DEVELOPMENTAL PHARMACOLOGY Release Date: January 5, 2000 RFA: HD-00-001 National Institute of Child Health and Human Development National Institute on Drug Abuse National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: March 7, 2000 Application Receipt Date: April 13, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute of Child Health and Human Development, the National Institute on Drug Abuse, and the National Institute of Neurological Disorders and Stroke invite research grant applications to study the ontogeny of drug metabolizing enzymes, transporters, and receptors, and the corresponding ion channels and related proteins. A major objective of this initiative is the characterization of the mechanisms involved in gene regulation and expression of these proteins during development, both prenatal and postnatal. This initiative is aimed at unraveling the effects of development on mechanisms of drug action, pharmacodynamics, and drug biotransformation, prenatally and from birth through adolescence. In addition, because drugs are now being developed to target specific receptors or modulators, it is imperative to determine their functional expression over time in the pediatric population. Applications should be designed around a central theme of ontogeny of processes that have pharmacologic relevance, with emphasis on the interaction and/or relationships between these processes (e.g., drug metabolism and drug transport, receptors and ion channels, or receptors and pharmacologic ligands). HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS- led national activity for setting priority areas. This Request for Applications (RFA) is related to one or more of the priority areas. Potential applicants may obtain "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research project grant (R01) funding mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA invites applicants to participate in a collaborative group of R01 grants. Applicants may apply independently or as part of such a collaborative group. The collaborative group approach encourages interaction and collaboration among independent scientists with common goals. It is intended to bring together research projects from investigators who wish to collaborate, but who do not require extensive shared resources. There should be constructive interchange of ideas, data, and/or materials (for example a shared pediatric human tissue bank). To form such a group, at least two independent investigators are encouraged to submit concurrent, collaborative, cross- referenced individual research project grant (R01) applications. These applications must be freestanding and contain independent hypotheses and aims. An application that provides only a service to other applicants is not acceptable. Although these applications must describe the objectives and scientific importance of the collaboration, each project should be able to be accomplished independently. The Principal Investigators may be from one or more institutions. Each application will be reviewed independently for scientific merit, and those judged to have substantial merit will be considered for funding both as an independent award and as a component of the proposed collaborative R01 group. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at https://grants.nih.gov/grants/funding/modular/modular.htm. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 29, 2000. FUNDS AVAILABLE The NICHD intends to commit approximately $1 million, the NINDS $600,000, and NIDA $500,000 in total costs (direct plus Facilities and Administrative) in FY 2000 to fund new grants in response to this RFA. It is anticipated that approximately three to five awards will be made by NICHD, two to three by NINDS, and one to three by NIDA. 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 research proposed may vary, it is anticipated that the size of awards also will vary. Although this program is provided for in the financial plans of the NICHD, NINDS, and NIDA, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of the highest scientific and technical merit. RESEARCH OBJECTIVES Background In the last two years, major drug legislative and regulatory events have occurred that will profoundly affect pediatric drug development in the future: 1) the enactment of the pediatric provisions of the Food and Drug Administration Modernization Act of 1997, and 2) the adoption by the Food and Drug Administration (FDA) of the Final Rule of 1998. The former provides for a six-month exclusivity for marketed drugs with remaining patent or any kind of exclusivity. The Final Rule of 1998 became effective on April 1999 and mandates pediatric studies on new drugs that can benefit children. An unprecedented surge in the number of pediatric drug trials has occurred as a result of these regulatory changes. The performance of drug trials in young children uncovered the need to expand the current knowledge of pediatric pharmacology. Similarly, given concerns about drug abuse and exposure in children and adolescents, expanding our understanding of pediatric pharmacology will greatly improve efforts to prevent and treat addiction in the pediatric population. Recent developments in the biological