consumption, typically associated with alcohol dependence (alcoholism), is an essential factor in the development of FAS. It is important to note that the rates of abstention from alcohol use by American Indian communities are greater than for the general U.S. population, for both men and women. However, American Indian women who do consume alcohol tend to be young, of child-bearing age, and to drink in a heavy episodic manner (binge drinking pattern) that would result in high blood alcohol levels, a risk factor for FAS and for other alcohol-related fetal effects. For example, in some Northern Plains communities researchers have found that 60 percent of pregnant women use or abuse alcohol, with binge drinking being the most common pattern. Similarly, a recent survey of an American Indian community found that slightly more than half of all women between the ages of 16 and 34 were current drinkers with binge drinking or intermittent heavy drinking as the typical consumption pattern. As a consequence, despite high abstention rates by the population in general, the prevalence of FAS in the U.S. Plains and Plateau American Indian cultures is nine per 1,000 among children ages one through four. This is well above the apparent North American FAS prevalence of two to three cases per 1,000 children. It is also important to note that the true magnitude of alcohol- derived problems in the fetus is likely greater than these numbers as the reported FAS prevalence does not include early or late fetal loss, or other expressions of fetal alcohol syndrome spectrum disorder such as other alcohol-related birth defects (ARBD) or alcohol-related neurodevelopmental disorders (ARND). While the rate of SIDS has declined nationally, the disparity in SIDS rates among racial/ethnic groups is growing. According to 1999 period linked files, the rate of SIDS was 1.3/1000 live births among blacks, 0.56/1000 among whites, 0.37/1000 among Hispanics, and 0.31/1000 among Asian/Pacific Islanders. Among American Indians and Alaskan Natives, SIDS is the leading cause of overall infant mortality, with a rate of 1.47/1000 live births, which is almost three times that of whites. While some of the disparity may be due differences in the sleep environment of the infants and the adoption of the back sleep position to reduce SIDS risk, recent studies indicate that other risk factors may be contributing significantly to the disparity. These risk factors include maternal cigarette smoking, and alcohol abuse, which might adversely affect the maturing fetus directly or through nutritional, inflammatory, and other chemical mediators. With respect to SIDS, the Aberdeen Area Infant Mortality Study, conducted recently among Northern Plains cultures by NICHD, IHS, CDC, and the Aberdeen Area Tribal Chairman's Health Board, found a six-fold increased risk for SIDS among children born to mothers who binged during the periconceptional period or the first trimester of pregnancy. Neurochemical analyses of brainstems of SIDS victims revealed deficits in serotinergic receptors in the arcuate nucleus –- findings similar to those seen in SIDS victims from other communities and racial and ethnic groups. Such studies suggest that harmful drinking patterns, and the risks to the developing fetus, are greatest during the early first trimester, or periconceptional period, a time when many women may not know that they are pregnant. Therefore, if these findings can be confirmed and generalized to the general population, they would have broad epidemiologic implications. The purpose of this solicitation is to support collaborative, multidisciplinary investigations using protocols with shared elements, within populations in which there is a high risk for alcohol use and abuse by women during pregnancy. The solicitation is intended to blend the expertise of investigators working on FAS, SIDS, and adverse pregnancy outcomes with active participation from members of the affected communities. The RFA solicits research proposals that explore the role of prenatal alcohol exposure in the risk for SIDS and adverse pregnancy outcomes, such as stillbirth and FAS, and study how they may be inter-related. The RFA specifically requests the use of methodologies in epidemiology, physiology, pathology, and the neurosciences to decipher the complex relationship between alcohol use and abuse during pregnancy, and their effect on the fetus at large. Scientific Knowledge to be Achieved through Research Supported by the RFA Because little is known about the complex interactions between prenatal alcohol exposure, other adverse health behaviors and social environment and their effects on fetal development in relation to poor pregnancy outcome and SIDS, research supported through this RFA may shed light on this important area of developmental biology. The RFA-funded studies may also uncover how and why alcohol adversely affects the fetus during the critical phases of organogenesis, how it affects maternal health during pregnancy and lactation, and how it might adversely influence the long-term neurodevelopmental outcome of the infant. The knowledge obtained may help public health programs to implement preventive strategies for SIDS and alcohol-related fetal disorders. Objectives of this Research Program This research program is designed to: o Investigate the association of alcohol consumption in pregnancy and after delivery in fetal death and SIDS. o Explore the biochemical, physiological, and neurodevelopmental mechanisms associated with alcohol-related adverse pregnancy outcome in the subject population. o Discover social and behavioral variables affecting alcohol