RESEARCH ON THE SCOPE AND CAUSES OF STILLBIRTH IN THE UNITED STATES RELEASE DATE: October 3, 2002 (see amendment NOT-HD-03-008) RFA: HD-02-025 National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) LETTER OF INTENT RECEIPT DATE: February 13,2003 APPLICATION RECEIPT DATE: March 13,2003 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 purpose of this solicitation is to create a network of clinical research sites with central data collection and analysis, which will develop and implement common research protocols to study stillbirth (fetal death 20 weeks or greater gestation). According to annual national vital statistics, the number of fetal deaths at 20 weeks or greater gestation is similar in magnitude to the total number of infant deaths in the U.S. Despite this significant and persistent burden of stillbirths, they have remained largely unstudied and, for at least half of all stillbirths, the cause is undetermined. The objective of this RFA is to create a network of multidisciplinary investigators to develop research diagnostic protocols as well as a body of data on the scope and causes of stillbirths among varied populations within the United States, while encouraging community involvement to obtain an adequate sampling of rural and urban populations and a diverse ethnic/racial makeup. The information that is obtained will aid in future research to improve preventive and therapeutic interventions and to understand the pathologic mechanisms leading to fetal death. RESEARCH OBJECTIVES Background Stillbirths account for a large proportion of perinatal mortality. According to annual national vital statistics, the number of fetal deaths, defined as deaths at 20 weeks or more gestation, is similar in magnitude to the total number of infant deaths in the U.S. In 1998, there were 28,371 infant deaths and 26,702 fetal deaths. More than half of these fetal deaths are of 28 weeks or more gestation and 20 percent, or about 5000 cases, are term gestation. In addition, the cause of about half of all stillbirths is undetermined. The stillbirth rate has been reduced dramatically since the 1950s with the introduction of interventions for gestational diabetes, pre-eclampsia, and Rh isoimmunization. However, while the infant mortality rate declined by about 32 percent between 1985 and 1998 from 10.6 to 7.2/1000 live births, the stillbirth rate declined by only about 14 percent from 7.8 to 6.7 deaths/1000 live births. Despite this significant and persistent burden of stillbirths, they have remained largely unstudied. The National Institute of Child Health and Human Development (NICHD) convened a workshop on March 26, 2001 with experts in the field to set a national agenda for stillbirth research. Among the identified gaps in knowledge that hamper progress in this field, were problems associated with current data on stillbirths in the U.S. These include: (1) the fetal death report is voluntary and under-reporting of stillbirths is as high as 10-15 percent; (2) there is variability in the quality and completeness of the fetal death certificates including certification of the cause of death; (3) there is no standard protocol for postmortem investigation of stillbirths, including serologic, toxicologic, and genetic tests; (4) while placental pathology is common, fetal autopsy rates are low; and (5) there are few geographic population-based, detailed investigations of reproductive and fetal risks associated with stillbirth. Some of the recent evidence points to the association of repeat fetal deaths with the genetic predisposition for thrombophilias (Factor V Leiden mutation) and genetic conditions (telomere mutations). Novel neuropathology findings of CNS insults point to specific findings related to fetal death, involving central nervous system insults. Other associations include maternal complications (diabetes, hypertension, anemia) and umbilical cord accidents; however, the limited ascertainment leads to a bias in the findings, as only a small portion have autopsies or tests performed. These deaths are devastating to the family. It is hoped that increased knowledge regarding the causes of stillbirths will benefit families who have experienced a loss, pregnant women, and their physicians, and may lead to the development and evaluation of improved clinical and preventive interventions. Objectives and Research Approach Because procedures in case ascertainment and registration of fetal deaths vary so widely across the U.S., we do not have a true picture of stillbirths. This information is necessary for future studies to elucidate pathogenic mechanisms and improve on current preventive and therapeutic strategies. The objective of this RFA is to establish a network of clinical research sites with central data collection and analysis to: (1) develop a standard stillbirth postmortem protocol, to include review of clinical history, protocols for autopsies and pathologic examinations of the fetus and placenta, other postmortem tests to illuminate genetic, maternal, and other environmental influences, and (2) obtain a geographic population-based determination of the incidence of fetal deaths at 20 weeks gestation or greater, their causes, and risk factors. This will involve a geographic population-based study of stillbirths enrolled at the time of demise, and a sub-cohort case-control study. Project Organization This RFA solicits applications for clinical sites to form a network to obtain an accurate ascertainment of the stillbirths