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RFA-HD-03-001: PEDIATRIC PHARMACOLOGY RESEARCH UNIT NETWORK PEDIATRIC PHARMACOLOGY RESEARCH UNIT NETWORK RELEASE DATE: November 18, 2002 RFA: HD-03-001 National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov) LETTER OF INTENT RECEIPT DATE: February 17, 2003 APPLICATION RECEIPT DATE: March 17, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Child Health and Human Development (NICHD) plans to continue to support an ongoing cooperative Network of Pediatric Pharmacology Research Units (PPRU) that serves as a resource for studies of drug action and disposition in infants, children, and adolescents. Such studies will be conducted by pediatric clinical pharmacologists, clinical trialists, and experts in pediatric diseases cooperatively with investigators at other Units in the Network, or collaboratively with pharmaceutical companies, or independently with other support. The goals of the Network are: 1) to provide the clinical data on new drugs and drugs already on the market that are necessary for U.S. Food and Drug Administration (FDA) approval for use in children; 2) to investigate the pharmacology of new molecular entities and biopharmaceuticals for use in children; 3) to provide the scientific foundation for drug studies in children; and 4) to collaborate with basic and/or translational research scientists in multidisciplinary interactive teams that seek to elucidate differences in biodisposition and response to drugs in children at different developmental stages and between children and adults. RESEARCH OBJECTIVES Background Federal law and the regulations of the FDA require that drugs be tested for safety and efficacy before they are approved for clinical use. This testing must take place in all populations in which the drug will be employed. Since both the qualitative and quantitative aspects of pharmacodynamics and pharmacokinetics are different in immature individuals, studies must be conducted in infants and children before a drug can be approved for use in them. Over the years, several practical problems discouraged the testing of drugs in children. These include the unforeseeable nature of some clinical responses in immature individuals; the possibility of catastrophic unanticipated reactions; the threat of effects on growth or health long after completion of the drug administration; the difficulty in predicting dose- response relationships by extrapolation from data obtained in adults; the ethical problems of conducting non-therapeutic research in children; the awkwardness of procedures for obtaining informed parental consent and children's assent; and the lack of a suitable infrastructure for the conduct of pediatric pharmacology research. In response to the need for appropriate drug therapy studies in pediatric patients, the NICHD established the Pediatric Pharmacology Research Unit Network in 1994. In 1994, the FDA implemented a regulation (Pediatric Rule of 1994) that allows labeling of drugs for pediatric use based on appropriate studies in adults and additional pharmacokinetics, pharmacodynamics, and safety studies in pediatric patients if the course of the disease and drug effects are similar in children and adults. This regulation was designed to encourage pediatric labeling. The FDA issued new regulations in August 1997 (Final Rule of 1997), requiring pediatric studies of certain new drugs. Also, in 1997 the Food and Drug Administration Modernization Act (FDAMA) was enacted into law. This legislation contained a provision (Section 111) that provided exclusivity incentives for the pharmaceutical industry (six months of patent exclusivity) to conduct pharmaceutical trials in children. The pediatric provisions of FDAMA expired in December 2001. The Best Pharmaceuticals Act for Children (BPCA), enacted in January 2002, extended the exclusivity incentives until December of 2007. The BPCA also provides a mechanism for the study of off-patent drugs and identifies the need to conduct studies in the newborn population. Since the implementation of the pediatric provisions of FDAMA in 1997, a number of drugs have received FDA approval for use in pediatric subjects. Despite significant progress, a large number of drugs lacking FDA approval continue to be used in infants and children. Because of this widespread use of unapproved drugs, studies leading to pediatric labeling remain a priority for the next funding cycle of this Network. The implementation of the FDAMA and the BPCA resulted in an impressive increase in the number of pharmaceutical industry-sponsored pediatric studies. Performance of these studies uncovered the need to provide the scientific underpinnings of drug trials in children. Along with these regulatory and legislative developments, the explosion of knowledge in pharmacogenomics has provided the tools to decipher the mechanisms responsible for changes in drug biodisposition during development and the effects of ontogeny on both drug disposition and effects. Objectives and Scope The purpose of this RFA is to continue the ongoing multi-center program of the Pediatric Pharmacology Research Units (PPRU) for another award period of five years. Each PPRU will have the following aims: (1) To provide a