use and abuse by women during pregnancy and lactation, especially in certain ethnic segments of our population, and show how such information may lead to implementing remedial programs. The following Specific Objectives for Phase I are listed below: o Establish functional community partnerships to conduct research on prenatal alcohol consumption and poor pregnancy outcomes and SIDS. These links would form the basis for clinical and epidemiological studies to address the main objectives of the RFA. These links also should be able to develop epidemiological and clinical protocols exploring social factors and family dynamics responsible for alcohol use and abuse during pregnancy and lactation, and other related issues; o Formalize the collaborative structure and operations between and among the investigative teams (see below); o Develop a set of testable hypotheses; o Develop core study protocol supplemented by site specific research; o Develop plans for data acquisition and analysis; o Pilot core protocol; o Produce a report summarizing the achievements and analyzing pilot data and protocol testing results toward these objectives, and an assessment of the feasibility of proceeding to Phase II, which will be study implementation and analysis. Research Approaches and Project Organization To facilitate the participation of groups with highest expertise in each of the various components of the larger research objectives, this RFA has been designed to include three component types, which will work collaboratively as a team. Potential applicants may apply to be a Comprehensive Clinical Site (CCS), or a Developmental Biology and Pathology Center (DBPC), or the Data Coordinating Analysis Center (DCAC). Applicants must meet the Special Requirements noted for each of the individual components (see below). The three components of the collaborative structure are as follows: o Comprehensive Clinical Sites (CCS) The applicant organization for the CCS should be able to conduct clinical, epidemiological, and physiological studies that address the association between alcohol consumption and risk for stillbirth and SIDS. Based on their links to high-risk communities, the CCS should be able to design and implement a broad range of clinical, biological, and epidemiological studies. These studies should address clinical epidemiology of alcohol abuse and its relation to stillbirth and SIDS, and study the social, demographic, and family support structures and their relationship to alcohol abuse during pregnancy and lactation. To accomplish these goals, women prior to or during the early periods of pregnancy may have to be enrolled, and studied through pregnancy and early childrearing periods. The sites should also be able to address related biological measures of alcohol effects on the mother, the fetus, and the infant in order to understand the mechanisms and identify pregnancies and infants at risk. Because the objective is to be able to study the largest possible segment of at-risk populations, the applicant organization should have either an existing collaborative arrangement or should be able to develop such partnerships within a reasonable timeframe, with the communities in which the studies will take place. It is possible for an applicant organization to link with more than one community. It is the intention to have more than one CCS. o Developmental Biology and Pathology Center (DBPC) The DBPC should be able to conduct basic and applied research related to molecular and biological aspects of alcohol-related injury to the brain and other vital organs, including the placenta in the subject population. The applicant organization should be able to perform diagnostic procedures, design studies on neurobiology of alcohol injury, and study the pathological processes operating such injuries. Studies may include the adverse influences on the developing brain, as well as alcohol-nutrition-and fetal growth interactions. One of main functions of the DBPC is to conduct biochemical and neuropathology studies utilizing the biological materials from the study subjects enrolled at the CCS. The materials may include fluid samples from the mother, the placenta, fetal tissues, and in the case of SIDS victims, pathological materials from the Medical Examiners'(ME) offices obtained at autopsy. It is possible that some of the expertise for these studies will also be available at the CCS, so it is expected that there will be scientific as well as operational collaboration between the DBPC and the CCS. To enable accomplishing the broad range of comprehensive research goals related to developmental biology and neurobiology issues, up to two awards may be made for a DBPC. o Data Coordinating and Analysis Center (DCAC) The DCAC applicant will collaborate with all component groups in developing policies for data collection, developing data collection tools and data management procedures, and guidelines for interim analyses. The DCAC will also conduct data analyses, share them with the investigators, and integrate them with the overall research teams. There will be a single DCAC award. Phase I to Phase II Transition During Phase I, all awardees representing the three components will work together to develop a comprehensive set of proposals for pilot testing. It is anticipated that Year 01 will be devoted to protocol development and Years 02-03 to piloting the protocol and data analysis. Only those applicants who are successful in receiving Phase I support will be eligible to compete for participation in Phase II. A Steering Committee will be assembled from among Phase I awardees. In the planning phase, the Steering Committee will provide a forum to share program activities and potential directions for Phase II. The Committee will consist of the Principal Investigators and Co-Principal Investigators of all awarded grants, and NIH staff. Each awardee, NICHD, and NIAAA, will have one vote on the Steering Committee. The Steering Committee will be charged with the task of combining multiple perspectives and research agendas across sites into a coherent plan of action. Applicants should request funds to attend four meetings in the Washington D.C. Area for the purpose of protocol development and information sharing in the first year. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Cooperative Research Project Grant (U01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. NICHD and NIAAA may create a future opportunity (Phase II) to implement the plan of action created by the collaboration established by this RFA. The anticipated award date is September 2003. The NIH U01 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award." Only applicants who are successful in receiving Phase I support will be eligible for participation in the Phase II competition. FUNDS AVAILABLE NICHD intends to commit approximately $800,000 in total costs and NIAAA intends to commit $800,000 in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund five to eight awards in response to this RFA: most of these would be for Comprehensive Clinical Sites applications, up to two for the Developmental Biology and Pathology Center, and one for the Data Analysis and Coordinating Center. Applicants should request a project period of three years. An applicant for a clinical site may request a base budget (see Budget Preparation, below) of $125,000 direct costs for the first year. An applicant for a DBPC may request a base budget (see Budget Preparation, below) of up to $125,000 direct costs for the first year of the project. An applicant for the DCAC may request a budget (see Budget Preparation, below) of up to $200,000 direct costs for the first year of the project. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary. Although the financial plans of the NICHD and 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. 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 Institutions applying to be a Comprehensive Clinical Site are not barred from applying to be the Data Coordinating and Analysis Center or a Developmental Biology and Pathology Center provided that independence of functions is demonstrated. Therefore, a separate application is required for the Comprehensive Clinical Site, the Data Coordinating and Analysis Center and Developmental biology and Pathology Center. An institution may apply to be the Data Coordinating and Analysis Center or a Developmental Biology and Pathology Center only. 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. SPECIAL REQUIREMENTS Minimum Applicant Requirements (1) For Comprehensive Clinical Site Applicants: o A documented link between the community(s) with a high risk for alcohol use and abuse by women during pregnancy, and the applicant organization. o Documentation of a high prevalence of alcohol-related fetal effects and/or risk drinking for adverse pregnancy outcomes (see Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment, Institute of Medicine, National Academy Press, 1996) within the community (communities, if a consortium). o A demonstrated willingness to work with the community leaders to allow clinical studies to be performed and ensure that human subject protection issues are addressed. o Clinical site applicants may be a consortium of sites. o Clinical sites should have a catchment of at least 2,000 births among the index communities per year, with more being preferred. The applicant must demonstrate that a large majority of the population receives prenatal care within the catchment population. o Clinical Sites should have experience in multi-center research investigations. o Clinical sites should have relevant experience in the screening and identification of at-risk maternal drinking. o The following expertise should be part of the research team: obstetrics, pediatrics, and epidemiology. There should also be a dedicated research nurse/community outreach worker. o Clinical sites should have the abilities to conduct epidemiological and physiological studies relevant to the main research questions. o The site should have a relationship with the Medical Examiner/coroner system that serves the patient community. o The site should have experience in community outreach to pregnant women and in working with community clinics, hospitals, and other organizations that provide support to pregnant women. o The investigators should be prepared to meet as a Steering Committee about four times in the first year to develop protocols and three times per year thereafter. o The investigators should be prepared to work collaboratively with the NICHD, NIAAA, and the Data Coordinating and Analysis Center to achieve the goals of this solicitation. o Departmental and institutional commitments to collaborative research should be clearly documented by providing letters to the Principal Investigator that should accompany the application. o The applicant must exhibit a preparedness to pursue capitation of particular operational costs of the protocol (see Budget Preparation). (2) For Developmental Biology and Pathology Center Applicants: o Expertise in pediatric neuropathology and in the evaluation of the architecture of the developing brain and its abnormalities including, but not limited to, studies related to neurotransmitters and analyses of molecular, cellular, and