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OBSTETRIC-FETAL PHARMACOLOGY RESEARCH UNITS RELEASE DATE: July 29, 2003 RFA: HD-03-017 Update: The following update relating to this announcement has been issued: December 16, 2008 - This RFA has been reissued as (RFA-HD-09-002). 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: October 24, 2003 APPLICATION RECEIPT DATE: November 24, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Child Health and Human Development (NICHD) invites cooperative agreement applications for the development of an Obstetric-Fetal Pharmacology Research Units (OPRU) Network to: (1) serve as a resource for pharmacologic studies of drug disposition and effect during normal and abnormal pregnancies; (2) conduct single-site and multi-site cooperative clinical trials; (3) conduct pharmacogenetic studies on the effect of pregnancy on drug metabolizing enzymes, transporters and effectors; (4) perform studies of placental transfer of drugs; (5) conduct studies of fetal and maternal pharmacology; (6) facilitate the utilization of clinical materials for basic research studies; and (7) enhance the exchange of information between basic scientists and obstetricians and among various specialists involved in treating pregnant women. The OPRUs will also serve as a resource for the training of health professionals in obstetric-fetal pharmacology and drug trials in pregnant women. RESEARCH OBJECTIVES Background The study of drugs used during pregnancy is one of the most neglected areas in the field of clinical pharmacology and drug research. The data available on drug biodisposition and effect are scarce, fragmentary and frequently contradictory. The lack of Food and Drug Administration obstetric labeling and the universal off-label use of drugs are the direct result of the lack of research and clinical trials of drugs in this special population. Epidemiological surveys have determined that nearly two thirds of all pregnant women take at least four or five drugs during pregnancy and labor. These data demonstrate that drug use during pregnancy is of public concern because it is primarily based on an empiric approach rather than a scientific basis and does not take into account the profound physiologic changes characteristic of pregnancy. These changes involve the mother, placenta and the fetus and may lead to variations in the absorption, distribution and elimination of drugs. A number of factors influence the pharmacokinetics (Pk) of drugs in pregnancy. For example, both the gastric emptying time and intestinal transit time are increased during pregnancy and could affect the gastrointestinal absorption of drugs. There is a dearth of bioavailability studies in pregnancy. The increase in cardiac output, plasma volume and extracellular water may profoundly affect the distribution of many drugs during pregnancy. Hypoalbuminemia, especially in the third trimester, is associated with a decrease in drug-binding capacity. The total (bound and free) drug concentration for a number of drugs is decreased (e.g., phenytoin) compared to the non-pregnant state. Drug elimination, by either metabolic inactivation or excretion, may also be altered by the pregnant state. Pregnancy has a dramatic effect on the plasma concentrations of sex hormones that are known to alter drug-metabolizing enzymes. These effects of the pregnant state on the biodisposition of drugs are superimposed on the changes associated with the female gender. Renal function is significantly altered by pregnancy. The glomerular filtration rate and renal plasma flow increase from the sixth week of pregnancy. As a consequence of these physiologic changes, there is an increase in the renal excretion of some drugs such as beta-lactam antibiotics and lithium. The increase in glomerular filtration observed during pregnancy is counterbalanced to a significant degree by modifications in tubular reabsorptive capacity. The effect of diurnal variations in renal function and their effect in drug elimination have not been sufficiently characterized. The physiologic changes during normal gestation can be substantially modified by the pathophysiologic processes associated with various conditions and disease states. Therefore, information accrued on the disposition and effects of drugs in normal pregnancy cannot be extrapolated to abnormal pregnancies. There is a dearth of information on the effects of the pathologic abnormalities associated with the disposition and action of drugs in abnormal pregnancies. Research Objectives and Scope A major goal of this program is to identify, characterize and study those drugs that are of therapeutic value during pregnancy and whose clinical pharmacology (both pharmacokinetics and pharmacodynamics) is altered by the pregnant state in normal or abnormal pregnancies. The development of studies of drugs in pregnancy is expected to follow sequential phases: Phase I: Population pharmacokinetic studies will be used as a screening tool to determine candidate drugs requiring intensive pharmacokinetic (Pk) studies. Phase II: Intensive pharmacokinetic, pharmacodynamic (Pd) and Pk-Pd correlations, as well as bioavailability studies, will be performed for drugs selected in Phase I. Drugs that are chronically administered during pregnancy will be studied serially during the second and third trimester and puerperium. Bioavailability studies will be performed as part of the overall pharmacologic