locus for the conduct of studies in bioavailability, formulations, drug metabolism, pharmacokinetics, pharmacodynamics, safety, and effectiveness of new drugs and drugs already the market. These studies may be investigator-initiated or they may originate with pharmaceutical companies, Contract Research Organizations (CROs) or the National Institutes of Health. (2) To gather or promote the accrual of the necessary clinical data for pediatric age-specific labeling of drugs. Studies of off-patent drugs and drugs used in the newborn population are highly encouraged. (3) To carry out research on novel approaches and innovation in pediatric pharmacology. Specific areas of interest include, but are not limited to: o Identification, development, validation, and/or extrapolation from adult studies of biomarkers of diagnosis, prognosis, efficacy, toxicity, and of disease activity. o Development and validation of non-invasive pharmacodynamic measurements. o Development and/or adaptation of novel pharmacokinetics-pharmacodynamics modeling technology in pediatrics (e.g., partial physiologic-based pharmacokinetics). o Development of new study designs in pediatrics. o Use of new molecular approaches. o Application of new drug delivery systems to pediatric subjects. (4) To implement studies on the developmental characteristics and genetic polymorphisms of drug metabolizing enzymes (DMEs), transporters, and receptors. Phenotypic-genotypic correlations. (5) To apply pharmacogenomic and proteomic tools in clinical studies. 6) To provide training in clinical and developmental pharmacology. Guidance and Management Structures The management of the PPRU Network includes three committees: (1) The Network Steering Committee, comprising all Network Principal Investigators, the NICHD Program Coordinator, and a non-voting FDA representative, 2) an Advisory Board, and (3) a Data Safety and Monitoring Committee. The roles of these committees are defined below in the section "Cooperative Agreement Terms and Conditions of Award." MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (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 January 1, 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 $4.8 million in FY 2004 to fund up to 13 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of five years and a budget for total costs of up to $375,000. 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 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 that operate as or are associated with a for-profit contract research organization performing pediatric drug trials are not eligible. 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 or 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 Principal Investigator (PI) should be a pediatrician with extensive training in pediatric clinical pharmacology or a clinical pharmacologist with extensive experience in clinical drug trials in pediatrics. In applications naming a non-physician as PI, a board-certified pediatrician must be identified separately. For the purpose of this RFA, NICHD will allow the designation of a pediatric subspecialist with extensive experience in clinical trials as the PI of the PPRU and a physician, Pharm.D. or Ph.D as an Associate Clinical Pharmacologist responsible for the design of pharmacology studies. It is expected that the investigator in charge of the pharmacologic component will have expertise in population pharmacokinetic modeling using sparse sampling and optimal sampling strategy and Bayesian forecasting. It is highly desirable that this investigator will use pk-pd modeling that relates mechanisms of drug action to physiologic processes. Evidence must be provided of the PI's and associate clinical pharmacologist's combined expertise in pharmacokinetics, pharmacodynamics, drug bioavailability and drug metabolism studies, pharmacogenetics, and study design of pediatric drug trials. SPECIAL REQUIREMENTS Components of a PPRU A. Principal Investigator (PI) The PI must be an established pediatric clinical pharmacologist or a clinical pharmacologist with extensive experience in clinical drug trials in pediatrics. In case of a non-physician PI or a non-pediatric PI, a board- certified pediatrician must be identified separately in the application (see INDIVIDUALS ELIGIBLE TO BECOME PRINICIPAL INVESTIGATORS, above). Those functions, whether PI alone or PI and pediatrician or PI and Associate Clinical Pharmacologist, may be supported up to 25 percent time and effort. B. Clinical Facility A designated physical site where the clinical research will be performed is required. To allow optimal opportunities for collaboration among PPRUs in the network, it is desirable that each PPRU have both inpatient and outpatient capability. These could be provided by a pediatric metabolic ward and an outpatient clinic, a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources and suitable for admitting children and caring for them as outpatients, or some other unit similarly equipped for conducting pediatric clinical research. Applicant institutions that wish to identify the GCRC as a site for conducting PPRU research should include with the application a letter of agreement from the GCRC Program Coordinator or PI. C. Core Laboratory A funded PPRU