This Program Announcement expires on February 1, 2004 unless reissued. BIOMARKERS AND CLINICAL ENDPOINTS IN PEDIATRIC CLINICAL TRIALS Release Date: January 18, 2001 PA NUMBER: PA-01-043 National Institute of Child Health and Human Development (http://www.nichd.nih.gov/) National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov/) National Institute of Mental Health (http://www.nimh.nih.gov/) National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov/) THIS PA USES MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICTION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PA. PURPOSE The overall goal of this initiative is to invite qualified researchers to submit new research grant applications to conduct mechanistic studies using patients, patient materials or information from multi-site pediatric drug trials sponsored by the National Institute of Child Health and Human Development (NICHD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Applications in response to this announcement should propose ancillary mechanistic studies of disease pathogenesis and/or of results of therapeutic intervention, determination of biomarkers or surrogate endpoints, and development and validation of clinical endpoints in infants and older children. These ancillary studies must not interfere with the objectives and the conduct of clinical trials. These studies can be performed in clinical trials supported by any source (industry, public and private). Current participation in a trial as a Principal Investigator, co-investigator, or clinical site investigator is not a prerequisite for submission of an ancillary study application. 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 Program Announcement (PA) is related to one or more of the priority areas. Potential applicants may obtain a copy of Healthy People 2010 at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, and laboratories, units of State and 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 PA will use the National Institutes of Health (NIH) research project grant (R01) and the interactive research project grants (IRPG) award mechanisms. The Interactive Research Project Grant (IRPG) (http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html) provides support for formal, investigator-initiated, collaborative relationships. An IRPG group consists of the coordinated submission of two or more applications for related research project grants (R01). Although the applications must describe both the objectives and the scientific importance of the collaboration, each project could be accomplished independently. Principal Investigators may be from separate institutions. Applications will be reviewed independently for scientific and technical merit with those judged to have significant and substantial merit considered for funding both as an independent award and as a component of the proposed IRPG group. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. For all competing applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by NIH. Complete and detailed instructions and information on Modular Grant applications can be found at: http://grants.nih.gov/grants/funding/modular/modular.htm. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. RESEARCH OBJECTIVES Background In the last three 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 (FDAMA) 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 in 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 marked increase in the number of drug studies that occurred after the implementation of FDAMA has brought to light the problem of finding enough children to conduct efficacy trials. This situation occurs despite the fact that a typical pediatric drug trial involves a relatively small number of patients compared to efficacy trials in adults. Regulatory requirements allow for extrapolation to children of the results of efficacy trials performed in adults if the response to therapy and the natural history of the disease is sufficiently similar in children and adults. For a number of conditions, the disease process is dissimilar or the comparison of the natural history of the disease in children and adults has not been undertaken. Another identified problem is the difficulty in establishing efficacy and safety for drugs used in the treatment of chronic childhood conditions because of the lack of adequate markers to establish disease severity, recurrence, and response to therapy. The need to shorten duration and cost of clinical trials in adults has stimulated interest in the development of biomarkers and surrogate endpoints that may substitute for clinical endpoints. This initiative follows the definitions of biomarkers and surrogate endpoints developed by the Definition Working Group NIH-FDA (http://www1.od.nih.gov/osp/ospp/biomarkers/biomarkers.htm). Diagnostic biomarkers or biomarkers of disease severity permit stratification of patients in more homogeneous groups and allow for a decrease in the needed sample size. Biomarkers can also be used to estimate the efficacy of drugs (efficacy biomarkers). These biomarkers must correlate with the clinical outcome, be mechanistically linked to the disease process, and must significantly capture the treatment effect of a drug. The pre-treatment variability of an efficacy biomarker must be small compared to the changes in the biomarker concentration or activity produced by therapy. The effect of drug on a proposed efficacy biomarker must be sustained to allow determination of efficacy. Currently, the majority of biomarkers proposed or developed in pediatrics have been for use in practice and not in clinical trials. A number of examples follow: Biologic substances measured in lung lavage aspirates have been proposed to determine the severity or course of asthma in children. These biomarkers are related to the activation of inflammatory cells and their mediators. Eosinophilic cationic protein, nitric oxide, S-Nitrosothiols, and bcl-2, an apoptosis marker in sputum eosinophils, have been proposed as biomarkers of disease severity. A non-invasive approach--measuring products of inflammatory cell activation in the urine (e.g., leukotriene E4, 9-alpha 11-beta prostaglandin F2)--has also been proposed as biomarkers to estimate activity of the