evaluation. Phase III: For those drugs that exhibit clinically significant changes in pharmacokinetics during pregnancy, a determination will be made as to the need to make dose adjustments and to test modified dosing regimens in subsequent clinical trials. Alterations in drug sensitivity during pregnancy, demonstrated by Pk-Pd correlation studies, may be elucidated by mechanistic studies of transporters, receptors or signaling pathways performed within the basic component of the OPRUs. In addition to the above studies specific areas of interest include: o Influence of the pregnancy on the expression and function of drug metabolizing enzymes, transport systems, receptors and signaling pathways. o Use of in vitro and animal models to study placental drug transfer and fetal disposition of maternally administered drugs. o Use of physiologic-based pharmacokinetic models and simulation technology for drug studies during pregnancy. o Identification and development of biomarkers of efficacy and/or toxicity applicable during pregnancy. o Performance of phenotypic-genotypic correlation studies to characterize and determine the clinical significance of changes in activity of DMEs and effectors during pregnancy and/or their polymorphic expression. o Studies of the relationship between the natural history of chronic diseases during pregnancy and drug efficacy and safety. o Studies of the influence of diseases or conditions complicating pregnancy (e.g., toxemia of pregnancy, cholestasis, gestational diabetes, hypertension, etc.) on the biodisposition and efficacy of drugs. o Studies of the effect of intrauterine exposure to drugs on fetal organ development and function. o Studies of genome and proteome changes associated with pregnancy and of pharmacogenomics and pharmacoproteomics during pregnancy. Collaboration of OPRUs with industry in the performance of pharmacologic studies, clinical trials and adjunct basic mechanistic studies is encouraged. Also strongly encouraged is collaboration of OPRUs with other NIH and non-NIH Networks (e.g., NICHD's Maternal Fetal Medicine, Neonatal, and Pediatric Pharmacology Research Unit networks; other NIH disease-specific networks; and the DHHS Centers of Excellence in Women's Health pharmacokinetic units). It is expected that the pharmacologic data gathered by the OPRUs will form the basis for the design of drug efficacy trials to be performed at the OPRUs, in cooperation with other Networks or exclusively in other Networks. To accelerate the acquisition of knowledge, interaction and collaboration with other investigators involved in ongoing basic and translational research, studies that complement or expand knowledge in specific areas of obstetric- fetal pharmacology are strongly encouraged. Each OPRU will include: (1) A pharmacologic component to conduct pharmacokinetic (Pk), pharmacodynamic (Pd) and Pk-Pd correlations to identify differences in drug biodisposition, effect and/or toxicity profiles of specific drug groups given during pregnancy compared to the non-pregnant state. The pharmacologic component will also be involved in Phase I and Phase II studies of new molecular entities (NMEs) specifically designed to treat pregnancy conditions or diseases. (2) A clinical trials component to test the efficacy of drugs whose pharmacologic profile was found to differ during pregnancy. Efficacy of new NMEs will also be studied by this component. (3) A multidisciplinary, interactive basic and/or pre-clinical research component to elucidate basic mechanisms for differences in biodisposition of drug response during normal and abnormal pregnancies. MECHANISM OF SUPPORT This RFA will use the NIH Cooperative Clinical Research (U10) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. The anticipated award date is July 01, 2004. 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 $2.5 million in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2004 to support two to four new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $500,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the 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. The Office of Research on Women's Health (ORWH)(http://www4.od.nih.gov/orwh/) has expressed interest in the potential co-funding of applications that focus on the improvement of the health of women through biomedical and behavioral research. 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 Domestic Foreign institutions are not eligible to apply. 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. The PI of the clinical component would ideally be an obstetrician with extensive training in clinical pharmacology and experience in clinical trials. It is recognized that availability of individuals trained in both disciplines is limited. To satisfy the requirements of this RFA, the NICHD will allow, if well justified, the designation of an obstetrician with experience in clinical trials as the PI of the OPRU and a physician, Pharm.D., or Ph.D. in pharmacology as the Co-Investigator responsible for the design, performance and analysis of the pharmacologic studies. It is expected that the investigator in charge of the pharmacology component will use diverse Pk-Pd modeling that relates mechanisms of drug action to physiologic processes. Evidence must be provided of the applicant's expertise in pharmacokinetics, pharmacodynamics, drug metabolism and drug bioavailability studies. SPECIAL REQUIREMENTS OPRU