may include a core laboratory dedicated to performing specialized analyses and/or data management functions for studies conducted in the PPRU. This should not include procedures routinely performed for a fee in institutional laboratories or available in the laboratories of the investigators utilizing the unit. The core laboratory may be staffed by a PPRU-supported doctoral-level core laboratory director (maximum 25 percent time and effort) and a core laboratory technician (maximum 50 percent time and effort), if the science proposed warrants. The core laboratory director, who reports to the PI, should have responsibility for quality control in that laboratory. The time and effort of the laboratory director may also be devoted to developing new methods for protocols being conducted with PPRU support and to standardizing procedures to be carried out for PPRU network collaborative protocols. In addition, the core laboratory director is responsible for the care and maintenance of the laboratory equipment, and will cooperate with the PI in assisting other investigators in their use of the Unit. D. Other Investigators Any person with pediatric privileges at the grantee institution is eligible to utilize the PPRU resources for studies of drug efficacy or metabolism, supported by independent research funds, if the protocols have been approved and prioritized by the Network Steering Committee. These individual investigator protocols must not delay or interfere with pursuit of the collaborative studies that are the PPRU's primary responsibility. For investigators inexperienced in clinical pharmacology, the PI is expected to provide advice and guidance. Clinical pharmacists are encouraged to participate in PPRU research in collaboration with physicians who bear the responsibility for patient care. No funds for Other Investigators are authorized. E. Nurse Coordinator and Research Nurse A qualified nurse coordinator is one of the most important assets of a PPRU. The nurse coordinator reports to and takes direction from the PI, whether or not he or she is a member of the institution's nursing service. The nurse coordinator, in cooperation with the Associate Clinical Pharmacologist, 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. He or she is responsible for data collection and organization, unless the latter responsibility is assigned to a data coordinator (see below). The nurse coordinator is a full-time position supported by the grant. If the need arises, an additional research nurse will assist the nurse coordinator in all the facets of clinical trials. One or more individuals may be supported in the research nurse position, at a total of one full-time equivalent (100 percent time and effort). 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 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 pediatrics, has completed subspecialty training, and wishes to gain experience in the conduct of pediatric 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 pediatric pharmacology and wishes to obtain additional supervised clinical experience. Support for the associate clinical pharmacologist from the PPRU 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 a PPRU. H. Data Coordinator Each PPRU 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 25 percent time and effort) by a PPRU grant. This person will organize the data in preparation for transmission to the PPRU Data Coordinating Center, NICHD and to other PPRUs 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. 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 PPRU (as shown on the Notice of Grant Award), within the ceilings set in these guidelines. PPRU grants are for five years, at a maximum level of $375,000 in total costs for the first year. Competing continuation applications from existing PPRUs may request an initial year increase of three percent above the level of the direct costs for the final year of the last funding cycle. Items supportable through a PPRU cooperative agreement award may include: 1) Administration o Personnel: Principal Investigator (maximum 25 percent time and effort); secretary (maximum 25 percent time and effort). o Administrative Support Services: supplies, duplication costs, telephone. o Travel: PI, Associate PIs, and Nurse Coordinator to all meetings of the NSC. 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, to up to a maximum of $50,000 total cost distributed over the first four years of the award, may be requested in a PPRU application, with appropriate justification. o Supplies: Appropriate for PPRU participation in collaborative protocols and for support of specialized analyses for investigator-initiated studies within the PPRU. o Other: Maintenance costs of equipment purchased with the award or otherwise dedicated to PPRU use. The maximum allowable total annual amount for Supplies plus Other in the core laboratory is $20,000. 3) Research Services Core o Personnel: Nurse Coordinator and research nurse (maximum 100 percent time and effort each); Adjunct Clinical Pharmacologist (maximum 50 percent time and effort); Data Coordinator (maximum 25 percent time and effort). Each proposed Network protocol should include an estimate of staff time and required hospital ancillary costs needed for the protocol. (These costs should NOT be included in the overall requested PPRU budget, since they will be distributed over all the Network participants in that protocol.) 