sciences now offer the opportunity to address problems fundamental to the understanding of drug action and disposition in children in a manner that was not possible a few years ago. Application of molecular biological techniques in pediatrics has permitted insights into a number of physiologic or pathophysiologic mechanisms (e.g., role of D1 and D2 receptors in brain development and of an immature Th2- predominance in the pathophysiology of asthma). Knowledge of the expression and function of genes is being accrued at a fast pace. Application of molecular biological techniques to drug biotransformation, drug transport proteins, and interaction with receptors, however, has been more limited. The ontogeny of drug metabolizing enzymes (DMEs) is only partially known. Although significant advances have been made in the elucidation of the expression patterns of individual CYP isoforms, the mechanisms determining both constitutive and induced expression of these enzymes remain largely unexplored. The mechanisms responsible for the developmental patterns of tissue-specific expression of CYP genes remain unknown. The marked species differences in the ontogeny of drug metabolizing enzymes limit the applicability to humans of animal data. Members of the cytochrome P450 family, such as CYP2D6 and CYP2A6, play important roles in the metabolism of exogenous drugs. CYP2D6 metabolizes drugs of abuse, including opiates, while CYP2A6 is the major nicotine C- oxidase. Like many other members of the cytochrome P450 family, CYP2D6and CYP2A6 are genetically polymorphic, and genetic variability may contribute to vulnerability to addiction. The developmental patterns of CYP2C19, CYP9 and CYP2D6 expression are not well characterized. As a group, Phase II enzymes such as CYP enzymes have not been well studied. Limited information suggests variable developmental patterns. The impact of dietary changes and nutritional status on CYP450 expression during development has not been characterized. An understanding of the role of drug transporters is fundamental for the characterization of drug disposition in children. The P-glycoprotein, a transmembrane ATP-dependent efflux pump, has been demonstrated in adult tissues including proximal renal tubule cells, blood-brain barrier interface, adrenal glands, intestine, interstitium, CD4 cells, and macrophages. There is evidence of drug transporters not only across cells, but also within cells. Anticancer drugs, calcium channel blockers, steroid hormones, certain antibiotics, and antiarrhythmic drugs are transported by P-glycoprotein. In the gastrointestinal tract, P-glycoprotein promotes the excretion of drugs in the lumen. In the brain, the P-glycoprotein efflux transport system can be a major impediment for the treatment of CNS disorders. P-glycoprotein and other newly described transport proteins are responsible for drug resistance to some chemotherapeutic agents and protease inhibitors. There is scant information on the ontogeny of P-glycoprotein in children. There is also a dearth of data on the ontogeny of receptors involved in pharmacologic activity. Most research has focused on the physiologic role of receptors. Age differences in alpha-adrenergic receptor expression have been demonstrated in a variety of animal species. Alpha-adrenergic receptor density decreases with development. Limited information is available on the regulation of receptor expression, although hormonal influences have been demonstrated for some receptors. Gastrointestinal motility is regulated by transmitters and a variety of receptors: cholinergic, adrenergic, dopamine, histamine, 5-hydroxytryptamine (5-HT), gamma aminobutyric (GABA), prostanoid, and dihydropyridine. Current knowledge of the ontogeny of this complex system is fragmentary and incomplete. The ontogenetic expression of dopamine receptors in the brain has been studied primarily in relation to their role in brain development. There is little knowledge, however, on the pharmacologic significance of various brain receptor assemblies during development. The increased use of psychotropic medications in children raises concerns about their short-term and long-term effects in brain development. The effects of antipsychotic drugs on receptor expression and function during development remain unknown. Similar types of receptors may have different developmental patterns. For example cardiac beta-receptors and their linkage to adenylcyclase are present early in development and increase with age. Conversely, in the liver there is a developmental decrease in beta-receptors with consequent decrease in adenylcyclase activity. There is evidence that a decrease in beta-adrenergic receptor function may contribute to the severity of asthma. There is a dearth of information on the ontogeny of airway beta-adrenergic receptors. There is increasing evidence that the effects of dopamine are attenuated in younger animals. Studies are needed to determine the ontogeny of differences in vascular and tubular dopamine receptors and their coupling mechanisms. The ontogeny of ion channels is another area of research need. As with DMEs, animal studies have documented marked species-dependent developmental changes. The characterization