GENOMIC AND PROTEOMIC NETWORK FOR PREMATURE BIRTH RESEARCH RELEASE DATE: June 18, 2004 RFA NUMBER: RFA-HD-04-002 EXPIRATION DATE: August 21, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.865 LETTER OF INTENT RECEIPT DATE: July 20, 2004 APPLICATION RECEIPT DATE: August 20, 2004 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 for premature birth research. The aim of this network is to accelerate the pace of premature birth research by focusing on global genomic and proteomic strategies and the dissemination of genomic and proteomic data to the scientific community. Specifically, the network will: 1) design and implement hypothesis-driven, mechanistic studies based on large-scale, high-output genomic and proteomic approaches, and 2) provide a public, web-based, genomic and proteomic database for data mining and data deposition by the research community. It is anticipated that the creation of this network will hasten a deeper understanding of the pathophysiology of premature birth, discover novel target molecules and diagnostic biomarkers, and ultimately aid in formulating more effective interventions to prevent premature birth. RESEARCH OBJECTIVES Background Premature birth, which is defined as birth prior to 37 weeks of gestation, is a leading cause of infant morbidity and mortality. In the U.S. population, approximately 10 percent of all births are premature. This accounts for approximately 400,000 infants born annually. The incidence of premature birth, however, is not equally distributed among races and ethnic groups. For example, African-Americans have the highest rate of premature birth, followed by Mexican-Americans, Asians, and Caucasians. Strikingly, a substantial health disparity exists between African-Americans and Caucasians, with African- Americans being 1.8 times more likely to deliver premature infants than Caucasians. Most of the infant mortality and morbidity of premature birth is associated with the one to two percent of infants born very premature (birth at less than 32 weeks of gestation). Excluding congenital malformations, premature birth accounts for approximately 70 percent of all neonatal deaths and nearly 50 percent of long-term neurological problems. These long-term neurological problems include serious physical and mental disabilities, such as cerebral palsy, mental retardation, as well as vision and hearing loss. Despite decades of research, there has been little progress in developing effective interventions to prevent premature birth. In fact, the rate of premature birth has increased slightly over the last several decades. Although advances have been made in identifying some of the possible causes of premature birth, such as intrauterine infection, uterine bleeding, excessive uterine stretch, maternal psychosocial stress, and fetal physiological stress, a much deeper understanding at the molecular level is necessary to aid in formulating effective interventions. Thus, a new initiative is required to address this need as a means to accelerate knowledge in the mechanisms of premature birth. Substantial strides have been made in the areas of genomics and proteomics, both of which have made major impacts in accelerating medical advances in many fields of medicine. However, the medical advances brought by these revolutionary technologies are generally due to coordinated, wide-scale, high- output endeavors that are presently beyond the resources of investigators in the field of premature birth research. In addition, the research community lacks a centralized database for data mining and the deposition of genomic and proteomic data. The purpose of this solicitation is to create a collaborative research network to more effectively coordinate and apply the power of genomics and proteomics to the problem of premature birth. It is anticipated that the creation of this network will hasten a deeper understanding of the pathophysiology of premature birth, the discovery of novel target molecules and diagnostic biomarkers, and ultimately aid in formulating more effective interventional strategies to prevent premature birth. Objectives and Scope The main objective of the Network will be to use wide-scale, high-output genomic and proteomic strategies to accelerate knowledge in the mechanisms responsible for premature birth. Another objective of the network will be to act as a resource to the scientific community by providing genomic and proteomic data quickly for secondary analysis and creating, as well as maintaining, a public genomic and proteomic database dedicated to premature birth research. Specifically, the network will: 1) design and implement hypothesis-driven, mechanistic studies based on wide-scale, high-output genomic and proteomic strategies and 2) provide a public, web-based, genomic and proteomic database for data mining and data deposition by the research community. It is anticipated that the Network will consist of the following: o A Clinical Core, comprising up to three clinical sites, responsible for subject recruitment and specimen collection; o An Analytical Core responsible for genomic and proteomic analyses; o A Data Management, Statistics, and Informatics Core responsible for central data collection, analysis, and management; information technology; and coordination of the administrative activities of the Network. The Clinical Core will consist of up to three separately awarded clinical research sites that will work cooperatively with one another. The Clinical Core will be responsible for recruitment of human subjects, collection of relevant clinical information, and collection and temporary storage of biological specimens. The Clinical Core will also be responsible for data entry into the Data Management, Statistics, and Informatics Core databases. The Analytical Core will be responsible for "state-of-the-art", high- throughput DNA, RNA, and protein analyses, as well as entry of data into the Data Management, Statistics and Informatics Core databases. This core will also be responsible for the receipt and storage of the biological specimens collected from the various clinical sites. In addition, the Analytical Core will be responsible for the computational analysis of genomic and proteomic data and synergistically interacting with the Data Management, Statistics, and Informatics Core in performing genomic