MECHANISMS OF ADVERSE DRUG REACTIONS IN CHILDREN RELEASE DATE: April 1, 2002 RFA: HD-02-001 National Institute of Child Health and Human Development (NICHD) ( LETTER OF INTENT RECEIPT DATE: June 26,2002 APPLICATION RECEIPT DATE: July 26,2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Child Health and Human Development (NICHD) invites applications to stimulate research on the mechanisms of adverse drug reactions (ADRs) in children. The primary objective of this Request for Applications (RFA) is to encourage and support the study of the molecular and cellular mechanisms involved in the production of ADRs in children. This objective includes research on the role of ontogeny and the characterization of pharmacogenetic and developmental variations of drug metabolizing enzymes (DMEs), transporters, ion channels, and receptors that are responsible for drug toxicity in the pediatric population. Research on the role of ontogeny in the production of, and immune responses to, reactive metabolites and research on the efficiency of detoxification mechanisms are particularly emphasized. The development of adequate animal models to spur discovery of the mechanisms of hypersensitivity reactions in children and the identification of toxicity biomarkers are an important part of this initiative. The purpose of this research is to support studies that are synergistic and complementary within the overall goal of RFA HD-02-001. RESEARCH OBJECTIVES Background Adverse drug reactions (ADRs) are an important clinical problem and represent a major contributor to mortality and morbidity in adults. Although most research to date has largely been confined to adults, the significance of ADRs in children has been increasingly recognized. ADRs in children differ from those manifested in adults in frequency, nature and severity. Upon exposure to some drugs, infants and young children are at a greater risk than adults for developing ADRs (e.g., acute central nervous system and hyperpyretic reactions to anticholinergic drugs such as atropine and scopolamine, and life-threatening adverse reactions to valproic acid. Conversely, children may also be less susceptible than adults to toxic reactions from other drugs. For example, infants are less likely to develop ototoxicity or nephrotoxicity from aminoglycosides, and the hepatocellular damage resulting from an acute acetaminophen overdose is considerably milder in young children than in adults. Mechanistically ADRs encompass a diverse group of reactions: o Dose-dependent, commonly known as Type A reactions. o Dose-independent, commonly referred to as Type B reactions. o End-of treatment reactions (i.e., withdrawal reactions). o Long-term effects such as teratogenesis or carcinogenesis. These two reactions fall outside the scope of this RFA. Type A reactions are dose-related and can be predicted from the known pharmacology of the drug. For example infants, especially preterm infants, are at risk for this type of ADR because of immaturity of their drug metabolizing enzymes (DMEs). The developmental patterns of many biotransformation enzymes (both Phase I and Phase II) have not been sufficiently characterized in children. There is evidence, however, that CYP3A4 activity increases in early childhood and surpasses the enzyme activity in adults. This knowledge raises the possibility that increased activity of some P450 isoforms may be a pathogenic mechanism in the generation of reactive metabolites involved in idiosyncratic reactions. Under normal circumstances reactive metabolites are inactivated by detoxification mechanisms. The glutathione pathway is important in the detoxification of exogenous and endogenous compounds and in the cellular defense against oxidative stress. The ontogeny of the enzymes involved in glutathione conjugation reactions (e.g. glutathione-S-transferase and glutathione peroxidase) and the factors that determine the size of the glutathione pool have not been sufficiently characterized in children. Genetic polymorphisms of DMEs, drug transporters, and drug targets may cause Type A reactions. In slow metabolizers, the reduced enzymatic activity of DMEs may result in severe toxicity when individuals receive standard doses of drugs. Genetic polymorphisms in drug transporters (e.g., MDR1-Type P- glycoprotein) may play an important role in drug accumulation and hypersensitivity reactions. Polymorphisms of drug targets (receptors or ion channels) may lead to toxicity. Drug-drug interactions may also produce ADRs in connection with genetic polymorphisms. Regardless of genotype, newborns have depressed activities of most DMEs, consequently, the phenotypic manifestations of polymorphisms (e.g., fast metabolizers) may not be apparent until later in the developmental continuum. Thus, phenotypic expression of dose-dependent ADRs depends on both ontogenic development and genetic polymorphisms. Type B ADRs are unpredictable and dose-independent. This group includes allergic, autoimmune, and hypersensitivity or idiosyncratic reactions. Allergic drug reactions have been characterized often on the basis of immunological reactions demonstrated in affected individuals. Unfortunately, the mechanisms involved are usually unknown. In penicillin-induced anaphylaxis, drug-specific IgE antibodies produce systemic mast cell release. The IgE antibodies are directed against penicillin covalently bound to proteins. Drug-specific