and understanding of causes. This RFA also solicits a Data Coordinating and Analysis Center. The grantees will form a cooperative network in scientific partnership with NICHD to conduct a geographic population-based study of stillbirths, which will require a highly effective surveillance system and at least 90 percent ascertainment. The catchment for the study will include a diversity of populations (urban/rural/different social and racial groups). The sites will employ a standardized protocol for evaluation of the cases. Clinical Sites: With a stillbirth rate estimated at five per 1000, we anticipate a sample size of 500 would be an adequate initial sampling. This would require four to seven clinical centers over a five-year period, anticipating the total geographic population pool has 100,000 deliveries. Importantly, the centers will be multidisciplinary and have significant community involvement to obtain an adequate sampling of rural and urban populations and a diverse ethnic/racial makeup. Data Coordinating and Analysis Center: The Data Coordinating and Analysis Center (DCAC) will be responsible for central data collection, quality control, management and analysis. The analytic plan will be developed by the Steering Committee. Steering Committee: A Steering Committee will be assembled and will consist of the Principal Investigators and Co-Principal Investigators of all awarded grants, and NICHD staff. Each site and NICHD will have one vote on the Steering Committee. The vote may be divided into shares at the discretion of the participating sites and the NICHD. The Steering Committee will be charged with the task of combining multiple perspectives and research agendas across sites into a coherent plan of action, to include the development of study protocols and the analytic plan. It is anticipated that protocol development and piloting will take place in year one, study implementation and data collection in years two through four, and data analysis in years three through five. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Cooperative Clinical Research (U10) award mechanism. This RFA is a one-time solicitation. The anticipated award date is September 26, 2003. The NIH U10 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." FUNDS AVAILABLE The NICHD intends to commit approximately $3 million in Total Costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund five to eight new grants in response to this RFA, one of which will be the DCAC. An applicant may request a project period of up to five years. An applicant for a clinical site may request a base budget (see Budget Preparation, below) for direct costs of up to $120,000 for the first year. An applicant for the Data Coordinating and Analysis Center may request a budget (see Budget Preparation, below) for direct costs of up to $250,000 for the first year. 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 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 Domestic Institutions applying to be a Clinical Site are not barred from applying to be the Data Coordinating and Analysis Center provided that independence of functions is demonstrated. Therefore, a separate application is required for the Data Coordinating and Analysis Center. An institution may apply to be the Data Coordinating and Analysis 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 Clinical Sites o Minimum Catchment Populations: Clinical Sites with urban populations should have a catchment population with at least 8,000 deliveries per year, and those with rural populations at least 3,000 deliveries per year in order to apply. Applicants may propose urban only, rural only, or urban and rural geographic areas for case ascertainment. The applicant must demonstrate that a large majority of the population receives prenatal care within the catchment. o Clinical Sites should have experience in multi-center research investigations. o Some, but not necessarily all, of the following expertise should be part of the research team: obstetrics, maternal-fetal medicine/perinatology, neonatology, perinatal pathology, genetics, infectious disease/immunology, epidemiology, and neuropathology. o There also should be a dedicated research nurse and a community outreach worker. 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 site must have an established perinatal data system, preferably computerized, to collect and tabulate perinatal data statistics. o The investigators should be prepared to meet as a Steering Committee about six 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 and the DCAC to achieve the goals of this solicitation. o Departmental and institutional commitments to collaborative research (including departments of obstetrics, pediatrics, genetics, pathology, etc.) 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). Data Analysis and Coordinating Center o The applicant must have demonstrated prior experience as a coordinating and statistical center in multi-center clinical studies. o The Principal Investigator, with other staff, must have appropriate biostatistical, computational, data management, and coordination expertise and capability. The applicant must have the ability to assist in designing protocols, study manuals, and data collection systems, including distributed data entry. 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 DCAC will report quarterly to the 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 six times in the first year to develop protocols and three times per year thereafter. o The applicant must be prepared to cooperate with the Clinical Sites and NICHD in all design, collection, and analysis functions. 