Network Organization a. Network Steering Committee (NSC) The NSC will be the main governing committee and the committee through which the NIH interacts and collaborates with the project. The NSC will consist of the Principal Investigators, the NICHD Program Scientists, a non-voting FDA representative and a non-voting independent chairperson appointed by the NICHD. b. Advisory Board This board, appointed by NICHD, will consist of scientists who will advise the NSC. c. Data, Safety and Quality Monitoring Board The NICHD will appoint an independent Data, Safety and Quality Monitoring Board. Meetings The Network Steering Committee will meet at least four times a year in the Washington D.C. area. In addition, PIs will communicate monthly by formal conference calls. Travel funds for these meetings should be included in the budget of the individual Center applications. Components of an OPRU A. Principal Investigator, basic/pre-clinical research co-investigator and other investigators The Principal Investigator is the person responsible for the overall management of the clinical pharmacology component including coordination of the participating specialists whether within a single institution or a consortium of institutions; design and submission of proposed protocols for pharmacologic studies; and implementation, monitoring and data submission and analysis of the clinical studies. The application must identify a basic/pre-clinical research co-investigator as the person responsible for coordinating the OPRU basic pre-clinical research scientists, whether within a single institution or a consortium of institutions, in development of adjunct basic/pre-clinical studies in cooperation with clinicians, conduct of the basic studies in conjunction with ongoing clinical trials/studies, and collaboration and sharing of basic resources and reagents within an OPRU and with other OPRUs. The application must list scientists who will be involved in the OPRU studies including medical subspecialists, geneticists, experimental pharmacologists, molecular and developmental biologists, developmental toxicologists, and maternal-fetal medicine specialists. The application must detail the role of all co-investigators. The collaboration of clinicians and/or basic scientists from different OPRUs is encouraged, based on shared interests and complementary talents. Other investigators with obstetric privileges at the awardee institution will be eligible to utilize the resources for studies of drug efficacy, metabolism and/or effects in pregnant patients, supported by independent research funds, if the protocols have been approved and prioritized by the NSC. These individual investigator protocols must not delay or interfere with the pursuit of the collaborative studies that are the OPRUs' primary responsibility. At each funded OPRU site, priority will be given to studies within the OPRU. B. Facilities Each OPRU must include a clinical pharmacology research component that encompasses participation by the multiple clinical specialists who have access to high-risk and general obstetric population. The clinical component may represent a single institution or a consortium of institutions within a close geographical region. Diseases amenable to clinical pharmacology intervention include, but are not limited to, asthma, hypertensive disorders, psychiatric illness, seizure disorders, diabetes, renal disease, autoimmune disorders, clotting disorders and other chronic high risk obstetrical conditions. Specialists who could participate in the clinical component include, but are not limited to, obstetricians, maternal-fetal medicine specialists, neurologists, endocrinologists, psychiatrics, anesthesiologists, hematologists, gastroenterologists, and infectious diseases specialists. The obstetrical unit must have at least 2,700 births per year currently in the unit, with a minimum of 30 percent high-risk pregnancies. Clinical Facility A designated physical site where the clinical pharmacology/clinical trials will be performed is required. It is desirable that each OPRU have both inpatient and outpatient capabilities. These could be provided by a metabolic ward and an outpatient clinic or a General Clinical Research Center (GCRC) that is suitable for admitting pregnant women or a unit similarly equipped for conducting clinical research. For extended Pk studies, visiting nurses may be used. A labor and delivery suite may be used occasionally for drug studies during labor and delivery. Other institutional components related to the OPRU must also be described. Established policies and procedures for conducting clinical research in these facilities, in both low-risk and complicated pregnancies, must be described. C. Core Laboratory A funded OPRU may include a core laboratory dedicated to perform specialized analysis (e.g., drug protein binding, radioreceptor assays, red cell drug partition studies, HPLS-MS drug assays). This laboratory may also support basic and/or preclinical studies approved by the NSC. D. Basic and/or pre-clinical research capabilities The clinical component will be linked to an experimental pharmacology department or similar facility with a pharmacogenetic and pharmacogenomics laboratory and have easy access to animal facilities for experimental studies in obstetrics and fetal pharmacology. The basic components of the application should identify the multi-disciplinary, interactive basic or preclinical