of multiple channel subtypes in the adult myocardium has led to significant advances in the treatment of arrhythmias. Developmental changes in ion channels expression and function are likely to markedly influence response to therapy in pediatric arrhythmias. The pathophysiology of convulsions and response to therapy is different in children, especially newborns, compared to adults. The mechanisms of action of anticonvulsants are characterized by sodium channel blockage, increase in GABA inhibition, and calcium channel blockage. The GABA(A) receptor is the site of action of phenobarbital and benzodiazepines. Phenytoin, carbamazepine, and lamotrigine appear to bind to sodium ion channel receptors. The mechanisms regulating the developmental expression and function of these receptors and channels remain obscure. Goals and Objectives The long-term goal of this RFA is to provide the scientific basis for the rational use of drugs in children of all ages, and to characterize the metabolism of drugs of abuse in children and adolescents. The objective is to encourage pre-clinical research on the ontogeny of those processes that are involved in the biotransformation, transport of drugs, drug and receptor interactions, and/or mechanisms of drug action in children. It is known that ontogeny is organ specific. Insights gleaned from developmental biology studies need to be applied to understanding the pharmacology of drugs used in children in an integrated manner. Development and organ maturation involve the completion of a series of complex and interlocking events that proceed as a continuum. Drugs are juxtaposed at different stages of the developmental continuum. The functional readiness of the processes of drug disposition and pharmacological effector mechanisms varies according to the age of the child. Clearly, chronologic age per se is a poor indicator of the stage of development because of large biologic variability. For the rational use of drugs in children and for an understanding of the metabolism of illicit substances in children, a functional map needs to be constructed based on the developmental stage of the processes involved in drug disposition and action. These developmental guideposts then can replace the current system of allocating children in drug trials and of grouping children in clinical studies of substance abuse solely on the basis of chronological age. This initiative seeks to stimulate cooperation and interaction among scientists working in different but complementary areas of research. For example, pathways of drug metabolism may require the sequential involvement of enzymes with different patterns of developmental expression. Also, a drug may be metabolized by more than one type of isoenzyme. The contribution of individual isoenzymes to the overall metabolism of a drug may vary according to the stage of development of the child and may be quite different from the adult pattern. In this context, drug-drug interactions also need to be considered, including the effect of interactions between illicit and therapeutic drugs, both in neonates exposed to drugs in utero and in children using illicit substances. The mechanisms regulating the developmental expression of pharmacological receptors constitute another fertile area of research to be supported by this initiative. Sometimes the low levels of receptors require modifications of the conventional techniques used for their detection. New techniques may be needed, in some instances, to study the tissue distribution of these proteins. Factors that modulate the ontogeny of transporters, DMEs, receptors, and ion channels are largely unknown. Research on the regulation of the ontogenetic expression of these proteins as well as the role of ethnicity and gender are within the scope of this RFA. Research Scope Research issues and topics that would be responsive to this RFA include, but are not limited to, the following examples. Applicants are encouraged to propose other topics that address the overall goals of this initiative. o Regulation and ontogenetic expression of DMEs, transporters, receptors, and related proteins including mechanisms involved, impact of disease processes, and roles of endogenous and exogenous modulators; o Characterization of the developmental patterns of the different isoforms of P450 and Type II enzymes; o Elaboration of the different factors that regulate the expression of P450 genes during different developmental stages; o Characterization of the ontogeny of extrahepatic DMEs; o Determination of the correlation between the developmental patterns of expression of Phase I and Phase II DMEs; o Developmental variations in P-glycoproteins and other related transporters; o The role of intestinal P-glycoprotein in drug bioavailability in children and its correlation with the activity of CYP3A4; o Environmental influences (e.g., nutrition, diet, chemicals, drugs of abuse) and modulating influences (hormones and other ligands) on DMEs and transporters during development; o Inducibility and imprinting of protein expression; o Characterizing the effect of interactions between illicit and therapeutic drugs on the ontogeny of DMEs, transporters, and ion channels; o Imprinting of