structural deficits. o Expertise in perinatal and pediatric pathology. This expertise would enhance the work related to autopsy studies on SIDS victims, stillbirths, placenta, and other organs. o Demonstrated prior experience in conducting experimental and clinical research. o The investigators should be prepared to meet as a Steering Committee about four times in the first year to develop protocols and three times per year thereafter. o The investigators should be prepared to work collaboratively with the NICHD, NIAAA, and the Data Coordinating and Analysis Center to achieve the goals of this solicitation. o Departmental and institutional commitments to collaborative research should be clearly documented by providing letters to the Principal Investigator that should accompany the application. o The applicant must exhibit a preparedness to pursue capitation of particular operational costs of the protocol (see Budget Preparation). (3) For Data Coordinating and Analysis Center Applicants: o The applicant must have demonstrated prior experience as a coordinating and statistical center in multi-center clinical and epidemiological studies. o The Principal Investigator, with other staff, must have appropriate biostatistical, data collection, data management, and coordination expertise and capability. The applicant must have the ability to assist in designing protocols, study manuals, and data collection systems. o The applicant must have experience in developing and maintaining a quality control system, and should demonstrate experience in monitoring quality assurance of data. o The applicant must have experience in data monitoring, patient tracking systems, and coordination. o The Data Coordinating and Analysis Center will report quarterly to the NIAAA, NICHD, and to the Steering Committee prior to/at each meeting regarding accumulated data and clinical unit performance. The applicant should document the ability to meet such reporting deadlines. o The investigators should be prepared to meet as a Steering Committee about four times in the first year to develop protocols and three times per year thereafter. o The applicant must be prepared to assist the NICHD in securing services of research sub-specialties to supplement the expertise of members of the Steering Committee. o The applicant must be prepared to cooperate with the other awardees, NIAAA, and NICHD in all design, collection, and analysis functions. Data Collection and Sharing It is anticipated that one site will serve as a Data Coordinating and Analysis Center for the entire team of researchers in this program through both Phase I and II. The awardees will develop plans for the activities of the DCAC and address issues related to human subject protection including confidentiality and community needs, and data sharing with investigators outside of the awardees. There will be central data collection, management, and analysis for this study. The Data Coordinating and Analysis Center, in collaboration with the Steering Committee, will develop and implement plans to create a database that is accessible to the public within a year of study completion. Because the data elements and study design will be developed after award, the data-sharing plan will not be reviewed at the time of application. It will be reviewed after award by the Steering Committee, NIAAA, and NICHD, and in the peer review of Phase II applications. Cooperative Agreement Terms and Conditions of Award Cooperative agreements are assistance mechanisms and are subject to the same administrative requirements as grants. The special Terms and Conditions of Award are in addition to, not in lieu of, otherwise applicable OMB administrative guidelines, HHS, PHS, and NIH grant regulations, policies, and procedures, with particular emphasis on HHS regulations at 42 CFR Part 74 and 92. Facilities and Administrative cost (indirect cost) award procedures will apply to cooperative agreement awards in the same manner as for grants. Business management aspects of these awards will be administered by the NIAAA and NICHD Grants Management Branch in accordance with HHS, PHS, and NIH grant administration requirements. The cooperative agreement funding mechanism will require collaboration among the NIAAA and NICHD Project Scientists and the Principal Investigators. The NIAAA and NICHD Project Scientists will coordinate the activities of the awardees, and will facilitate communication and the exchange of information as specified below. 1. The Primary Rights and Responsibilities of the Awardees All awardees will agree to accept the participatory and cooperative nature of the group process. All awardees are required to submit annual progress reports to NIAAA and NICHD, as appropriate, and to provide study and site performance information as stipulated by NIAAA and NICHD. The Principal Investigator of each CCS will play an important role in the design of the Phase I plan of action. Each Principal Investigator will have primary responsibility for work that establishes a community link at their site and to gather preliminary information necessary to prepare their site for Phase II studies. The awardees will retain custody of, and primary rights to their data developed under this award, subject to Government rights of access, consistent with current HHS, PHS, and NIH policies. Each investigator will have the right to publish based on the work of their individual research programs, according to the publication policies developed by the Steering Committee. All awardees will: o Work cooperatively with other CCS, DBPC, and DCAC awardees to develop hypotheses and study protocols. o