team of researchers committed to perform studies on elucidation of different mechanisms of drug action during pregnancy compared to the non- pregnant state, as well as studies of placental transport of xenobiotics and fetal pharmacology. The team should be able to conduct fetal pharmacokinetics and toxicokinetics, and determination of fetal dose exposure and secondary pharmacologic and/or toxic drug effects on fetal organ development. E. Nurse Coordinator A qualified nurse coordinator is one of the most important assets of an OPRU. The nurse coordinator reports to and takes direction from the PI. The nurse coordinator, in cooperation with the Adjunct Clinical Pharmacologist (see below), carries out as many parts of the research protocols as possible, dovetailing schedules for maximum efficiency and instructing and supervising the other nursing staff in those operations or procedures for which he or she is unavailable. The nurse coordinator is a full-time position supported by the grant. F. Patient Recruiter A patient recruiter may be justified to insure the efficient recruitment of patients required in Network protocols. This individual maintains a registry of potential study candidates, gathers recruitment information from different areas of the hospital, clinics and private offices to match potential study patients with specific protocols (up to 50 percent time and effort). G. Adjunct Clinical Pharmacologist This position applies to those applications in which the PI of the OPRU is both an obstetrician and a clinical pharmacologist. An applicant may request support for salaries and fringe benefits for this position (maximum 50 percent time and effort). The Adjunct Clinical Pharmacologist may be a physician who is fully trained in obstetrics, may have completed subspecialty training, and wishes to gain experience in the conduct of obstetric or fetal pharmacology research under the guidance and supervision of the PI or some other appropriate person. Alternatively, the adjunct clinical pharmacologist may be a non-physician holding the Pharm.D. degree or a Ph.D. in Pharmacology who has had special training in clinical pharmacology and wishes to obtain additional supervised clinical experience. Support for the associate clinical pharmacologist from the OPRU is for research time and effort only, unless this person is a licensed physician who assists the PI in supervising patient care in the Unit. A qualified individual may be supported for up to two years as an associate clinical pharmacologist at an OPRU. H. Data Coordinator Each OPRU application should include information about the data management system to be used in the Unit for collaborative studies being performed by the Network. If justified by the expected volume of work, a data coordinator may be supported (up to 20 percent time and effort) by an OPRU grant. This person will organize the data in preparation for transmission to a future OPRU Data Coordinating Center, to the NICHD and to other OPRUs when appropriate. These functions are critical to the success of the Network. I. Pharmacy The availability of a pharmacy capable of supporting clinical research activities and experienced in the preparation of materials for randomized clinical trials should be documented. Minimum Application Requirements o The academic productivity of the investigators who will be involved in the clinical core must be documented. Evidence of the ability of the PI to recruit patients for clinical studies must be provided. o Principal Investigators of the basic and/or pre-clinical research components must be established researchers, preferably holding peer-reviewed grant and/or contract support, and must provide evidence of academic productivity. o The application must list facilities available for fetal and placental research and indicate whether primate animal facilities will be available for obstetric-pharmacology research activities. o Evidence of participation in multi-center trials and/or collaborative efforts. o Evidence of an established computerized perinatal data system. o Letters of support and history of clinical and basic research productivity must be provided to document departmental and institutional commitments to collaborative research. o Evidence of access to obstetrical patients with a variety of medical conditions who are available for drug studies must be provided. Letters of commitment by subspecialists and evidence of previous collaborations must be provided. o Evidence should be provided of the proposed OPRU's adherence to the International Conference on Harmonization (ICH) Good Clinical Practice guidelines. Applicants should describe how the unit complies or intends to comply with ICH Good Clinical Practice guidelines adopted by the Food and Drug Administration (FR 62:90, 1997). o To provide peer reviewers and the NICHD with an idea of the capabilities of the investigators, applicants must submit one sample protocol that they would propose to the Network NSC. This example should be a draft (up to six pages in length) of a sequential drug study design following the phases outlined under Research Objectives and Scope. The draft research project should include a hypothesis, brief background information, and a narrative of the procedures to be employed. Applicants should include details of statistical and pharmacokinetic and pharmacodynamic designs and methods of analysis, and enough additional specific material for