DME expression due to environmental chemical exposure in early development; o Identification of the mechanisms responsible for activity levels in children of some DMEs (e.g., CYP3A4, CYP1A2) surpassing the activity levels found in adults; o Regulation of constitutive expression of DMEs, transporters, pharmacological receptors, and ion channels during development; o Interrelationship of DMEs and transporters. Is co-expression developmentally regulated? o Developmental regulation of brain GABA(A) receptor expression, the role of GABA(A) receptors in epileptogenesis, and their modulation by neurosteroids, therapeutic drugs, and substances of abuse; o Ontogeny of airway and lung adrenergic receptors; o Ontogeny of ion channels. Characterization of how the pharmacology of these ion channels changes during development; o Ontogeny of polymorphic expression of DMEs and transporters exhibiting genetic polymorphisms; o Mechanisms of action of antiarrhythmic drugs in the immature heart; effects of these drugs on ion channels; o Role of ethnicity in the ontogeny of DMEs, transporters, and receptors; o Ontogeny of 5 HT, dopamine, GABA , and other receptors, and their pharmacological significance in different tissues; o Ontogeny of opioid receptors and their pharmacological significance; o Ontogeny of brain NMDA receptors/ion channel complex and pharmacological prevention of hypoxic damage; o Pharmacokinetic-pharmacodynamic models assessing the sensitivity of the CNS, and other organs, to therapeutic drugs and drugs of abuse; o Effects of hypoxia-ischemia, cold exposure, seizures, and other transient pathophysiologic stresses on the developmental ontogeny of receptors, transporters, and signal transduction systems in specific brain regions during infancy and childhood; o Defining the critical period of neuromodulation by endogenous hormonal influences such as CRF, FSH, and LH on the excitability of neural systems of the neonatal brain. The use of appropriate and newer techniques for the study of ontogeny from a pharmacological perspective is encouraged (e.g., knockout animals and drug applications in vivo, gene expression over time in living animals). An overriding consideration in the proposed research must be the appropriateness of testing models and extrapolation to humans of animal data. SPECIAL REQUIREMENTS Applications that propose descriptive studies and do not contain hypothesis- driven studies directed at understanding the ontogeny of DMEs, transporters, and receptors of pharmacologic significance in pediatrics will not be considered responsive to the RFA. The principal focus of applications should be pre-clinical studies of developmental pharmacology in the areas described above. Multidisciplinary investigations bringing together investigators with expertise in pharmacology, developmental biology, and genetics are strongly encouraged. Development of methodologies to enhance the study of the research areas covered by this RFA is strongly encouraged. Clinical studies are not within the scope of this RFA. 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 are provided 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 research involving human subjects should follow the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at: https://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit 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 this RFA. 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 allows NICHD staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. George P. Giacoia at the address listed under INQUIRIES by March 7, 2000. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone 301-710-0267, E-mail: GrantsInfo@nih.gov, and on the Internet at https://grants.nih.gov/grants/funding/phs398/phs398.html. Application Instructions: Collaborative R01 Modular grant application procedures, described below, must be followed. A separate application must be prepared by each participating institution/Principal Investigator. It is crucial that all applications comprising the collaborative R01 group cite this RFA in section 2 on the application face page (see below). Each participating application must be prepared with the same detail and thoroughness required of any R01 application. Each project must be capable of standing on its own scientifically and of being accomplished independently. If there is a question about the appropriateness of a set of applications for a collaborative R01 group, applicants are encouraged to discuss the issues with one of the NIH staff contacts listed under INQUIRIES. Application Instructions: Modular Grants/Just-in-Time The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Modular grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form Page. Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus Facilities and Administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations. o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and telephone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The RFA label found in the PHS 398 (rev. 4/98) application form must be attached to the bottom of the face page of the application and must display the number of this RFA (HD-00-001). A sample RFA label is available at https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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 (Developmental Pharmacology) and number (HD-00-001) must be typed on line 2 of the face page of the application form, and the YES box must be marked. 