Carry out pilot studies developed by the Steering Committee. o Present research concepts, plans, progress, and results to the Steering Committee. o Publish and disseminate results of both independent and shared research. When joint protocols are completed, publish in collaboration with other involved sites. o Collaborate with other awardees and the NIH. o Obtain local institutional review board (IRB) approval of all study protocols implemented at U.S. or foreign sites and comply with both IRB and Steering Committee policies and procedures. o Attend and participate in all Steering Committee meetings. In addition, the Comprehensive Clinical Sites specifically will: o Develop active community links at their site to sustain the development and conduct of study protocols in Phase I and Phase II. In addition, the Development Biology and Pathology Center specifically will: o Be responsible for the storage and cataloguing of biologic materials from the enrolled subjects; o Be responsible for conducting standardized diagnostic and research procedures on biologic materials form the enrolled subjects; In addition, the Data Coordinating Analysis Center specifically will: o Be responsible for central data collection, quality control, management, and analysis; o Be responsible for contracting with consultants to the Steering Committee on an as needed basis. 2. NIAAA and NICHD Responsibilities NIAAA and NICHD Project Scientists The NIH Project Scientists will be staff from the Pregnancy and Perinatology Branch, NICHD, and the NIAAA, who will have substantial involvement above and beyond the normal program stewardship of the award. The Project Scientist is a partner within the research team representing the government's interest in the substantive work of the research team. The primary role of the Project Scientists is to facilitate the work of the awardees and the Steering Committee. He/she will: o Assist in all functions of the Steering Committee, including: reviewing and commenting on each stage of the program before subsequent stages are started; recommending the options of adding, modifying or terminating aspects of the program. o Recommend consultants for appointment to the Steering Committee on an as needed basis. o Assist with accomplishing the objectives of Phase I. o Assist in the analysis, interpretation, and reporting of findings in the scientific literature and other media to the community at large and the public policy community within the Federal government. NIAAA and NICHD Project Officers NIAAA and NICHD will appoint a Project Officer, apart from the Project Scientists, who will: o Have the option to withhold support to a participating institution if technical performance requirements, such as compliance with the protocol, are not met. o Carry out continuous review of all activities to ensure objectives are being met. o Exercise the normal stewardship responsibilities of an NIH Program Officer. 3. Collaborative Responsibilities Steering Committee The overall guidance and management of the research team will be provided by a Steering Committee. Steering Committee responsibilities will include planning and implementation of the cooperative aspects of the study. The Steering Committee will consist of the Principal Investigator and Co-Principal Investigator from each participating awardee institution and the NIH Project Scientists. Each awardee, NICHD, and NIAAA will each have one vote. An outside chairperson, who is not participating as a Principal Investigator, will be selected by NICHD and NIAAA. The Steering Committee will: o Plan the design and implementation of the plan of action for Phase II. o Participate in decision-making regarding gathering preliminary information at the participating sites and operationalizing key constructs regarding the community and other environmental factors at participating sites. o Formulate publication policy and appoint a Publication Subcommittee, as judged necessary by the Steering Committee. Publish results, conclusions, and interpretations of the cooperative planning activity. Due publication credit will be given to all work done cooperatively. o Agree to accept the coordinating role of the committee and the cooperative nature of the group process. Data Safety and Monitoring Committee A Data Safety and Monitoring Committee (DSMC) will be established by NIAAA and NICHD, and will advise the Steering Committee on research design issues, data quality and analysis, and ethical and human subject issues. 4. Arbitration Procedures When agreement between an awardee and NIH staff cannot be reached on programmatic and scientific-technical issues that may arise after the award, an arbitration panel will be formed. The panel will consist of one person selected by the Principal Investigators, one person selected by the NIAAA and NICHD staff, and a third person selected by these two members. The decision of the arbitration panel, by majority vote, will be binding. These special arbitration procedures in no way affect the awardees right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. 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: o Direct your questions about scientific/research issues to: Marian Willinger, Ph.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6896 FAX: (301) 496-3790 Email: mw75q@nih.gov Or Tonse N.K. Raju, M.