a scientific review. o To provide peer reviewers and the NICHD with an idea of the investigators capacity to interact with other researchers, applicants must submit two sample protocols of a basic and a translational or preclinical research project in obstetric and fetal pharmacology that the investigators would propose to the NSC for collaboration with other investigators. The research projects proposed should provide evidence of synergy. This sample protocol should be a draft for consideration by other participants in the program, and should include enough detail (hypothesis, design, rationale, significance, procedures, resources required, and discussion of feasibility) to permit evaluation of the proposal for scientific merit. The research proposed should complement the specific research proposed in response to the previous paragraph. These protocols should be presented in no more than six pages. Budget Preparation Allowable costs in NIH cooperative agreements are governed by rules set forth in the NIH Grants Policy Statement and as stated in the Notice of Grant Award. Under these rules, the PI may exercise flexibility to meet unexpected requirements by rebudgeting or requesting approval to rebudget among categories within the total direct cost budget of the OPRU (as shown on the Notice of Grant Award), within the ceilings set in these guidelines. OPRU grants are for five years, at a maximum level of $500,000 in direct costs for the first year. The maximum level may be exceeded by the amount of F&A costs for subcontracts. Items supportable through an OPRU cooperative agreement award may include: (1) Administration o Personnel: Principal Investigator (maximum of 15 percent time and effort); Principal Investigator and Co-Investigator (maximum 20 percent time and effort for both); Co-Investigator for basic/translational research (maximum 10 percent time and effort). o Administrative Support Services: supplies, duplication costs, telephone (not to exceed $4,500). o Travel: PI, Associate PIs, and Nurse Coordinator to all meetings of the NSC (a total of 12 trips a year). o Other costs (itemized and individually justified) not to exceed $2,500. (2) Core Laboratory o Personnel: Core laboratory director (maximum 25 percent time and effort); core laboratory technician (maximum 50 percent time and effort). o Equipment: The equipment used in the core laboratory should be primarily that available to the investigators or obtainable from institutional resources. New equipment, up to a maximum of $50,000 total cost distributed over the first four years of the award, may be requested in an OPRU application, with appropriate justification. o Supplies: Appropriate for OPRU participation in collaborative protocols and for support of specialized analyses for investigator-initiated studies within the OPRU. o Other: Maintenance costs of equipment purchased with the award or otherwise dedicated to OPRU use. The maximum allowable total annual amount for Supplies plus Other in the core laboratory is $20,000. (3) Protocol Implementation Support o Personnel: Nurse Coordinator (maximum 100 percent time and effort each); Adjunct Clinical Pharmacologist (maximum 50 percent time and effort); Data Coordinator (maximum 20 percent time and effort). For studies performed in collaboration with pharmaceutical firms, those firms should pay the fees for research-related clinical determinations. For investigator-initiated studies in which pharmaceutical firms do not participate, costs must be supported by sources other than OPRU funding. Studies of drugs with no commercial sponsors may be funded through a capitation system. Specific protocol-related costs will be capitated according to the anticipated number of patients to be enrolled at the applicant OPRU. Level of funding will be based on actual recruitment. Allocations for this purpose will depend on the availability of funds. For drug company-initiated protocols being performed in the OPRUs, there must be appropriate reimbursements from non-OPRU sources for core laboratory equipment maintenance, supplies, and personnel time, as well as for data management costs. These reimbursements must be used to offset OPRU costs and should be reported as grant-related income. The following items are not fundable through an OPRU grant: (1) Costs of clinical care, such as patient bed costs, outpatient visit fees, and clinical laboratory determinations. These costs must be paid by the pharmaceutical companies for protocols performed on their initiative or by third-party carriers or other sources for investigator-initiated protocols. (2) Laboratory costs (outside the core laboratory) for projects being performed by non-OPRU investigators using the OPRU. (3) Travel to scientific meetings or for any other purpose except to attend meetings of the NSC. 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 U10, 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 NICHD Program Scientists. Facilities and Administrative cost (indirect cost) award procedures apply to cooperative agreements 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 administrative requirements. 