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 PPRU funding. Studies of drugs already on the market 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 PPRU. 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 pursued in the PPRUs, there must be appropriate reimbursements from non-PPRU sources for core laboratory equipment maintenance, supplies, and personnel time, as well as for data management costs. These reimbursements must be used to offset PPRU costs and should be reported as grant-related income. The following items are not fundable through a PPRU 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-PPRU investigators using the PPRU. 3) Travel to scientific meetings or for any other purpose except for the PI, associate PI's, Nurse Coordinator, and budget personnel to attend meetings of the NSC. Meetings The Network Steering Committee will meet at least four times per year. Applicants should include costs for travel to these meetings in their budget request. Collaboration It is expected that most of the studies conducted in the PPRU Network will be clinical and/or translational for the pediatric age group. In addition to studies leading to pediatric labeling, joint NICHD-industry sponsored research in the development and testing of new molecular entities for the treatment of pediatric conditions is strongly encouraged. Clinical trials in conjunction with other NICHD networks (e.g., Neonatal Research and Maternal-Fetal Medicine Networks) or other NIH pediatric networks designed to provide definitive evidence of the efficacy or lack of efficacy of drugs for specific indications are highly encouraged. Pre-clinical basic studies may be conducted (with other support) in a PPRU's core laboratory. Since advances in pediatric pharmacology depend on studies involving basic, translational, and clinical drug research, it is highly desirable that the PPRU investigators interact and develop joint projects with investigators involved in basic research on the ontogeny of drug metabolizing enzymes, transporters, and receptors, and on mechanisms of pediatric adverse drug reactions. It is expected that all Principal Investigators will cooperate with the NICHD PPRU Program Coordinator in identifying research areas of high priority and in the development of an overall research plan for implementation during the funding cycle. It is expected that all participating PPRUs will be involved in collaborative clinical trials of drugs with other units in the Network through protocols determined by consensus and that individual PPRU will have different and complementary research strengths in pediatric clinical pharmacology. A major consideration in the design of protocols is the thematic integration and synergistic interaction of PPRUs. Local protocols will be permitted only if they fulfill objectives 3, 4 or 5 (above) or if the proposed local study would provide the basis for an anticipated Network protocol. Local protocols must conform to the research priorities established by the Network Steering Committee (NSC) rather than being isolated and unrelated projects. The NSC must approve all local protocols. Pharmacokinetics studies requested by pharmaceutical companies for pediatric labeling purposes and assigned by the NSC to a single PPRU are not considered local protocols. All investigator-initiated protocols must be approved by the NSC. Data Safety and Monitoring For proposals including human subjects, investigators must submit a description of a data safety and monitoring plan that meets the 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 and NIH Guide for Grants and Contracts, June 5, 2000: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html). 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, PHS, 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 NIH program staff. 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 administration requirements. (1) Awardee Responsibilities The PI is responsible for developing and maintaining the PPRU as an institutional and national resource and for overseeing the work of the associate clinical pharmacologist and other members of the PPRU staff. It is expected that the PI will be active in conducting research within the PPRU and in negotiating support from proprietary pharmaceutical organizations. The PI may be responsible for industry-sponsored Network protocols. The PI will assist other investigators in conducting PPRU Network research protocols. The PI will attend the meetings of the Network Steering Committee and participate in its deliberations. Each PI will have primary responsibility to define objectives and approaches and to plan, analyze, and publish results, interpretations, and conclusions of his/her studies. For Network collaborative protocols, this responsibility will be shared with other Network members and the NICHD PPRU Program Coordinator (see below). The awardees retain custody of and primary rights to the data developed under those awards, subject to government rights of access, consistent with current HHS and NIH policies. Awardees