NETWORK OF PEDIATRIC PHARMACOLOGY RESEARCH UNITS NIH Guide, Volume 26, Number 38, November 21, 1997 RFA: HD-98-002 P.T. National Institute of Child Health and Human Development Letter of Intent Receipt Date: January 12, 1998 Application Receipt Date: March 17, 1998 PURPOSE 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 serve as a resource for studies of drug action and disposition in infants, children and adolescents. These studies will be conducted by pediatric clinical pharmacologists, either cooperatively with investigators at other Units in the Network, collaboratively with pharmaceutical companies, or independently with other support. The goals of studies conducted by 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, and 2) to investigate the pharmacology of new molecular entities and biopharmaceuticals for use in children. The Network will also serve as a resource for the training of health professionals in pediatric pharmacology and clinical trials. It is anticipated that up to 10 clinical centers will be involved in the program. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention goals of "Healthy People 2000," a PHS-led national activity for setting priorities. This Request for Applications (RFA), Network of Pediatric Pharmacology Research Units, is related to the priority areas of food and drug safety and maternal and infant health. Copies of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0, or Summary Report: Stock No. 017-001-00473-1) are available through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic non-profit organizations, public and private. Awards will be made to children"s hospitals or their equivalent or to educational institutions with accredited medical schools, within the United States. Each PPRU must be an identifiable unit within its institution, its Principal Investigator reporting to the chief of pediatrics or to the chairperson of the pediatrics department. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. Current Network participants are eligible for competing continuation awards. The applicant institution must also meet the standard eligibility requirements for research grants established in the Public Health Service Grants Policy Statement # (OASH) 90-50,000, Rev. 4/1/94. There should be at the applicant institution an ongoing program of excellence in clinical pharmacology, preferably with an emphasis on pediatric applications. The quality of this program must be evident from the receipt by its staff of research support in peer-reviewed competition, or from their consistent record of publication in peer-reviewed research journals. In addition, the applicant institution must have available and accessible a sufficient number of eligible research subjects in the pediatric age groups: newborns, infants, children, pre-adolescents, and adolescents. This is an essential component of the network and must be spelled out in detail in the application. (See Special Requirements) MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an assistance mechanism (rather than an acquisition mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipient"s activity by working jointly with the award recipients in a partner role. Details are discussed later in this document under the section Terms of Agreement. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is January 1, 1999. FUNDS AVAILABLE It is expected that up to 10 applications, including competing continuation and new awards, will be funded. An estimated total cost of $3,000,000 will be available for the first year. Therefore, the maximum total cost request (first year) for individual applications should not exceed $300,000.The number of awards is dependent on the receipt of a sufficient number of applications of high scientific merit. 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. Several practical problems discourage 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 nontherapeutic research in children, the awkwardness of procedures for obtaining informed parental consent and children"s assent in children, the lack of a suitable infrastructure for the conduct of pediatric pharmacology research, the high cost of pediatric studies, and the absence of a financial incentive for the pharmaceutical industry to conduct pediatric pharmaceutical trials if children are a minority of the population for which the drug might be prescribed. The result of these practical problems and the regulatory requirements is that more than three-quarters of the drugs marketed in the United States, including many of the most useful agents in modern therapy, are not approved as safe and effective for use in children. Since the provision of pediatric care without the use of these agents would be unacceptable, they are commonly administered "off-label" (without specific FDA approval) by pediatricians, anesthesiologists, general practitioners, surgeons, and others. Under these conditions the child is at risk of an inadequate therapeutic response or some unanticipated adverse reaction. Physicians can face medicolegal actions as a result of such accidents, but they can also risk suit for failure to utilize an effective drug for a child"s illness, even if that drug does not have specific FDA approval for use in children. Modern pediatric pharmacology is a sophisticated clinical discipline capable of carrying out the studies necessary for the safe and ethical evaluation of drugs in children. Pursuit of such studies, however, is limited by the scarcity of available facilities in which to follow children receiving drugs and to collect data in a systematic way, as well as the insufficient number of qualified clinical investigators interested in this problem. In response to the need for appropriate drug therapy studies in pediatric patients, the NICHD established the Pediatric Pharmacology Research Unit Network (PPRU) in 1994. Seven university units were selected among respondents to an RFA. The Network Steering Committee (NSC) which consists of principal investigators, NICHD staff and an outside chairman, selected protocols for study by the network. In 1995 the FDA implemented a regulation which 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 their disease and drug effects are similar in children and adults. This regulation was designed to encourage pediatric labeling. By April 1997 pharmaceutical companies were required to submit information about the pediatric use of their products, frequency of use, therapeutic