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 should be sent to: Director Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Blvd., Room 5E03, MSC 7510 Bethesda, MD 29892-7510 Rockville, MD 20852 (for express/courier service) Applications must be received by April 13, 2000. If the 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 CSR and responsiveness by NICHD, NIDA, and NINDS. 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, a process will be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council of NICHD, NIDA or NINDS. 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 the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged to have major scientific impact and thus deserve a high priority score. For example, an investigator 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 this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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 other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, applied to the evaluation of all research projects, applications proposing participation in a collaborative R01 group also will be evaluated with respect to the intended group interactions. In an administrative note, the reviewers will indicate the effectiveness and feasibility of the proposed collaborative R01 group interactions, whether or not they enhance the prospects for reaching the stated objectives of the group, and the extent of the synergy among the various projects. The criteria for review of the shared resources requested for the collaborative R01 group, which are evaluated independently from the research project, are the following: o Qualifications of key personnel; o Adequacy of approaches, methods, and facilities; o Appropriateness for the collaborative group; o Adequacy of procedures to ensure access to data, sharing of data and resources (both within and outside a collaborative group), publication rights, and means of arbitrating and resolving publication disagreements among the participating investigators. The reviewers also may make recommendations about the shared resource(s) and the reasonableness of the budget request. These recommendations will be considered when funding decisions are made by the awarding institute. The amount awarded for shared resources may depend on the number of component projects awarded. In addition to the above criteria, in accordance with NIH policy, all applications also will be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects also will be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent that they may be adversely affected by the project proposed in the application. Schedule Letter of Intent Receipt Date: March 7, 2000 Application Receipt Date: April 13, 2000 Date of Initial Review: July 2000 Review by Advisory Council: September 2000 Earliest Anticipated Award Date: September 2000 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific and technical merit (as determined by peer review) o Total costs of the proposed project and availability of funds o Program priorities and program balance o For collaborative R01 groups, the interactive nature of the program and component R01s. INQUIRIES 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 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 E-mail: gg65m@NIH.GOV Rebekah Rasooly, Ph.D. Division of Neurobiology and Behavioral Research National Institute on Drug Abuse 6001 Executive Blvd., Room 4260, MSC 9555 Bethesda, MD 20892-9555 Telephone: 301-443-6300 E-mail: RRASOOLY@ngmsmtp.nida.nih.gov Philip H. Sheridan, M.D. Developmental Neurobiology National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2138, MSC 9527 Bethesda, Maryland 20892-9527 Telephone: 301-496-5821 Fax: 301-402-1501 E-mail: ps59i@nih.gov Direct inquiries regarding fiscal matters to: Mary E. Daley Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03D, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-496-1305 Fax: 301-402-0915 E-mail: md74u@nih.gov Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard Rockville, MD 20892-9537 Telephone: 301-443-6710 Fax: 301-594-6847 E-mail: gf6s@nih.gov King P. Bond, Jr. Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3254, MSC 9537 Bethesda, MD 20892-9537 Telephone: 301-496-9231 Fax: 301-402-0219 E-mail: kb33s@nih.gov Although they are not participants in this RFA, the National Institute of Environmental Health Sciences (NIEHS) and the National Heart, Lung and Blood Institute (NHLBI) maintain an interest in this area of research and should be contacted directly for information about their programs. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, Nos. 93.865 (NICHD), 93.853 (NINDS), and 93.279 (NIDA). Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or a Health Systems Agency Review. The PHS strongly encourages all grant 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 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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