antibodies, however, are often not demonstrated (e.g.,drug fever). Hypersensitivity reactions are unpredictable and rare. Drug reactions similar to those seen in humans are difficult to produce in animal models. Hypersensitivity reactions have been linked to the formation of reactive metabolites that can cause cellular injury. Although Phase I enzymes play a pivotal role in the bioactivation process, occasionally reactive metabolites may be generated by Phase II enzymes. Variations in activity due to polymorphisms may be an important pathogenic factor. It is widely believed that after the initial activation process, the subsequent step in the pathogenesis of hypersensitivity reactions is the formation of adducts (drug-protein conjugates). Recent evidence indicates that covalent binding to plasma or cellular proteins is not a prerequisite and that unmodified drugs may elicit an immune response. The cascade of events initiated by a reactive metabolite that produces the immune response characteristic of drug hypersensitivity remains uncertain. The development of immune reactions requires T helper cell (Th cell) activation. It has been postulated that a balance between T helper cells subtypes (Th1 and Th2) determines the type of immune response. Drug hypersensitivity reactions in children occur at a time of significant changes in the development of the immune system. Not known is whether these ontogenic changes influence the expression and/or severity of pediatric hypersensitivity reactions. At birth, children have a predominance of Th2 immunity that wanes in the first few years of life. Maturation of the immune response may be delayed by environmental or viral infections. There are phenotypic and functional differences in T lymphocytes that may lead to delayed or weaker antigen- specific response in young children. The apparent variability in the susceptibility to ADRs in children compared to adults appears to be multifactorial. It is known that viral infections, which are common in early childhood, are associated with an increased risk of ADRs, but the mechanism is unknown. In addition to inadequate identification and recognition systems, ontogenic variations in drug metabolism and immune reactivity together with genetic, environmental, and nutritional factors may all play significant roles in the observed differences in ADRs between children and adults. Research Objectives and Scope The objective of RFA HD-02-001 is to encourage and support mechanistically based research in pediatric ADRs, focusing specifically on the role of ontogeny in the production of dose-dependent and dose-independent reactions. To accomplish this goal the ontogeny of the immune system in children needs to be taken into account. Emphasis should be placed on differences in the pathogenesis of ADRs between children and adults. Although the study population may range between newborns and adolescents, the determination of windows of vulnerability (i.e., age periods when ADRs are likely to occur or to have long-lasting consequences) is important for the purpose of this RFA. This initiative encourages significant, innovative, and hypothesis-driven research rather than descriptive studies. The development of innovative molecular, genetic, proteomic, and immunologic methods, techniques, and strategies is encouraged to characterize the mechanisms responsible for dose-related ADRs and hypersensitivity reactions in children. Investigators are also encouraged to develop interdisciplinary approaches involving clinical pharmacologists, geneticists, toxicologists, immunologists and molecular and developmental biologists. The identification and testing of age-related phenotyping probes and biomarkers of bioactivation are important components in achieving the overall goal of RFA HD-02-001 and should be integrated into the proposed research program. Matching phenotypes with DNA sequencing data will be needed to establish functional significance of genetic polymorphisms of DMEs and effectors of drug action. Applications focusing on the ontogeny of DMEs, receptors, transporters, and ion channels must establish a mechanistic link to the pathogenesis of ADRs. Non-invasive techniques (e.g., use of urinary cells or blood cells) or use of in vitro systems with human tissues will be needed for the identification of receptor, ion channel or transporter polymorphisms. However the relevance of cell culture studies needs to be established. Research issues and topics that would be responsive to RFA HD-02-001 include, but are not limited to, the following examples. Applicants are encouraged to propose other topics that address the overall goals of this initiative. Sample research topics: o Role of the ontogeny of DMEs, transporters and ion channels in the production of idiosyncratic and dose-related ADRs in children. o Mechanisms by which an immune effect initiated by reactive metabolites results in hypersensitivity. o Mechanisms by which viral and other infections facilitate the development of hypersensitivity reactions. o Role of gender and age in the development of ADRs in children. o Ontogeny of detoxification pathways particularly glutathione-S-transferase. o Role of ontogeny of the immune system in the production of ADRs in children. o Study of the immune recognition processes that result from the binding of drugs to cellular macromolecules. o Use of proteomic