1. Awardee Rights and Responsibilities The awardee will have the primary responsibility for defining the details of the project within the guidelines of RFA-HD-03-017 and for performing the scientific activities. The PI is the person responsible for the overall management of the clinical pharmacology component. A basic/pre-clinical research co-investigator is responsible for coordinating the OPRU basic pre-clinical research scientists. The PI agrees to accept close coordination, cooperation, and participation of the NICHD Program Scientists, the Network Steering Committee (NSC) and the Advisory Board in those aspects of scientific and technical management of the project described below. Specifically, the awardees will: o Identify priority issues for research; o Maintain a clinical pharmacology research component, a designated physical site where the clinical pharmacology/clinical trials will be performed, and a core laboratory; the obstetrical unit must have at least 2,700 births per year currently in the unit, with a minimum of 30 percent high-risk pregnancies. o Develop and implement protocols; o Collect and transmit data in an accurate manner; o Execute and supervise the design of pharmacologic studies and clinical trials; o Determine experimental approaches, design protocols, direct experiments, and set project milestones, in consultation with the NSC; o Implement approved plans for sharing research resources; o Submit periodic progress reports in a standard format, as agreed upon by the Network Steering Committee; o Present results and plans at NSC meetings; o Accept and implement the common guidelines and procedures approved by the NSC; o Release data and publish results, as agreed upon by the NSC; and o Implement Data Safety Monitoring plans following NIH guidelines. The OPRU PI may be responsible for industry-sponsored studies leading to labeling of drugs in obstetrics. Other investigators with obstetric privileges at the grantee institution are eligible to utilize the resources for studies of drug efficacy, metabolism and/or effects in pregnant patients, supported by independent research funds, if the protocols have been approved and prioritized by the NSC. These individual investigator protocols must not delay or interfere with the pursuit of the collaborative studies that are the OPRUs' primary responsibility. At each funded OPRU site, priority is given to studies within the OPRU. 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 Program Scientists: Two NICHD Program Scientists will have substantial involvement above and beyond the normal stewardship of the award. The two NICHD Program Scientists will be staff from the Endocrinology, Nutrition and Growth Branch (Pharmacologist) and the Pregnancy and Perinatology Branch (Obstetrician). The role of the NICHD Program Scientists will be to aid the awardees and the NSC in the following ways: o Provide relevant expertise and overall knowledge; o Provide information about ongoing NIH-supported research and resource collections; o Communicate with members of professional organizations of obstetricians and pharmacologists to determine their preference in prescribing drugs for pregnant women and, as part of the NSC, prioritize those drugs in need of study by the OPRU Network; o Attend NSC meetings as one voting member and participate with other NSC members in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Program Scientists will assist and facilitate the group process and not direct it. They will help develop operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist must be informed of all major interactions of NSC members; o Serve as liaison to the Advisory Board; attend Advisory Board meetings as a non-voting member to help coordinate the activities of the projects with those of other NIH pharmacology initiatives. The NICHD Program Scientists will also coordinate the activities of projects funded under this RFA with other U.S. and international efforts; o Serve as liaison between the grantees and the other NIH program staff; o Coordinate the project's activities with NIH-funded repositories and databases to ensure the rapid and efficient distribution and long-term storage of biomaterials and data; o Participate in data analysis, interpretations, and, where warranted, co- author publications that report results of studies performed under this RFA; o Provide assistance to the NSC in the development of procedures for monitoring the performance of the studies. This includes participation in periodic on-site monitoring with respect to compliance with protocol specifications, quality control and accuracy of data recording, and accrual. The NICHD plans to establish a separate Data center to provide statistical consultation, data management, and data analysis, in addition to various logistical services required for Phase III drug trials. NICHD Project Officer: The NICHD will appoint a Project Officer, apart from the Program Scientists, 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 Guidance and Management Structure o The Network Steering Committee (NSC) The NSC will be the overall main governing and management committee and the committee through which the NIH interacts and collaborates with the project. The Network Steering Committee will meet at least four times a year in the Washington D.C. area. In addition< PIs will communicate monthly by formal conference calls. The NSC will consist of the Principal Investigators, the NICHD Program Scientists, a non-voting FDA representative and a non-voting independent chairperson appointed by the NICHD. Each PI will have one vote and the NIH Program Scientists will have a total of one vote. The NSC will establish the Policies and Procedures that govern the