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B03D, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 402-1872 FAX: (301) 496-3790 Email: rajut@mail.nih.gov Or Deidra Roach, M.D. Office of Collaborative Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 302, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-5820 FAX: (301) 480-2358 Email: droach@willco.niaaa.nih.gov o Direct your questions about peer review issues to: Eugene G. Hayunga, Ph.D. Chief, Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda MD 20892-7003 Telephone: (301) 443-4375 FAX: (301) 443-6077 Email: hayungae@mail.nih.gov o Direct your questions about financial or grants management matters to: Chris Myers Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17K, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6996 FAX: (301) 402-0915 Email: myresc@mail.nih.gov Judy Fox Simons Chief, Grants Management Branch Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 504, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4704 FAX: (301) 443-3891 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 NIAAA and NICHD 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: Marian Willinger, Ph.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6896 FAX: (301) 496-3790 E-mail: mw75q@nih.gov 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. SUPPLEMENTAL INSTRUCTIONS: Comprehensive Clinical Sites Please provide the following in your application: (1) Patient population o Descriptions of catchment populations (size and demographic characteristics) to include the number of births per year overall and within racial/ethnic groups; o Documented fetal deaths (20 weeks or greater gestation)and infant mortality rates, SIDS rate overall and within racial/ethnic groups 1995-1999; o Documentation of rates of prenatal alcohol exposure in the catchment population; (2) Staffing and procedures o Descriptions of the staff and programs in place for the recruitment and evaluation of families and infants at risk within the community, for counseling and support as might be clinically needed. o Demonstrated capacity to conduct obstetric, pediatric, and social and behavioral research; documentation of the formation of an interdisciplinary team combining appropriate biomedical, social, and behavioral expertise to include their expertise and strengths to achieve the objectives of the RFA. o A description of special areas of expertise among your applicant team that would benefit this multi-center cooperative study of the relationship between prenatal alcohol exposure and adverse pregnancy and infant outcomes. Such strengths would represent state-of-the-art scientific capabilities that might be shared or made available to the Steering Committee, to expand the scientific productivity of the research beyond what it might be otherwise. Capabilities in areas such as genetics, comprehensive pediatric and developmental follow-up program, abilities to carry out advanced neuroimaging studies such as MRI, FMRI. o Evidence of a working relationship with the index community(s). (3) Sample Study The Research Methods section of the application should include a description of one sample research study that will lead to assessment of relationship between alcohol consumption during pregnancy and rates of stillbirths and SIDS. The sample research study will serve as a starting point for deliberations within the Steering Committee and will enable reviewers to evaluate the substantive approaches that the site is best equipped to perform. Investigators will not be expected to perform these studies at their site during Phase I, nor is it likely that the study as submitted would be conducted. The sample study should be designed based on a theoretical total catchment of the CCS of about 40,000 pregnancies and deliveries over four years of enrollment among 4-5 CCS, a SIDS rate of 1.5/1000 live births, and stillbirth rate of 5/1000 stillbirths plus live births. The description should include specific aims and hypotheses regarding the role alcohol in adverse pregnancy and infant outcome and the study design to achieve these specific aims. It should not be a complete protocol and should not exceed seven pages. (4) Intent to Participate o There must be a clearly expressed intent to participate in a cooperative manner with the DBPC, DCAC, and the NIH in all aspects of collaborative research as outlined in this RFA. Developmental Biology and Pathology Center Please provide the following in your application: (1) Research Experience o Description of previous research experience in areas related to objectives of this RFA to include developmental neuroscience, neuropathology, perinatal pathology, molecular and biochemical studies of alcohol effects in humans. o Description of applicant's perception of their role in the study. (2) Sample Research Study The Research Methods section of the application should include descriptions of one sample research study that will lead to an understanding of relationship between alcohol consumption during pregnancy and rates of still births and SIDS. The sample research study will serve as a starting point for deliberations within the Steering Committee and will enable reviewers to evaluate the substantive approaches that the site is best equipped to perform. Investigators will not be expected to perform these studies at their site during Phase I, nor is it likely that the study as submitted would be conducted. The sample study should be designed based on a theoretical total catchment of the CCS of about 40,000 pregnancies and deliveries per year over four years of enrollment among 4-5 CCS, a SIDS rate of 1.5/1000 live births, and stillbirth rate of 5/1000 stillbirths plus live births. The description should include specific aims and hypotheses regarding the role alcohol in adverse pregnancy and infant outcome; elements of the system to obtain biological and autopsy specimens; and research and diagnostic approaches