technology in the discovery and identification of toxicity biomarkers. o Development of animal models in species that develop idiosyncratic reactions similar to humans. o Use of animal models for expression genomic studies that may distinguish those animals which develop idiosyncratic reactions and those which do not. o Study of the role of reactive metabolites produced in extrahepatic tissues in the production of toxic and/or hypersensitivity reactions. o Efficiency of macromolecular adducts repair mechanisms in children compared to adults. o Determination of the cellular and molecular effects of botanicals in interactive paradigms with proprietary drugs, or studies which may help to predict the toxic effects of botanicals in children. o Role of immunologic tolerance to macromolecular adducts in the pathogenesis of pediatric ADRs. o Use of genomics to define patterns of genes associated with pediatric ADRs. o Role of imbalance between the activities of Phase I and Phase II enzymes in the production of pediatric ADRs. o Determination of the role of the developmental profile of Phase I DMEs involved in the biotransformation of a drug in the pathogenesis of ADRs. Other Considerations Clinical material for phenotyping poor or extensive metabolizers and for studying transporters, receptors, or ion channels may be obtained from patients participating in ongoing pediatric clinical drug trials. Applicants responding to this RFA may or may not be investigators of the parent clinical trial(s) whose data and/or materials and/or subjects they propose to use. It is expected that applicant Principal Investigators who are not parent study investigators will work together with the parent study investigators in developing their applications, documentation of access to participants in a study whose PI is not the applicant investigator must be included with the application. Collaboration with the NICHD Pediatric Pharmacology Research Network is strongly encouraged. For studies of dose-dependent ADRs, the subset of patients more sensitive to a study drug should be selected for further study. Ethical considerations may preclude the use of inaccessible human tissues, and the type of research proposed may require the use of animal models. An overriding consideration in the proposed research must be the appropriateness of testing models and extrapolation to humans of animal data. MECHANISM OF SUPPORT This RFA will use NIH cooperative research project grant (UO1) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. RFA HD-02-001 is a one-time solicitation. The anticipated award date is April, 2003. This RFA uses just-in-time concepts. The NIH UO1 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 $1,500,000 in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund four to six new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $250,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NICHD provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. 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 INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Responsiveness Applications that propose descriptive studies and which do not contain hypothesis-driven studies directed at understanding the mechanisms of adverse drug reactions in children will not be considered responsive to RFA HD-02-001. Development of methodologies to enhance the study of the research areas covered in this RFA is strongly encouraged. Access to Research Subjects Applicants must provide documentation of access to participants if they are to be obtained from among subjects participating in another study. Minimum Requirements The minimum requirements for applicants are as follows (see also REVIEW CONSIDERATIONS below): o A competent, experienced Principal Investigator who is committed to investigate mechanisms of ADRs in children and is willing to cooperate with other Principal Investigators and the NICHD Project Coordinator. o To provide peer reviewers and the NICHD an idea of the capabilities of the investigators, applicants must submit one example of a research protocol on specific aspects of ADRs that participating investigators intend to pursue if funded (see Supplemental Instructions, below). Meetings PIs are expected to participate in two SC meeting annually. The purpose of these meetings is to assess scientific progress, identify new research opportunities, establish priorities, and discuss strategy. Budget requests should include travel funds for the PI and critical staff to attend those meetings in the Bethesda, MD area. Milestones and Evaluations Applications should define yearly milestones, which may be modified at the time of the award. The awardee"s milestones will be provided to the SC. It is expected that the milestones should be adjusted annually at the award anniversary date, both to incorporate the group"s scientific accomplishments and progress in the field in general, as well as to reflect the recommendations of the SC and the Developmental and Clinical Pharmacology Advisory Panel (DCPAP). In accordance with the procedure described under Terms and Conditions of Award, below, NICHD program staff may recommend reducing or withholding funds if a project substantially fails to meet its milestones or fails to remain state-of-the-art. Changes in program activities and/or withholding of funds recommended by the NICHD staff will be approved by the Director of NICHD. The NICHD expects that biologic samples and associated clinical data will be made available to the broader scientific community at an appropriate juncture to support further studies related to mechanisms of ADRs. Reviewers will assess the adequacy of the proposed data sharing plan. Protection of confidentiality of research subjects must be assured. 