must be willing to participate and collaborate with other awardees and with NICHD staff. Awardees will be required to accept and implement common protocols and procedures approved by the Network Steering Committee. (2) NICHD Responsibilities NICHD PPRU Program Coordinator: The NICHD Program Coordinator is responsible for the overall scientific administration of the PPRU Network. The role of the NICHD Program Coordinator will be to aid the awardees and the Network Steering Committee in the following ways: o Assist in the efficient conduct of studies, interventions and trials, including ongoing review of progress, possible redirection of activities to improve performance, and frequent communication with other members of the Network Steering Committee. o Assist in the development of study protocols. o Assist in the review and evaluation of the program and in the development of new research goals through the funding cycle in conjunction with the Steering Committee and the Advisory Board. o Assist in reporting results in the community of investigators and health care recipients. o Serve as liaison between the grantees and the other researchers involved in basic and translational research in developmental pharmacology to foster scientific collaboration and interaction. o Coordinate the PPRU Network activities with other NIH-funded pediatric clinical trials networks to facilitate development of joint projects, avoid duplication, and maximize efficiency. o Participate in data analysis, interpretations and, where warranted, co- author publications that report results of studies performed under RFA HD-03- 001. o Provide assistance to the Network Steering Committee 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. NICHD Project Officer: The NICHD will appoint a Project Officer, apart from the Program Coordinator, who will: o Assure the scientific merit of studies, interventions, and trials done under this initiative, including the option to withhold support of a participating PPRU if technical performance requirements such as protocol compliance and enrollment targets are not met. o Initiate a decision to modify or terminate a study based on the advice of the Data Safety and Monitoring Committee and the Advisory Board after consultation with the Network Steering Committee. o Perform other duties required for normal program stewardship of grants. The NICHD reserves the right to terminate or curtail a study (or an individual award) in the event of substantial shortfall in participant recruitment, follow-up, data reporting, quality control or other major breach of a protocol; if a study reaches a major study endpoint substantially before schedule with persuasive statistical significance; if qualified scientific investigators are not available to participate in the study; if an awardee fails to participate in the committee/group activities; or if there are human subject ethical issues that may dictate a premature termination. (3) Collaborative Responsibilities The management of the PPRU Network includes three committees: o The Network Steering Committee (NSC) will be responsible for protocol development and review assisted by the Advisory Board and by a Data Safety and Monitoring Committee (see below). The NSC will have responsibility for the conduct of protocols, preparation of publications, and update of Network Policies and Procedures. The Network Steering Committee will consist of the Principal Investigators, the NICHD Program Coordinator, and a non-voting FDA representative. The NSC will be chaired by a non-voting outside chairperson selected by the NICHD. The members of the NSC will meet at least quarterly and will communicate biweekly by formal conference calls. o An Advisory Board will advise the NSC on the identification and prioritization of drugs for study and recommend research initiatives. The Advisory Board (chosen by the NICHD with the advice of the Steering Committee) will be composed of individuals with expertise in clinical and developmental pharmacology and clinical trials and drug development in children. Ad hoc members for evaluation of quality of science and of specific research initiatives will be appointed by the NICHD. The research initiatives necessary to fulfill objectives (3) and (4) of this RFA will be approved by the Advisory Board. The NICHD Program Coordinator will serve as Executive Secretary of the Advisory Board, reporting findings to the Steering Committee and protocol investigators. o A Data Safety and Monitoring Committee will monitor the safety of ongoing trials in investigator-initiated trials that do not have pharmaceutical company sponsorship. The Committee will be established by the NICHD and will be composed of individuals with expertise in the design and conduct of clinical trials, ethics, and pharmacology. The Data Safety and Monitoring Committee reports to both the NICHD and the NSC. (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 designee of the NSC chosen without the NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen 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. 