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. Data Collection and Sharing o 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. o 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 Advisory Board (see below) and the NICHD, before implementation. 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 NICHD Grants Management Branch in accordance with HHS and NIH grant administration requirements. The cooperative agreement funding mechanism will require collaboration among the NICHD Project Scientists and the Principal Investigators of the Clinical Sites and the Data Coordinating and Analysis Center. The NICHD Project Scientists will coordinate the activities of the Stillbirth Research Collaboration, and will facilitate communication and the exchange of information as described 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 NICHD, as appropriate, and to provide study and site performance information as stipulated by NICHD. The responsibilities and rights of the awardees will be as follows: o Identification of priority issues for research. o Development and implementation of protocols. o Collection and transmission of accurate data in a timely manner. o Analysis of data and publication of results. The DCAC will be responsible for central data collection, quality control, management, and analysis. The DCAC will also be responsible for contracting with consultants to the Steering Committee on an as-needed basis. All parties will agree to accept the coordinating role of the group and the participatory and cooperative nature of the group process. Awardees will retain custody of, and primary rights to, their data developed under the award, subject to Government rights of access consistent with current HHS and NIH policies. 2. NICHD Staff Responsibilities NICHD Project Scientists: The role of the NICHD Stillbirth Project Scientists will be to aid the awardees and the Steering Committee in the following ways: o Assistance in the identification of important areas of study. o Assistance in the development of study protocols. o Assistance in the development and review of capitation-based budgets, including the identification of study costs and special institutional needs. o Assistance in the review and evaluation of each stage of the program before subsequent stages are started, in conjunction with the Steering Committee and the Advisory Board. o Assistance in reporting results in the community of investigators and health care recipients. o Assistance in the efficient conduct of the study, including ongoing review of progress; possible redirection of activities to improve performance and cooperation; and frequent communication with other members of the Steering Committee. o Participation on the Steering Committee and all active subcommittees. o Recommend consultants for appointment to the Steering Committee on an as needed basis. NICHD Program Official: The NICHD will appoint a Stillbirth Program Official, apart from the Stillbirth Project Scientist, who will: o Assure the scientific merit of the study, including the option to withhold support of a participating center if technical performance requirements such as protocol compliance and enrollment targets are not met. o Initiate a decision to modify or terminate a study based on the advice of the Data Safety and Monitoring Committee and the Advisory Board with the mutual consent of the Steering Committee. o Perform other duties required for normal program stewardship of grants. 3. Collaborative Responsibilities The guidance and management of the Stillbirth Research Network will include, but not be limited to the following committees whose functions are as follows: Steering Committee: A Steering Committee will be responsible for protocol development, assisted by the Advisory Board and, at times, consultants to the Steering Committee. The Steering Committee will have primary responsibility for the conduct of protocols and the preparation of publications. The Steering Committee will comprise all Principal Investigators, one representative from the Data Center, and two NICHD staff. Participating NICHD staff will include the Pregnancy and Perinatology Branch Stillbirth Project Scientists. There will be only one vote for NICHD staff, which will be shared by the Stillbirth Project Scientists. A nonvoting member of the NICHD Grants Management Branch will advise the Steering Committee on administrative and funding matters. An outside chairperson, who is not participating as a Principal Investigator, will be selected by the NICHD. The responsibilities of the Steering Committee are as follows: o Develop the study protocols to include postmortem protocols for diagnosis, protocols for surveillance and case enrollment, and protocols sub-cohort case-control study. o Develop a data management plan, with primary input from the DCAC, to include plans for quality assurance and plans for public access to the database. o Monitor surveillance and enrollment upon study initiation. o Establish Policies and Procedures that govern its operations, including publications. o Develop an analytic plan in collaboration with the Data Coordinating and Analysis Center. Advisory Board: An Advisory Board will advise the Steering Committee in the development of research protocols. The Advisory Board, chosen by the NICHD with the advice of the Steering Committee, will comprise individuals with expertise in obstetrics, perinatal pathology, biostatistics, epidemiology, perinatology, neonatology, and genetics. The Chairperson of the Steering Committee, the Principal Investigator of the Data Coordinating and Analysis Center, and the Stillbirth Project Scientists may attend Advisory Board meetings to provide information as needed. Additional members will participate based on the need for specific expertise. Data Safety and Monitoring Committee: A Data Safety and Monitoring Committee (DSMC) will monitor the safety of ongoing study protocols. This committee will be established by NICHD and will represent expertise in ethics, clinical trials/epidemiology, perinatology, neonatology, genetics, and pathology. 