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: and NIH Guide for Grants and Contracts, June 5, 2000: 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 U01, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the PI is anticipated during performance of the activities. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the PI"s activities by involvement in and otherwise working jointly with the PI in a partnership role, it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the PI for the project as a whole, although specific tasks and activities may be shared between the awardee and NICHD Project Coordinator. 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, PHS, and NIH grant administrative requirements. 1. Awardee Rights and Responsibilities The PI will coordinate project activities scientifically and administratively at the awardee institution and at other sites that may be supported by subcontracts to this award. The PI will have the primary responsibility for defining the details of the project within the guidelines of RFA HD-02-001, and for performing the scientific activities. The PI will agree to accept close coordination, cooperation, and participation of the NICHD Project Coordinator, the SC and the DCPAP in those aspects of scientific and technical management of the project Specifically, the PI will: o Determine experimental approaches, design protocols, direct experiments, and set project milestones, in consultation with NICHD Project Coordinator and the SC, o Implement approved plans for sharing research resources, o Present results and plans at SC meetings, o Accept and implement the common guidelines and procedures approved by the SC and the DCPAP, o Solicit the views of the broad biomedical research community for the phenotypes and/or genotypes of interest, o Release data and publish results. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. 2. NICHD Responsibilities NICHD Project Coordinator: The NICHD Project Coordinator will be staff member(s) of the Endocrinology, Nutrition and Growth Branch. They will have substantial scientific/programming involvement that includes facilitating the partnership between NIH and the proposed research projects, helping to balance the project?s activities with new and emerging research opportunities, and ensuring that the project?s activities are consistent with the mission of NICHD. They will help to maintain scientific balance between accomplishing goals and addressing emerging research opportunities. The role of the NICHD Project Coordinator will be to facilitate, but not to direct activities. It is anticipated that decisions will be reached by consensus with the PI through the SC. The Project Coordinator will participate as a member of the SC. NICHD staff will have a total of one vote. The NICHD Project Coordinator will: o Provide relevant expertise and overall knowledge. o Provide information about ongoing NIH-supported research and resource collections. o Attend SC meetings as one voting member participate with other SC members in the group process of setting research priorities based on thematic integration and synergy, and contribute to the adjustment of research protocols or approaches as warranted. The Project Coordinator will assist and facilitate the group process and not direct it. He will help develop operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. The Project Coordinator must be included in all major interactions of SC members. o Serve as liaison to the DCPAP, attend DCPAP meetings as a non-voting member to help coordinate the activities of the projects with those of other NIH pediatric or developmental pharmacology initiatives. The Project Coordinator will also coordinate the activities of projects funded under RFA HD-02-001 with other US and international efforts. o Serve as liaison between the grantees and the other NIH program staff. o Coordinate the project"s activities with NIH-funded repositories and databases to ensure the rapid and efficient distribution and long-term storage of biomaterials and data. o Participate in data analysis, interpretations and, where warranted, co- author publications that report results of studies performed under RFA HD-02- 001. o Provide assistance to the SC 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 Project Coordinator, who will: o Carry out continuous review of all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines. o Have the option to withhold support to a participating institution if technical performance requirements are not met. o Perform other duties required for normal program stewardship of grants. 