significance and safety risks. The FDA issued new regulations in August 1997, to be effective six months later, requiring pediatric studies of certain new drugs. An overwhelming number of drugs lacking FDA approval in pediatrics 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 training of pediatric clinical pharmacologists and health care professionals involved in pediatric drug trials remains a priority because of the increased demand and scarcity of qualified individuals. Objectives and Scope The purpose of this RFA is to continue the ongoing multicenter program of Pediatric Pharmacology Research Units for another award period of five years. Each PPRU will have five specific 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 in the market. These studies may be investigator initiated or they may originate with pharmaceutical companies or Contract Research Organizations (CROs). (2) To gather or promote the accrual of the necessary clinical data for pediatric age- specific labeling of drugs. (3) To conduct research on new pediatric therapeutic modalities, including: a) molecular approaches to the treatment of diseases, b) application of new technology to pharmacodynamic studies and drug delivery systems, c) development of pediatric formulations, and d) validation of new endpoints or surrogate markers. (4) To conduct studies on the developmental characteristics and genetic polymorphism of drug metabolizing enzymes, pharmacokinetic modeling, and simulation technology. (5) To provide a teaching environment in which pediatricians, pharmacists, nurses and others can gain supervised experience in pediatric clinical trials and training in evidence-based pediatric pharmacology. It is expected that most of the studies conducted in the PPRU network will be clinical and for the pediatric age group. Nevertheless, pre-clinical studies may sometimes be conducted (with other support) in a Unit"s core laboratory if these are important as preliminaries or adjuncts to clinical projects in research areas that conform to guidelines developed by the Network Steering Committee (NSC) with the advice of the Advisory Board (see below). Similarly, limited clinical studies in adults may sometimes justify PPRU support if they are necessary for adapting existing protocols to children. It is expected that principal investigators will cooperate with the NICHD Program Coordinator in identifying research areas of high priority for the Network. It is expected that all participating units will be involved in collaborative clinical trials of drugs with other units in the Network through protocols determined by consensus and that individual units will have different and complementary research strengths in pediatric clinical pharmacology. Local protocols will be permitted only if they fulfill objectives 3 or 4 or if the proposed study would provide the basis for an anticipated Network protocol. All local protocols must be approved by the NSC. Pharmacokinetics studies requested by pharmaceutical companies for pediatric labeling purposes and assigned by the NSC to a single Unit are not considered local protocols. Guidance and Management Structures The management of the PPRU Network includes four committees:(1) The Network Steering Committee,(2) an Advisory Board, (3) a Data Safety and Monitoring Committee and (4) an Utilization Review Committee. The roles of these committees are defined in the section Terms and Conditions of this RFA. TERMS AND CONDITIONS OF AWARDS These special Terms and Conditions of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Part 74, and other HHS, PHS, and NIH grant administration policies and procedures. The administrative and funding instrument used for this program is a cooperative agreement, an "assistance" mechanism (rather than "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support/or stimulate the recipient"s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be share among the awardees and the NICHD staff. 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 Unit staff. It is expected that the PI will be active in conducting research within the Unit 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 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, conduct, 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 PPRU Program Coordinator. 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, PHS, 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. NICHD Responsibilities The NICHD Program Coordinator is responsible for the overall scientific administration of the PPRU Network.This role will include the following: oversight to assure the scientific merit of studies, interventions and trials done under this initiative, assistance 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 Steering Committee, and initiation of a decision to modify or terminate a study based on the advice of the Data Safety and Monitoring Committee, the Advisory Board, and/or the Steering Committee. 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, a study reaches a major study endpoint substantially before schedule with persuasive statistical significance, qualified scientific investigators are not available to participate in the study, an awardee"s nonparticipation in the committee/group activities, or human subject ethical issues that may dictate a premature termination. Collaborative Responsibilities The management of the PPRU Network includes four committees: 1) 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, update of Network Policies and Procedures and analysis of reports prepared by the Utilization Review Committee. 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 communicate biweekly by formal conference calls. 2) An Advisory Board will advice 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 trials and drug development in children representing the Center for Drug Evaluation (CDER)FDA,the Committee on Drugs of the American Academy of Pediatrics, the Pediatric Committee of the Pharmaceutical Research and Manufacturers of America, and the Pediatric Committee of the US Pharmacopeia. 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. 