and proteomic statistical analyses. The Data Management, Statistics, and Informatics Core will be responsible for central data collection, analysis, and management. It will integrate clinical data with genomic and proteomic data. It will be responsible for the statistical analysis of data aided, in part, by the Analytical Core. It will also be responsible for creating and maintaining an internal and a public web- based database. In addition, it will act as an administrative coordinating center for the Network. Guidance and Management Structure A Steering Committee will be assembled consisting of the Principal Investigators, participating NICHD staff, and other appropriate members. This committee will be responsible for the formulation of new projects, review of proposed projects, prioritization of workload, consideration of long-term strategic issues, policy and budgetary matters, and development of guidelines for operation of the Network. An outside advisory panel will also be formed to provide general oversight of the Network, as well as to provide technical and operational advice. MECHANISM OF SUPPORT This RFA will use the 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. The anticipated award date is April 01, 2005. 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." FUNDS AVAILABLE The NICHD intends to commit approximately $2.5 million in Total Costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2005 to fund up to three clinical sites comprising the Clinical Core, one site comprising the Analytical Core, and one site comprising the Data Management, Statistics and Informatics Core. An applicant may request a project period of up to five years. An applicant for a clinical site in the Clinical Core or an applicant for the Analytical Core may request a base budget for direct costs of up to $125,000 for the first year (see SUBMITTING AN APPLICATION/SUPPLEMENTARY INSTRUCTIONS section under Budget Preparation). An applicant for the Data Management, Statistics and Informatics Core may request a budget for direct costs of up to $250,000 for the first year (see SUBMITTING AN APPLICATION/SUPPLEMENTARY INSTRUCTIONS section under Budget Preparation). Subsequent budgets will be negotiated and consist of a base budget plus protocol-specific expenses. 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 Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his/her 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 Application Requirements Applicants may submit applications for one or more cores described in this RFA. If applying to be more than one core, applicants must submit separate applications, each focusing on a particular core. Only one award, however, will be made to a single institution. Due to the scope of this solicitation, it is anticipated that applicants may have to form consortiums with other entities, since a single entity may not have the sufficient catchment study population, expertise or facilities to carry out all aspects expected of each of the cores as described. Minimum requirements for applicants are listed below. Detailed application instructions can be found in the SUBMITTING AN APPLICATION section under SUPPLEMENTARY INSTRUCTIONS. All Applicants: o All applicants should be prepared to work collectively and in a cooperative manner with each other and the NICHD 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 All applicant Principal Investigators, or their appropriate representatives, should be prepared to meet as a Steering Committee to develop the necessary infrastructure and study protocols. It is anticipated that the Steering Committee will meet about six times in the first year and three times per year afterwards. Expenses related to these meeting should be included in the application budget request (see Budget Preparation section under SUBMITTING AN APPLICATION/SUPPLEMENTARY INSTRUCTIONS, below). o The applicant must exhibit a preparedness to pursue capitation of particular operational costs of the protocol (see Budget Preparation section under SUBMITTING AN APPLICATION/SUPPLEMENTARY INSTRUCTIONS, below). o The applicant must agree to the conditions of data and resource sharing as described below. Clinical Core Applicants: o Each of the clinical sites must have a catchment population of at least 2500 deliveries per year. o The Principal Investigator for each site must have expertise in obstetrics. o Clinical sites must have a research team with expertise in obstetrics with special interest in premature birth research. o The assembled research team must have sufficient familiarity in genomics and proteomics to effectively participate in the formulation of study protocols. o Each clinical site must have an established perinatal data system, preferably computerized, to collect and tabulate perinatal statistics, as well as the ability to easily extract data for export. o Each clinical site must have a research nurse designated as the Nurse Coordinator. Analytical Core Applicants: o The applicant must have the ability to appropriately store biological specimens. o The applicant must have the ability to perform genetic analyses at high- throughput and/or genome-wide capacity, such as sequencing, genotyping, haplotyping, and gene expression analysis. o The applicant must have the ability to perform proteomic profiling of complex mixtures such as tissue and biological fluids, using high-throughput platforms such as mass spectrometry analysis (e.g., coupled to liquid chromatography-MS, SELDI-TOF-MS, etc.) and protein microarray. o The applicant must demonstrate the ability to perform genomic and proteomic computational and statistical analyses. o The applicant must demonstrate the potential of incorporating other types of existing and evolving genomic and proteomic technologies. o The applicant must have most of the infrastructure necessary (e.g., instrumentation, computer hardware and software, etc.) to carry out the objectives of the Analytical Core. Data Management, Statistics and Informatics Core Applicants: o The Data Management, Statistics and Informatics Core must have the ability to develop and disseminate protocol materials (e.g., data collection instruments, procedural manuals, etc.), train study site personnel for centralized data entry, monitor data quality, and carry out data analysis and reporting. o