3. Collaborative Responsibilities Guidance and Management Structure The overall guidance and management of the program will be provided by a Steering Committee (SC). Additional advice will be provided by the DCPAP, which helps integrate and coordinate the projects funded under RFA HD-02-001 with other related projects. It consists of scientists who are not affiliated with any of the projects. Steering Committee Functions: The Steering Committee (SC) will be the main governing body of the projects to be funded by RFA HD-02-001. It will oversee and coordinate interactions among the projects, and will mediate interactions between the projects and the NIH. The SC will discuss scientific goals and progress, and recommend further research activities based on research findings of ongoing projects. It will help to monitor the plans for sharing research resources. It will also address the recommendations made by the DCPAP. The SC will consist of the PIs of each of the projects, and the NICHD Project Coordinator. Each PI will have one vote and the NIH staff will have a total of one vote. DCPAP Functions: The DCPAP evaluates and makes recommendations regarding appropriateness of projects and of the coordination of activities funded by RFA HD-02-001. The DCPAP also makes recommendations on the appropriateness of research methodology used during the span of this cooperative agreement and on the incorporation of new knowledge in the research area covered by RFA HD-02-001. The DCPAP consists of scientists in clinical pharmacology, immunology, genetics and molecular and developmental biology. The DCPAP is chosen by the NICHD with the advice of the SC. Ad hoc members will be appointed by the NICHD for evaluation of quality of science and of specific research initiatives. 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 SC 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. Endocrinology, Nutrition and Growth Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11B, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5589 FAX: (301) 480-9791 Email: o Direct your questions about peer review issues to: Robert Stretch, Ph.D. Acting Director Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1485 Email: o Direct your questions about financial or grants management matters to: Mary Daley Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A07E, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1305 FAX: (301) 402-0915 Email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NICHD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: George P. Giacoia, M.D. Endocrinology, Nutrition and Growth Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11B, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5589 FAX: (301) 480-9791 Email: 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 in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SUPPLEMENTAL INSTRUCTIONS: The proposed research project should include a clearly identified hypothesis, brief background information, and a narrative of the procedures to be employed. Applicants should include details of statistical design and enough additional specific material for a scientific review. In addition, the PI should provide a brief justification and details about complementary types of research that could be undertaken by other SC investigators. 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: 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. Acting 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 Child Health and Human Development Council. REVIEW CRITERIA 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. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? What will be the expected impact of the information produced by this project on our understanding of the mechanisms responsible for ADRs in children? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? If applicable, is the conceptual framework for studying the ontogeny and conducting phenotyping and genotyping studies of transporters, receptors or ion channels adequately developed and appropriate to the aims of this RFA? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? Does the project proposed challenge existing paradigms or develop new methodologies or technologies? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below.) o 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. OTHER REVIEW CRITERIA: o Willingness to share patient data, as needed, and specimens derived from collaborative studies. o Adequacy of plans to ensure accurate collection, confidentiality, and timely transmission of study data. o Documentation of the expertise of the investigators relevant to the goals of this RFA as evidenced by past accomplishments and by the proposed protocol(s). RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: June 26,2002 Application Receipt Date: July 26,2002 Peer Review Date: October/November 2002 Council Review: January 2003 Earliest Anticipated Start Date: April 2003 AWARD CRITERIA Award 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. o Synergy with other research proposals: In addition to the application?s overall score, selection for funding will also take into account thematic integration and evidence of synergy with other research proposals responding to this RFA. 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: 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 ( , a complete copy of the updated Guidelines are available at 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 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 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: 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 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 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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