3) A Data Safety and Monitoring Committee will monitor the safety of ongoing trials in investigator initiated trials which 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 Safety Committee reports to both the NICHD and the NSC. 4) Utilization Review Committee This Committee will evaluate periodically the information provided by the NICHD Program Coordinator to insure that clinical trials are performed in a cost- effective and time-expedient manner and to monitor performance measured by specified parameters set by the NSC. For pharmacokinetics studies requiring a small number of patients, the Utilization Committee will ensure that the number of protocols are evenly distributed among the different units taking into account factors such recruitment characteristics and protocol complexity. Members of the Utilization Committee will include the NICHD Program Coordinator and two principal investigators selected by the NSC. This Committee will report its findings to the NSC. Arbitration Any disagreement that may arise on scientific matters (within the scope of the award), between award recipients and the NICHD may be brought to arbitration. An arbitration panel will be composed of three members-- one person selected by the individual awardee, one selected by the NICHD Program Coordinator, and a third person selected by these two members. The decision of the arbitration panel, by majority vote, will be binding. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50 Subpart D and HHS regulation at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as subjects in Clinical Research," which were published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. The usual NIH policies concerning research on human subjects also apply. All applications for clinical research submitted to the NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. Investigators may also obtain copies of the policy from program staff under INQUIRES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by January 12, 1998, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning. It allows NICHD staff to estimate the potential review workload and to avoid possible conflict of interest in the review. The letter of intent is to be sent to: George P. Giacoia M.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development Building 61E, Room 4B11/MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 Email: GiacoiaG@HD01.NICHD.NIH.GOV APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, Email: asknih@od.nih.gov. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. 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. Applicants should follow the instructions included with PHS Form 398 except where these are at variance with instructions in this RFA. SPECIFIC REQUIREMENTS FOR APPLICANTS The 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 group: newborn 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 Principal Investigator (PI) of a PPRU must be an established pediatric clinical pharmacologist, preferably holding independent peer-reviewed grant or contract support, actively publishing in the field, and familiar with academic and proprietary research in pharmacology and pharmacokinetics. Evidence should be provided of research by the applicant 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 Network research during the current award period. New applicants should describe their research achievements and their participation in randomized trials. 6) Evidence should be presented of the Units"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 unit complies or intends to comply with ICH Good Clinical Practice (FR 62:90, 1997). A list should be provided indicating the documents generated and filed before, during, and after clinical trials. 7) Description of the equipment available and pharmacological studies performed in the Pediatric Pharmacology 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 Unit to guide the activities needed to plan, conduct and manage single or multicenter clinical trials should be provided. 10) A detailed description of the clinical and research capabilities of the PPRU should be provided, including a description of pharmacokinetics and pharmacodynamic capabilities and other strengths in pediatric pharmacology. 11) To provide peer reviewers and the NICHD 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 (see Objectives 1 and 2). These examples should be drafts (up to 6 pages) 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. 12) Competing renewal 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). These protocols should be presented in no more than 6 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. 13) 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. 14) Description of the training program in pediatric clinical pharmacology and in the conduct of pediatric drug trials. The description of 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 Associate Clinical Pharmacologist should be described. Components of a PPRU A. Principal Investigator (PI) The PI is expected to hold final authority and responsibility for the care of PPRU patients, reporting only to the chief of pediatrics or the chairperson of the pediatrics department, even though the regular care of the patients may be in the hands of other investigators or house officers. The PI must, therefore, be state-licensed as a physician and board-certified in pediatrics. The PI may be supported for up to 25 percent time and effort in the program, and may be assisted by a part-time secretary (20 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 units 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 director 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 Unit. 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 so 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 from 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 Unit"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 Investigator 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. Associate Clinical Pharmacologist Units may request support for salaries and fringe benefits for this position (maximum 50 percent time and effort). The associate 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 associate 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. It is expected that each PPRU will serve as the data coordinating center for one or more collaborative protocols. 