Applicants must have the ability to coordinate the activities of the Network by scheduling and coordinating, as well as documenting Network meeting activities, including the dissemination of meeting documents. o The core must have the ability to electronically collect and store data generated by the Clinical and Analytical Cores and provide an interactive user interface for all components of the Network. o The core must have the ability to devise methods for integrating clinical data with genomic and proteomic data into a database. o The core must have the ability to perform biostatistics, including the statistical analysis of genomic and proteomic data. o The core must have the ability to incorporate the proper informatics and bioinformatics tools to facilitate analysis, extraction, and efficient dissemination of information from these databases to the Network members. o The core must have the ability to create and maintain a public, web- accessible database for secondary analysis of the data generated by the Network and to provide the necessary bioinformatic tools to mine this database. o The core must have the ability to disseminate data generated by the Network to the National Center for Biotechnology databases; act as a conduit for the deposition of genomic and proteomic data eventually submitted to the core by researchers, outside of the Network, investigating premature birth; and to integrate this data into the public, web-accessible database described above. Data and Resource Sharing The NICHD expects that the Network investigators benefit from the first and continuing use, but not from prolonged exclusive use of data and resources. One of the major intents of this initiative is to make the data quickly available to the research community for secondary analyses. In order to accomplish this goal, the RFA sets a limit to the exclusive use of final data sets generated by the Network. This is defined as the following: The final data set for a particular protocol generated by the Network will be made publicly available after the date of acceptance of publication or no longer than one year after the final collection and analysis of a data set for a particular protocol, whichever occurs first. Another purpose of this RFA is to allow investigators, outside the Network, access to Network resources. Thus, research studies proposed by investigators outside the Network will be accepted and reviewed by the Network for possible execution of the study using the Network's infrastructure, according to the guidelines established by the Network's Steering Committee. In addition, excess or archival specimens biological specimens or derivatives thereof, which are not anticipated to be used or no longer required for analyses by the Network, will be made available to outside investigators, also according to the guidelines established by the Network's Steering Committee. Cooperative Agreement Terms and Conditions of Award The following Terms and Conditions will be incorporated into the award statement. They are to be followed in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92, and other HHS and NIH grant administration policies. The administrative and funding instrument used for this program will be the U01, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the PI is anticipated during performance of the activities. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the PI's activities by involvement in and otherwise working jointly with the PI in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the PI for the project as a whole, although specific tasks and activities may be shared between the awardee and the NICHD Project Scientist. Business management aspects of these awards will be administered by the NICHD Grants Management Branch in accordance with HHS and NIH grant administrative requirements. 1. Awardee Rights and Responsibilities 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 o Sharing of data and resources, following the procedures developed by the Network Steering Committee according to the guidelines specified in RFA-HD-04- 002. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. 2. NIH Responsibilities NICHD Project Scientists: Two Project Scientists will be appointed by the NICHD. Their roles 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 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 Project Officer: The NICHD will appoint a Project Officer, apart from the Project Scientist, who will: o Carry out continuous review of all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines. o Have the option to withhold support to a participating institution if technical performance requirements are not met. o Perform other duties required for normal program stewardship of grants. 3. Collaborative Responsibilities The guidance and management structure of the Network will include the following: 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 the Principal Investigators (voting members), two designated NICHD Project Scientists from the Pregnancy and Perinatology Branch (who will share one vote), and other non-voting and non-NIH members who are deemed necessary for the conduct of the Network. All members of the Steering Committee are expected to play an active role in Steering Committee activities. An outside chairperson, who is not participating as a Principal Investigator, will be selected by the NICHD. The chairperson will act as a voting member only in case of a tie vote. The responsibilities of the Steering Committee are as follows: o Development of guidelines and procedures for the operation of the Network o Formulation of new projects o Review of proposed projects o Prioritization of workload o Consideration of long-term strategic issues o Policy and budgetary matters Advisory Board An Advisory Board will be formed to provide general oversight of the Network, as well as to provide technical and operational advice to the Steering Committee, as needed. This board, chosen by the NICHD with the advice of the Steering Committee, will be composed of individuals not associated with the Network or its members. The board will include members with expertise in premature birth, genomics, proteomics, molecular epidemiology, bioinformatics, and bioethics. The Chairperson of the Steering Committee and the NICHD Project Scientist may attend Advisory Board meetings to provide information as needed. Additional members will participate based on the need for specific expertise. 