Networks' operations, including publications. These documents will undergo periodic review. The NSC will determine all major scientific decisions. The NSC will be responsible for protocol development and review, assisted by a Data Safety, Quality and Monitoring Committee and an Advisory Board. The NSC will also be responsible for facilitating the conduct of translational and basic research related to OPRUs trials/studies, promoting trans-OPRUs collaboration among and between clinical and basic components, analyzing and interpreting OPRU- wide study data, and establishing procedures for reporting results of OPRU trials/studies. Proposed protocols for clinical trials/studies to be performed by a single OPRU or group of OPRUs will be submitted to the NSC for review and evaluation. The three phases of development for the study of drugs in pregnancy will be addressed by the OPRU Network that emerges from this RFA. Protocols to be implemented will be selected by the Network Steering Committee in accordance with criteria and procedures established by the NSC; criteria will include thematic integration and evidence of integrated synergy of proposed research projects. After approval, those clinical investigators participating in the trial/study, in collaboration with investigators from the basic components who will be performing adjunct basic mechanistic studies, will develop detailed protocols. As needed, the NSC may establish subcommittees for special purposes. It is expected that most of the work of the NSC will be performed in these subcommittees. Clinical trials/studies will proceed into the implementation stage only with the concurrence of the NSC and the NICHD. The NSC will appoint a Research Committee to evaluate basic and translational research proposals responsive to the objectives of RFA-HD-03-017. The membership will include the PIs of the basic/preclinical research components of the OPRUs and ad hoc members. The NSC and the NICHD will jointly appoint ad hoc members for the evaluation of quality of science of specific research initiatives. The NICHD plans to establish a separate OPRU Data Center to provide statistical consultation, data management, and data analysis, in addition to various logistical services required for Phase III drug trials. The PI of this Data Center will be a member of the NSC. o Advisory Board An Advisory Board of scientists will advise the NSC on the identification and prioritization of drugs, evaluate and make recommendations regarding appropriateness and coordination of OPRU activities, and make recommendations for adequate communication and sharing of information with other related projects (e.g., NICHD's MFMU and PPRU Networks) to avoid redundant activities and maximize research output. The Advisory Board, chosen by the NICHD with the advice of the NSC, will consist of scientists who are not affiliated with any of the projects and have expertise in clinical pharmacology, maternal-fetal medicine, obstetrics, genetics, pharmacogenomics, molecular and developmental biology, and developmental toxicology. Ad-hoc members will be appointed by the NICHD for evaluation of quality of science and of specific research initiatives. o Data, Safety and Quality Monitoring Board The NICHD will appoint an independent Data, Safety and Quality Monitoring Board to review the endpoint and safety data for all trials/studies on an ongoing basis and report directly to the NICHD Program Scientists. This Board will review protocols and data collection and quality assurance procedures in an advisory capacity. This Board will be funded separately from the Centers. 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: George P. Giacoia, M.D. Endocrinology, Nutrition and Growth Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11B, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5589 FAX: (301) 480-9791 Email: gg65m@nih.gov Catherine Y. Spong, M.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B03B, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6894 FAX: (301) 496-3790 E-mail: spongc@exchange.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: Kathy Hancock Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5482 FAX: (301) 402-0915 Email: kh246t@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: George P. Giacoia, M.D. Endocrinology, Nutrition and Growth Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11B, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5589 FAX: (301) 480-9791 Email: gg65m@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 https://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. SUPPLEMENTAL INSTRUCTIONS: Page Limitations Because applicants will be proposing at least three research plans, a clinical, translational, and a basic proposal, the page limit for the Research Plan sections of the application is 25 pages plus six pages for each proposed protocol. See the SPECIAL REQUIREMENTS section, above, for additional application instructions. 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: https://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 five sets of any appendix material 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. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. 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 CRITERIA FOR EVALUATION OF CONCEPT PROTOCOLS: A) Sequential study design protocol The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment SIGNIFICANCE: Does the drug selected address an important therapeutic dilemma in obstetrics? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of this RFA? Are the sequential phases to study a drug as outlined under Research Objectives properly characterized? Are the pharmacokinetic and pharmacodynamic models appropriate for the study drug and for use in pregnant women? INNOVATION: Does the project employ novel concepts, approaches or methods or will the proposed study optimize the use of the study drug in pregnant women? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and to that of other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Does the project(s) proposed take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? B) Translational or basic research protocol(s) The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment SIGNIFICANCE: Does the study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is there evidence of integrated synergy with other proposed protocols? Do these protocols complement the specific research proposed in the sequential study design protocol? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and to that of other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? REVIEW CRITERIA FOR THE EVALUATION OF THE CORE LABORATORY (if any): o Qualifications, experience, and commitment of the core laboratory director and other core personnel. o The quality of services provided. o The cost effectiveness and quality control of the core laboratory. o The utility of the core laboratory to the overall program. REVIEW CRITERIA FOR THE EVALUATION OF THE OVERALL PROGRAM APPLICATION: The overall program application is evaluated by considering the research projects, supporting cores, and the administrative structure, and how these multi-disciplinary components function together to achieve the goals of this RFA. Overall Assessment: o Scientific merit of the program as a whole, as well as of the individual parts. o Significance of the overall program goals. This includes the significance and importance of the research program to furthering knowledge in obstetric pharmacology. Qualifications, Experience, and Commitment of Key Personnel: o Past accomplishments of the research team (Principal Investigators, Co- Investigator responsible for the pharmacology studies, and Core Leaders). o Evidence of knowledge of the conduct of collaborative clinical research, especially obstetric drug trials (Phases I, II and III). o Evidence of knowledge and expertise in the design and analysis of randomized clinical trials. o Evidence of the applicant's expertise in pharmacokinetics, pharmacodynamics, drug metabolism and drug bioavailability studies. o Evidence of knowledge and expertise in the use of diverse Pk-Pd modeling that relates mechanisms of drug action to physiologic processes. o Quality of the OPRU's participation in either investigator-initiated protocols or Phase I, II and III obstetric drug clinical trials in the recent past. o Evidence of previous successful research collaborations with industry or of efforts to arrange future collaborations. o Willingness to work and cooperate with other OPRUs and the NICHD in the manner summarized in this RFA. Facilities, Procedures and Support: o Adequacy of administrative, clinical, laboratory, animal facilities and data organizational management facilities as described under Special Requirements. o Institutional assurance to provide support to the study in such areas as fiscal administration, personnel management, space allocation, procurement, planning, equipment, and budget. o Suitability of the proposed clinical locus for the Unit in the applicant institution or its affiliated hospital, such as a metabolic ward and outpatient clinic, a GCRC with staff accustomed to conducting studies in obstetric patients, or some unit similarly staffed and equipped. o Availability of and access to suitable populations to participate as research subjects in OPRU studies. o Demonstrated ability of the OPRU to recruit patients for obstetric drug studies. o Evidence of compliance with the Good Clinical Practice and Good Laboratory Practice guidelines that apply to investigators and/or institutions. o Training environment including the institutional commitment, the quality of the facilities, and the availability of research support. 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 DATA SHARING: The adequacy of the proposed plan to share data. 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: October 24, 2003 Application Receipt Date: November 24, 2003 Peer Review Date: March 2004 Council Review: June 2004 Earliest Anticipated Start Date: July 01, 2004 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 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 MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at https://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 https://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 https://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 https://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. 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). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). 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 https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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 https://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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