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 NICHD and 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. J. Budget preparation Allowable costs in NIH cooperative agreements are governed by rules set forth in the Public Health Service Grants Policy Statement and as stated on 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 $300,000 in total costs for the first year. They are renewable through competing continuation applications, provided funds are available. Competing continuations from existing PPRU"s 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. Personnel: Principal investigator (maximum 25 percent time and effort), secretary (maximum 25 percent time and effort). Administrative Support Services: supplies, duplication costs, telephone. Travel: PI, Associate PI"s and Nurse Coordinator to meetings of the NSC. Budget personnel may attend up to two meetings each year if needed. 2. Core Laboratory. Personnel: Core laboratory director (maximum 25 percent time and effort), core laboratory technician (maximum 50 percent time and effort). 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 cooperative agreement, with appropriate justification. Supplies: Appropriate for unit participation in collaborative protocols and for support of specialized analyses for investigator-initiated studies on the Unit. Other: Maintenance costs of equipment purchased with the award or otherwise dedicated to Unit use. The maximum allowable total annual amount for supplies plus other in the core laboratory is $20,000. 3. Research Services Core. Personnel: Nurse Coordinator and research nurse (maximum 100 percent time and effort each), Associate 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 Unit 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, these costs must be supported from sources other than the 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 on the units, 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 unit costs and should be reported as grant-related income. The following items are not fundable through a PPRU grant: 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. Laboratory costs (outside the core laboratory) for projects being performed by non-PPRU investigators using the Unit. 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. Since applicants will be proposing at least two research plans, the individual and the collaborative, the page limit for the Research Plan sections of the application is 25 pages plus 6 pages for each proposed protocol.For questions related to application format, applicants may contact one of the individuals under INQUIRIES. 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, Suite 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: Susan Streufert, Ph.D. Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E01 - MSC 7510 Bethesda, MD 20892-7510 Applications must be received by March 17, 1998. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD. Incomplete or non-responsive applications will be returned to the applicant without further consideration. Complete and responsive applications 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, a process may be used by the scientific review group in which applications are determined to be competitive or non- competitive based on their scientific merit relative to other applications received in response to this RFA. Applications judged to be competitive will be discussed and assigned a priority score. Applications determined to be non- competitive will be withdrawn from further consideration and a summary statement containing reviewers"s comments will be sent to the PI. Following initial peer review, applications will be evaluated by the National Advisory Child Health and Human Development (NACHHD) Council for program relevance and policy issues before awards are made. Review criteria: o Qualifications and research experience of the PI and staff in clinical pharmacology, a record of research productivity and a demonstrated interest in pharmacological research in children. o An explicitly stated willingness by these investigators to generate protocols to perform on the Unit, to propose protocols to the NSC for collaborative pursuit, and to collaborate with pharmaceutical firms in testing useful drugs in children is required. 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 Scientific and technical merit and relevance to the objectives of this RFA of the sample protocols proposed for pursuit in the Network and in the local PPRU. o Evidence of previous successful research collaborations with industry or of efforts to arrange future collaborations. o Adequacy of facilities, functions, and probable value to the research of any proposed core laboratory. o Adequacy of clinical data management resources available to support PPRU protocols. o Evidence of compliance with the Good Clinical Practice and Good Laboratory Practice guidelines that apply to investigators and/or institutions. o Evidence of institutional commitment to the long-term activities of the PPRU network. 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. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the research. o Appropriateness of proposed budget and duration in relation to the proposed research. The scientific review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA The anticipated date of award is January 1, 1999. Awards will be made on scientific merit as determined by peer review. The availability of appropriate study populations, the extent of investigator experience, adequacy of equipment and facilities, and program balance will also be taken into account. Although this program is provided for in the financial plans of the NICHD, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Timetable Letter of Intent Receipt Date: January 12, 1997 Application Receipt Date: March 17, 1998 Review by NACHHD Council: September 1998 Earliest Possible Award Date: January 1, 1999 INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: George P. Giacoia M.D. Endocrinology, Nutrition and Growth Branch Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11 - MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 E-mail: GIACOIAG@HD01.NICHD.NIH.GOV Direct inquiries regarding fiscal matters to: Mary D. Tozzolo Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17 - MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 E-mail: TOZZOLOM@EXCHANGE.NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.865, Research for Mothers and Children. Awards are made under authorization of the Public Health Service Act, Section 301 (42 USC 421), and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all and contract recipients to provide a smoke free workplace and promote the non-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 the 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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