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 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)496-9254 Email: stretchr@mail.nih.gov o Direct your questions about financial or grants management matters to: Dianna N. Bailey Grants Management Specialist National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A07E, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6978 FAX: (301) 402-0915 Email: Baileydi@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 the institute 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. 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 Grants Info, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: The application requirements for all applicants are as follows: 1) Participants must be based in a Children's Hospital or its equivalent with access to a sufficient number of eligible research subjects in the pediatric age groups: newborn infants (including prematurely born infants), children, preadolescents and adolescents. This is an essential component of the application and must be detailed in the application. Statistical information should contain data for both inpatient and outpatient facilities, including clinics and access to pediatric practices that may contribute research subjects. 2) Departmental and Institutional commitments to collaborative research must be documented by letters to the applicant and by evidence of past support and history of clinical research productivity. 3) Evidence of access to pediatric patients with a wide variety of medical conditions who are available for drug studies must be provided. Letters of commitment by pediatric subspecialists and evidence of previous collaborations must be provided. The pediatric subspecialties for which no collaboration is anticipated should be listed. 4) Evidence of the ability to recruit patients for pediatric drug studies must be provided. A list of clinical trials performed during the last four years should be provided with the following information: a) investigator initiated or pharmaceutical company sponsored; b) single center or multicenter study; c) number of centers involved and total number of patients studied; d) type of study (pharmacokinetics, pharmacodynamics, drug metabolism, bioavailability, efficacy or safety); e) number of patients studied in the PPRU; f) gender and racial/ethnic composition of the study subjects; g) whether the study was completed; and h) major findings of the study. 5) Qualifications of Principal Investigator and his or her academic productivity must be documented. The PI and/or associate clinical pharmacologist must hold an independent peer-reviewed grant(s) or contract(s) support, must be actively publishing, and must be familiar with academic and proprietary research in pediatric pharmacology. Evidence must be provided of the PI's and associate clinical pharmacologist's combined expertise in pharmacokinetics, pharmacodynamics, drug bioavailability and drug metabolism studies, pharmacogenetics, and design of pediatric drug trials. In addition, evidence should be provided of the applicant's research in previous or ongoing clinical trials, especially of a multicenter nature. Contributions in key areas such as protocol design, data analysis, and interpretation are important. Applicants who are current PPRU Principal Investigators should describe their participation in PPRU Network research during the current award period, including responsiveness to Terms and Conditions of Award. New applicants should describe their research achievements and their participation in randomized trials. 6) Evidence should be presented of the PPRU's adherence to the International Conference on Harmonization (ICH) Good Clinical Practice guidelines adopted by the FDA on May 9, 1997. Applicants should describe how the PPRU complies or intends to comply with ICH Good Clinical Practice (FR 62:90, 1997). 7) A description of the equipment available and pharmacological studies performed in the PPRU's laboratory should be provided. It should be stated whether the laboratory is certified for Good Laboratory Practice by the FDA. 8) A description of the data management system used in clinical trials should be provided. 9) A description of the standard operating procedures adopted in the PPRU to guide the activities needed to plan, conduct and manage single or multi- center clinical trials should be provided. 10) Information about the data management system to be used in the Unit for collaborative studies being performed by the Network should be provided. 11) 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. 12) A detailed description of the clinical and research capabilities of the PPRU should be provided, including a description of pharmacokinetics and pharmacodynamic capabilities, access to a pharmacogenetics laboratory and other strengths in pediatric pharmacology, both in basic and clinical research. 13) To provide peer reviewers and the NICHD with an idea of the capabilities of the Unit's investigators, new applicants must submit one or two examples of drug evaluation studies that they would propose as Network protocols to the Network Steering Committee (Objectives 1 and 2). These examples should be drafts (up to six pages in length) for consideration by other participants in the program, and should include enough detail (hypothesis, design, rationale, significance, procedures, resources required, end points, power calculations, and discussion of feasibility) to permit evaluation of the proposals for scientific merit. 