4. Arbitration Procedures When agreement between an awardee and NICHD 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 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 E-mail: mw75q@nih.gov o Direct your questions about peer review issues to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda MD 20892-7510 Rockville MD 20852 (for express/courier service) Telephone: (301) 496-1485 FAX: (301) 402-4104 E-mail: stretchr@mail.nih.gov o Direct your questions about financial or grants management matters to: Christopher P. Myers Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17H, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6996 FAX: (301) 402-0915 E-mail: cm143g@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 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: Clinical Sites Please provide the following in your application: (1) Patient population o Geographic definition of the catchment area proposed for a population-based assessment of stillbirths by the applicant organization. o Documentation of number of deliveries at or later than 20 weeks within the catchment geographic population from 1995-1999 to include: (a) each pregnancy outcome (fetal death, live birth,) stratified by race/ethnicity; (b) each pregnancy outcome stratified by gestational age (20-23 weeks, 24-27 weeks, 28-31 weeks, 32-36 weeks, 37 plus weeks); (c) proportion receiving prenatal care within the catchment stratified by trimester. o Estimated rates of fetal deaths at or later than 20 weeks per 1000 live births plus stillbirths, and rates of fetal autopsy and placental pathology from 1995-1999. o Distribution of causes of fetal deaths at or later than 20 weeks from 1995- 1999. (2) Staffing and Procedures o Descriptions of the staff and programs in place for surveillance of deliveries in the catchment area to identify all eligible fetal deaths at or later than 20 weeks, and proposals for expansion of services if needed. This includes creative proposals for partnering with community-based organizations including health departments. o Descriptions of staff and subspecialty services, support services and laboratories necessary for evaluating and investigating the cause of death. Provision should be made for a dedicated research nurse and a community outreach worker. o An enrollment plan to include procedures for approaching the families to optimize enrollment, a sample consent form, and procedures for supplying grief support to the families. o Descriptions of recent research productivity by the applicant clinical site in previous or present cooperative multicenter studies. Specifically, contributions in key areas such as protocol design, patient recruitment, data analysis and interpretation, and publication are important. o A description of special areas of expertise among your applicant team that would benefit this multi-center cooperative study of stillbirth. Such strengths would represent state-of-the-art scientific capabilities that might be shared or made available to the Network, to expand the scientific productivity of the research beyond what it might be otherwise. Capabilities in areas such as genetics, placental function, or perinatal pathology are examples of relevant strengths that could be included. o Letters of collaboration from prenatal clinics, community hospitals, and medical centers within the catchment area to participate in a geographic population-based study of stillbirth. This includes a commitment for timely notification of eligible stillbirths for enrollment into study, utilization of a standard postmortem protocol, and availability of medical records for abstraction. (3) Sample Study Provide a description of a sample multi-center, geographic population based study of stillbirth that meets the objectives of the RFA. The description should include elements of the surveillance system, diagnostic procedures, and information to be collected. It should not be a complete protocol and should not exceed five pages. The sample research study will serve as a starting point for deliberations within the Steering Committee and will enable reviewers to evaluate the applicant's ability to identify the critical issues to be addressed in a geographic population-based assessment of stillbirth, and to conceptualize a multi-center investigation of fetal deaths. Investigators will not be expected to perform these studies at their site. (4) Intent to Participate o There must be a clearly expressed intent to participate in a cooperative manner with other Clinical Sites, the NICHD, and the data center, in all aspects of Network research as outlined in this RFA. (4) Perinatal Data System o A perinatal data system, preferably computerized, to collect and tabulate perinatal statistics is desirable. Applicants must provide a detailed description of the variables collected, and the data quality and management activities. The applicant must also illustrate how the system has been used recently to plan and perform clinical research. All successful applicants must be willing to provide complete, accurate, and timely data to the study. (5) Acceptance of Budgetary Mechanism (see also Budget Preparation below) o Assurance of willingness and ability to cooperate with the policy of capitation of research costs for each individual protocol, in addition to a base budget, should be provided from the department and from the institutional office of sponsored research programs. 