to meet the objectives of the specific aims. It should not be a complete protocol and should not exceed seven pages. (3) Intent to Participate o There must be a clearly expressed intent to participate in a cooperative manner with the CCS, the DCAC, and the NIH in all aspects of collaborative research as outlined in this RFA. Data Coordinating and Analysis Center Please provide the following in your application: (1) Research Experience o Description of previous experience in managing multi-center clinical research studies. o Description of applicant's perception of their role in the study. (2) Staffing and Procedures o Description of staff and computing, data processing, and analytic capability. o A plan detailing methods of data receipt, quality control, analysis and reporting, including communication with clinical and administrative personnel. This plan should be based on the assumption that there will be a patient tracking system, and a database that will include information from maternal interview, medical records, specialized clinical studies, and specialized laboratory studies (e.g., pathology, genetics, neurochemistry). (3) Intent to Participate o There must be a clearly expressed intent to participate in a cooperative manner with the CCS, DBPC, and the NIH in all aspects of the collaborative research as outlined in this RFA. Budget Preparation Comprehensive Clinical Sites: The first-year budget at the time of application will be limited to a BASE BUDGET with maximum allowances as follows: o Principal Investigator/Co-Principal Investigator(s): up to a total of 30 percent effort o Research Nurse Coordinator/outreach worker: 50 percent effort o Data Entry Clerk: 50 percent effort o Supplies and Small Equipment (itemized and justified): Not to Exceed $4,500 o Travel (a maximum of 12 person trips to Bethesda): as appropriate o Other costs (itemized and individually justified): Not to Exceed $2,500 When an application has been reviewed and is being considered for funding, the applicant will be required to complete the budgets based on capitation funding. Each Clinical Site will be given base costs (listed above) in addition to a flat fee per subject. When protocol development is near completion, a final per-subject rate will be determined, which will include costs, which cannot be estimated at this time, such as pathology and laboratory tests. After protocol development, the individual member sites will be required to project subject enrollment during a specified time frame. Taking this information into account, NICHD will determine the capitation level and make an award. Continuation and level of funding for future years will be based on the number of subjects successfully enrolled and completed. Future years' budgets should be limited to base budget costs, with an annual increment of base salary and travel not to exceed three percent. The maximum amount available for equipment, supplies and other costs will not increase. Federal agencies shall use negotiated rates for F&A costs in effect at the time of the initial award throughout each competitive segment of the project. Award levels for sponsored agreements may not be adjusted in future years as a result of changes in negotiated rates. Developmental Biology and Pathology Center: The first-year budget at the time of application will be limited to a BASE BUDGET with maximum allowances as follows: o Principal Investigator/Co-Principal Investigator(s): up to a total of 30 percent effort o Research Technician: 50 percent effort o Supplies and Small Equipment (itemized and justified): Not to Exceed $10,000 o Travel (a maximum of 12 person trips to Bethesda): as appropriate o Other costs (itemized and individually justified): Not to Exceed $2,500 When an application has been reviewed and is being considered for funding, the applicant will be required to complete a budget based on operational costs. The DBPC will be given base costs (listed above) in addition to operational costs. When protocol development is near completion, operational costs will be determined, which will include costs, which cannot be estimated at this time, such as those related to the storage and processing of biologic samples. Taking subject enrollment estimates into account, NICHD will determine the level of operational costs and make an award. Continuation and level of funding for future years will be based on the number of subjects successfully enrolled and completed. Future years' budgets should be limited to base budget costs, with an annual increment of base salary and travel costs not to exceed three percent. The maximum amount available for supplies and other costs not increase. Federal agencies shall use negotiated rates for F&A costs in effect at the time of the initial award throughout each competitive segment of the project. Award levels for sponsored agreements may not be adjusted in future years as a result of changes in negotiated rates. Data Coordinating and Analysis Center: The first-year budget at the time of application will be limited to a BASE BUDGET with maximum allowances as follows: o Principal Investigator/Biostatistician team: up to 100 percent effort o Programmer/Systems Analyst: 50 percent effort o Study Coordinator/Administrative Assistant: 50 percent effort o Travel (a total of 12 person trips to Bethesda): as appropriate o Consultants for protocol development and one meeting of the DSMC: $10,000 o Supplies and small equipment: $10,000 When an application has been reviewed and is being considered for funding, the applicant will be required to complete a budget based on operational costs. The data center will be given