14) Competing continuation applications, as well as new applications, should include one or two examples of research protocols on specific aspects of pediatric pharmacology that participating investigators intend to pursue if the PPRU is funded (see Objectives 3 and 4 and 5). These protocols should be presented in no more than six pages. Each should include a clearly identified hypothesis, brief background information, and a narrative of the procedures to be employed. They should include details of statistical design and enough additional specific material for a scientific review. In addition, each protocol should provide a brief justification of its need for PPRU resources. 15) An explicit statement of the applicant's preparedness to participate in PPRU Network clinical trials according to the terms of the RFA should be in the application, and evidence of a long-term institutional commitment to the needs of the PPRU is required. This may take various forms, including (but not limited to) the waiver of facility fees or bed costs for use of an outpatient clinic or research ward for patients on protocol; equipment and space for a core laboratory; released time for faculty to perform clinical pharmacology research in children; and/or funding for support personnel. 16) A description of the proposed training program in pediatric clinical pharmacology and in the conduct of pediatric drug trials should be included. The training program should include a clinical and research component. The training of nurses, pharmacists, and other health professionals in the conduct of pediatric drug trials should be detailed. The objectives, design, and the direction of the research training program of the Adjunct Clinical Pharmacologist should be described. Page Limitations Because applicants will be proposing at least two research plans, an individual and a collaborative, the page limit for the Research Plan sections of the application is 25 pages plus six pages for each proposed protocol. For questions related to application format, applicants may contact one of the individuals listed under WHERE TO SEND INQUIRIES, above. 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 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/couriers service) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory of Child Health and Human Development Council. REVIEW CRITERIA 1) Criteria for Evaluation of Concept 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your applications overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does the protocol(s) address an important problem in pediatric pharmacology? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of this RFA? INNOVATION: Does the project employ novel concepts, approaches or methods? 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? 2) Criteria for Evaluation of Overall Application Qualifications, Experience, and Commitment of Key Personnel: o Scientific, clinical, and administrative abilities and academic productivity of the Principal Investigator, Associate Clinical Pharmacologist, and other team members. o Knowledge of the conduct of collaborative clinical research, especially pediatric drug trials (Phases I, II and III). This should include specific experience in pharmacokinetic and pharmacodynamic analysis and study design and analysis of randomized clinical trials. Protocols and Procedures: o Quality of the PPRU's participation in either (a) (current Network members) Network protocols, especially investigator-initiated protocols; or b) (new applicants) Phase I, II and III pediatric drug clinical trials in the recent past; o Willingness to work and cooperate with other PPRUs and the NICHD in the manner summarized in this RFA. o Adequacy of administrative, clinical, laboratory, 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 pediatric metabolic ward and outpatient clinic, a GCRC with staff accustomed to conducting studies in children, or some unit similarly staffed and equipped. o Availability of and access to suitable populations to participate as research subjects in PPRU studies. o Demonstrated ability of the PPRU to recruit patients for pediatric drug studies. o Evidence of previous successful research collaborations with industry or of efforts to arrange future collaborations. 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. o Objectives, design, and direction of the training program in clinical pediatric pharmacology and pediatric drug trials. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the section on Federal Citations, below.) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 17 2003 Application Receipt Date: March 17 2003 Peer Review Date: July 2003 Council Review: September 2003 Earliest Anticipated Start Date: January 1, 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 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 AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (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. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.865 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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