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 medical records and specialized laboratory studies (genetics, pathology, and maternal interview. (3) Intent to Participate o There must be a clearly expressed intent to participate in a cooperative manner with the Clinical Sites and the NICHD in all aspects of Network research as outlined in this RFA. BUDGET PREPARATION: The instructions for budget requests provided with the research grant application form PHS 398 (rev 5/01) should be followed. F&A costs will be awarded in the same manner as for research project grants. Budgets will be reviewed on the basis of appropriateness for the work proposed. Allowable costs and policies governing the research grants programs of the NIH will prevail. In planning the budget section of the application, each applicant should submit budget estimates for all years. 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 total of 18 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, that 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' budget requests should be limited to base budget costs, with an annual increment of base salary not to exceed three percent. The travel should be reduced to 12 person trips per year after the first year, with an annual increment 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. 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, that 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' budget requests 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: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda MD 20892-7510 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. 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 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 REVIEW CRITERIA Clinical Sites: (1) Qualifications, Experience, and Commitment of Key Personnel o Scientific, clinical, and administrative abilities and academic productivity of the Principal Investigator and other team members; o Knowledge and experience in areas relevant to the conduct of collaborative clinical research, especially in maternal-fetal medicine. This should include specific experience in research design; o Commitment of staff time for the satisfactory conduct of the study; o Experience and qualifications of team members who would be responsible for data quality and management activities. (2) Documentation and Procedures o Adequacy of documentation of the patient population as outlined in supplemental instructions; o Quality of the site's participation in collaborative clinical research; o Adequacy of surveillance procedures and enrollment plan and ability to carryout the surveillance, enrollment and diagnostic procedures. o Willingness to work and cooperate with other sites, the DCAC, and the NICHD in the manner summarized in this RFA; o Additional research strengths, as presented. (3) Description of sample study o Adequacy of the conceptual framework and design to meet the objectives of the RFA. o Potential of the proposed study elements to advance knowledge, methodology, and/or concepts relating to the scope and causes of fetal death in the United States. (4)Facilities and Management o Adequacy of administrative, clinical, and data organizational management facilities as described in supplemental instructions; this includes documentation of collaborative arrangements to ensure geographic population- based surveillance and enrollment within the catchment area; o Institutional commitment to provide support to the study in such areas as fiscal administration, personnel management, space allocation, procurement, planning, and budgeting; Data Coordinating and Analysis Center: (1) 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. (2) Protocols and Procedures: Quality of past performance and proposed plans for study coordination, data collection, analysis, and monitoring. (3) 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. (4) Willingness to work cooperatively with other awardees and NICHD in the manner summarized in the Cooperative Agreement Terms and Conditions of Award. 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 in light of the budget guidelines listed under "Budget Preparation" and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 13, 2003 Application Receipt Date: March 13, 2003 Peer Review Date: June/July 2003 Council Review: 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. These include but are not limited to community outreach, perinatal pathology, and epidemiology. o Availability of funds o Programmatic priorities to include geographic and subpopulation diversity. REQUIRED FEDERAL CITATIONS 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 No. 93.865 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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