base costs (listed above) in addition to operational costs. When protocol development is near completion, operational costs will be determined, which will include costs, which cannot be estimated at this time, such as data entry and management, quality control costs, software, printing and duplication of forms, distribution and storage of forms, and service contracts, logistic support to the study, report generation, and data analysis. Taking subject enrollment estimates into account, NICHD will determine the level of operational costs and make an award. Continuation and level of funding for future years will be based on the number of subjects successfully enrolled and completed. Future years' budgets should be limited to base budget costs, with an annual increment of base salary and travel costs not to exceed three percent. The maximum amount available for supplies and other costs not increase. Federal agencies shall use negotiated rates for F&A costs in effect at the time of the initial award throughout each competitive segment of the project. Award levels for sponsored agreements may not be adjusted in future years as a result of changes in negotiated rates. 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: Extramural Project Review Branch ATTN: HD-03-004 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) 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 the NICHD and NIAAA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 the NICHD and 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 Advisory Child Health and Human Development Council and the National Advisory Alcohol Abuse and Alcoholism Council. REVIEW CRITERIA Criteria for Review of Comprehensive Clinical Site (CCS) and Developmental Biology and Pathology Center (DBPC) Applications 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. SIGNIFICANCE: Does research proposed address an important problem? If the aims of the sample studies are achieved, how do they advance scientific knowledge and improve the public health? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analytic plans outlined in the sample studies appropriate to the aims of the research objectives as outlined in the RFA? Are the sample studies feasible in the context of the community served by your application. Do you acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does your project employ novel concepts? Do the sample studies employ novel approaches or methods? Does your project challenge existing paradigms or develop new methodologies or technologies? 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)? Is an appropriate multidisciplinary team assembled to carry out the work? ENVIRONMENT: Does the scientific and community environment in which the work will be done contribute to the probability of success? Do the proposed approaches take advantage of unique features of the scientific and community environment and employ useful collaborative arrangements? Is there evidence of institutional support? Criteria for Review of Data Coordinating and Analysis Center (DCAC) Applications o Qualifications, Experience, and Commitment of Key Personnel: Scientific and administrative abilities of the Principal Investigator and other team members; experience of the Principal Investigator and other key personnel in statistical data management, quality control, study coordination, and administrative aspects. o Protocols and Procedures: Quality of past performance and proposed plans for study coordination, data collection, analysis and monitoring. o Facilities and Management: Evidence of satisfactory facilities and supporting environment, including space and equipment for work proposed (any new equipment requested under this award must be adequately justified); evidence of institutional support for participation in a long-term collaborative project. OTHER REVIEW CRITERIA: Other Criteria for Review of Comprehensive Clinical Site (CCS) Applications o Adequacy of documentation of the patient population as outlined in supplemental instructions; o Adequacy of ability to implement clinical, biological, or epidemiological studies, based upon links to high-risk communities. o Ability to address related biological measures of alcohol effect on the mother, the fetus, and the infant. o Adequacy of existing collaborative arrangements with communities in which the studies will take place, or plans to develop such arrangements. Other Criteria for Review of Developmental Biology and Pathology Center (DBPC) Applications o Ability to design studies on neurobiology of alcohol injury and the pathological processes operating such injuries. o Adequacy of plans to store and examine samples from the mother, the placenta, fetal tissues, and/or materials obtained at autopsy. o Adequacy of plans for scientific and operational collaboration between the DBPC and CCS. 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 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: February 17,2003 Application Receipt Date: March 17,2003 Peer Review Date: June/July 2003 Council Review: August/September 2003 Earliest Anticipated Start Date: September 2003 AWARD CRITERIA Criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review). The combined expertise of all sites will play a role in the selection of grants for award. o Availability of funds o Programmatic priorities to include geographic and subpopulation diversity. 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 is 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 Nos. 93.864, 93.865, and 93.891, 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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