4. Arbitration Process Any disagreements that may arise in scientific or programmatic matters within the scope of the award between grantees and the NIH may be brought to arbitration. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D, and HHS regulation at 45 CFR Part 16. An Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work that restrict progress. The Arbitration Panel will be composed of three members: a member selected by the Steering Committee without NIH staff voting, a member selected by NICHD, and a member with expertise in the relevant area selected by the other two members. 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: John V. Ilekis, Ph.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 4B03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6895 FAX: (301) 496-3760 Email: ilekisj@mail.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 Telephone: (301) 496-1485 FAX: (301) 402-4104 Email: stretchr@mail.nih.gov o Direct your questions about financial or grants management matters to: John Chris Robey Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6996 FAX: (301) 480-4783 Email: robeyj@mail.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: John V. Ilekis, Ph.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 4B03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6895 FAX: (301) 496-3760 Email: ilekisj@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: All applications should be prepared according to the instructions accompanying PHS 398, with the following specific information provided. Please see Minimum Application Requirements, above, in addition to the following. Clinical Core applicants, please provide the following descriptions in your application: o The facilities and clinical services available o The quality of the facilities and services provided o The qualifications, experience, and commitment of the personnel o Prior experience related to performing clinical research such as protocol design, data analysis and interpretation (include relevant publications) o The number of births and the percentage of spontaneous and induced preterm births, stratified by gestational age (20-23 weeks, 24-27 weeks, 28-31 weeks, 32-36 weeks, 37 plus weeks), race, and ethnicity o The proportion of women who give birth at the site who also receive prenatal care within the site. Include the definition of prenatal care as well as the number of visits that constitutes prenatal care o The perinatal data system available to collect and tabulate perinatal statistics, including the variables collected, and the data quality and management activities o Procedures for subject enrollment and recruitment o The success rate for subject enrollment and maintaining subject participation in an ongoing or recently completed study o The cost associated with recruiting and maintaining subject participation o Description of special talents or resources pertinent to the objective of this RFA Analytical Core and Data Management, Statistics and Informatics Core applicants, please provide the following descriptions in your application: o The quality of the facilities or services provided by the core (including procedures, techniques, and quality control) o The qualifications, experience, and commitment of the personnel involved in the core o Prior experience related to the objectives and functions of the core (include relevant publications) o Description of special talents or resources pertinent to the objective of the RFA o The cost associated with performing various analyses based on volume (Analytical Core only) o The cost associated with data integration, data analysis, database development, and database maintenance (Data Management, Statistics and Informatics Core only) Concept Protocol In addition to the items listed above, all applicants must submit a "concept protocol." This should be included at the end of the Research Plan section of the application. The concept protocol is a three- to six-page narrative to provide peer reviewers and the NICHD an idea of the capabilities of the investigators described as follows: o Applicants for a clinical site within the Clinical Core must submit a concept protocol that describes two separate research projects, one that focuses on a genomic approach and the other on a proteomic approach consistent with the intent of the RFA. These projects must be hypothesis driven and may address the same or different clinically relevant questions regarding elucidating mechanisms involved in premature birth. Although the description for one project may be longer or shorter than the other, the concept protocol in total should not exceed six pages in length. o Applicants for the Analytical Core must submit a concept protocol that describes the overall scheme for specimen handling and storage, genomic and proteomic analyses, and genomic and proteomic computational and statistical capabilities to meet the objectives of the Analytical Core as stated above in Objectives and Scope. o Applicants for the Data Management, Statistics and Informatics Core must submit a concept protocol that describes the overall scheme for coordinating Network activities, central data collection, data integration, statistical analysis, database development and maintenance, bioinformatics, and informatics to meet the objectives of this core as stated in the Objectives and Scope section. Budget Preparation The instructions for budget requests provided with the research grant application form PHS 398 (rev 5/2001) should be followed. F&A costs will be awarded in the same manner as for research project grants (R01). 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 based on a Base Budget. The base budget consists of the expenses to create and/or maintain a basic infrastructure until a particular protocol is introduced. First year base budgets in direct costs are limited to $125,000 per clinical site in the Clinical Core, $125,000 for the Analytical Core, and $250,000 for the Data Management, Statistics and Informatics Core. This should include such expenses as personnel, supplies and equipment, and travel to Bethesda for Steering Committee meetings (estimated to be six trips in the first year and three trips per year afterwards). All requests for supplies and equipment have to be itemized and justified. Travel for each site in the Clinical Core will be limited to the Principal Investigator and Research Nurse Coordinator. Travel for the Analytical Core and Data Management, Statistics and Informatics Core will be limited to two individuals each, one of which will include the Principle Investigator. The first-year budget for each of the Clinical Core sites, the Analytical Core and Data Management, Statistics and Informatics Core at the time of application will be limited to a BASE BUDGET with the maximum allowances as follows: o Principal Investigator: up to a total of 25 percent effort o Research Nurse Coordinator: up to a total of 100 percent effort (Clinical Core sites only) o Data Entry Clerk: up to a total of 25 percent effort (Clinical Core sites only) o Office Supplies and Office Equipment (itemized and justified): Not to Exceed $5,000 o Travel expenses: Not to exceed $12,000 o Other costs (itemized and individually justified) Once the Network has initiated a protocol, subsequent budgets will consist of a base budget plus protocol specific expenses, and funding will be based on a capitation system as follows: The Principal Investigator of each of the clinical sites in the Clinical Core will be given base budget costs, in addition to the expenses associated with a particular protocol. The Principal Investigator of each of the clinical sites in the Clinical Core will be required to project subject enrollment for a specific protocol during a specified time frame. Continuation and the level of funding will be based on actual recruitment with a flat fee paid per subject recruited and successfully carried on the protocol. The Analytical Core will be given base budget costs, in addition to the expenses associated with a particular protocol. The Principal Investigator will be required to project expenses associated with specimen handling and the type(s) of analyses associated with a specific protocol during a specified time frame. Continuation and the level of funding will be based on the actual number of specimens handled and analyzed. The Data Management, Statistics and Informatics Core will be given base budget costs, in addition to expenses associated with a particular protocol. The Principal Investigator will be required to project expenses for a particular protocol during a specified time frame. 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 and all appendix materials 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 on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for 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 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 written critique o Receive a second level review by the National Advisory Child Health and Human Development Council. REVIEW CRITERIA Review Criteria for all Applicants (1) Qualifications, Experience, and Commitment of Key Personnel o Scientific, administrative, and/or clinical abilities of the Principal Investigator and other key personnel o Experience of the Principal Investigator and other key personnel relevant to the objectives of the respective core o Commitment of personnel time for the satisfactory conduct of the study (2) Protocols and/or Procedures o Adequacy of protocols and/or procedures o Cost effectiveness and quality control o Quality of past performance (3) Facilities and Management o Adequacy of administrative, clinical, and/or data management facilities o 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) o Evidence of institutional support for participation in a long-term collaborative project o Institutional commitment to provide support to the study in such areas as fiscal administration, personnel management, space allocation, procurement, planning, and budgeting (4) Concept Protocol o Adequacy of the conceptual framework and design o Innovation in terms of approaches, methods, and/or analyses Specialized Review Criteria for Particular Core Applicants Clinical Core Sites: o Adequacy of the study population O Ability to recruit and retain study subjects o Adequacy of surveillance procedures and enrollment plan and ability to carryout the surveillance, enrollment and diagnostic procedures o Quality of the site's participation in collaborative clinical research o Significance of the concept protocol in terms of addressing the problem of premature birth using genomic and proteomic strategies Analytical Core: o Adequacy of the facilities and procedures for receipt and storage of biological specimens for analysis o Proficiency in performing "state of the art" high-throughput DNA, RNA and protein analyses o Proficiency in genomic and proteomic computational and statistical analyses. Data Management, Statistics and Informatics Core: o Capability to act as an administrative coordinating center for the Network o Adequacy of the facilities and procedures for central data collection, statistical analysis and management o Proficiency in biostatistics, including the statistical analysis of genomic and proteomic data o Proficiency in bioinformatics and informatics, including creating and maintaining web-accessible, interactive databases ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below.) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below.) ADDITIONAL CONSIDERATIONS 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: July 20, 2004 Application Receipt Date: August 20, 2004 Peer Review Date: October/November 2004 Council Review: January 2005 Earliest Anticipated Start Date: April 01, 2005 AWARD CRITERIA Criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities In addition, final selection of sites for the Clinical Core will also be based on plans for maintaining satisfactory racial and ethnic representation in the overall study population. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm). 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 "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. 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information," the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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 at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. 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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