asthmatic process. Biomarkers of disease activity have also been proposed in cystic fibrosis, a disease characterized by chronic inflammation and infection of the lungs and airways. Measurements of elastin degradation products in urine, lipocalcin concentration in serum, and markers of inflammation in sputum have all been suggested, but have not been systematically studied. CD4 counts and viral load determinations has been well studied as surrogate endpoints in children with human immunodeficiency virus (HIV)infections. Clonal markers have been developed to quantify cells in acute lymphoblastic leukemia of childhood. This technology allows for the determination of minimal residual disease. Clonal markers may be used as prognostic biomarkers in acute lymphoblastic leukemia of childhood. Current research into the pathophysiology of diabetes and other endocrine and metabolic diseases has identified candidates for surrogate markers. Examples in type 1 diabetes include the biochemical islet cell antibody markers of GAD65, ICA512/IA2, and IAA; these markers and combinations of these markers need further refinement as to their correlation and specificity to type 1 diabetes, and how they vary by age and ethnicity. New measures which need more extensive research include markers of T cell reactivity to islet cell components, cytokines, the use of MHC-class II tetramers for identifying antigen-specific T cells, and imaging of B-cell inflammation and mass. Such markers may also be useful for distinguishing between type 1 and type 2 diabetes in children, as this is sometimes difficult using clinical criteria alone. Also needed are surrogate markers to predict the development and track the progression of diabetic complications. The identification and development of biomarkers for neurological disorders in children is necessary for the ascertainment of natural history and effect of treatment. A number of gene discoveries have been made on pediatric neurogenetic diseases that cause progressive and/or life- long disability. In addition, there are a number of acquired conditions, such as injury to the developing brain, for which there is a growing understanding of the pathological mechanisms. Great excitement exists in translational research involving experimental therapeutics for these once thought to be untreatable neurological conditions. It is paramount that biomarkers reflective of disease state, progression or complications be established to assess potential therapeutic manipulations. Imaging technology can also be used for the development of diagnostic or mechanistic biomarkers for estimating treatment effects of drug action at the tissue level. Neuroimaging technology, including MR spectroscopy, diffusion tensor imaging, functional magnetic imaging, cranial neonatal ultrasound, and near infrared spectroscopy, can also provide important assessments of the treatment effects of a variety of therapeutic agents in treating acquired, metabolic, and genetic brain disorders of children, and/or monitoring potential complications of the disease or treatment side effects. Ultrasound technology has been used sparingly for the development of biomarkers in pediatrics. For example, high resolution ultrasound monitoring can detect atheromatous plaque formation in young children. The majority of markers proposed or developed in pediatrics have not been subjected to the rigorous validation process needed for their use in clinical trials that lead to drug labeling. In fact most biomarkers have been suggested on the basis of a small number of patients, often without controls and without knowledge of the variability and time course in untreated patients. There are a number of factors that may affect the usefulness of potential biomarkers and surrogate endpoints in pediatrics. The marked difference in the natural history of several diseases when children are compared with adults must be taken into account when biomarkers developed for the adult population are used in pediatrics. Developmental issues are also important. The concentration or activity of many biomarkers used in pediatrics varies according to age. Examples of biomarkers that vary with age include glycosylated hemoglobin, prealbumin, beta-2 microglobulin, adhesion molecules and host immunologic markers. The importance of variation with age has been clearly demonstrated when CD4 counts have been used as prognostic biomarkers in children with AIDS. In normal children, CD4 counts change with age, and in young infants the biologic variability can be quite large. These developmental characteristics must be taken into account when using this laboratory measurement as a biomarker. Ethical considerations may limit the application of biomarkers. The use of controls for validation purposes, invasive procedures, or the use of radioactive materials as biomarkers may lead to the classification of studies as non-beneficial research in normal children. The small sample size characteristic of pediatric drug trials may also prevent the validation of surrogate endpoints and, for certain conditions such as hypertension and hyperlipidemias, the time to endpoint is too long. Clinical endpoints are considered the gold standard for determining efficacy. In the past, drug trials in pediatrics were limited to a few therapeutic categories (e.g., antibiotics, analgesics). The incentives created by FDAMA resulted in the study of a wide range of therapeutic categories not previously studied in children. The establishment of efficacy for a number of drugs is based on clinical endpoints that have not been validated. For example, pain scales in young infants are based on behavioral studies and not specifically designed to test the efficacy of analgesics, and parent’s diaries to establish efficacy of bronchodilators are a poor substitute for measurements of bronchial function. Also diagnosis of certain conditions (e.g., asthma) may be difficult in young infants. Research Scope The following are examples of topics that might be proposed for study in response to this announcement. However, these are only examples and are not meant to be limiting. (Please note that Institutes interest in these topics does not guarantee approval by a trial’s organization leadership). o Identification, development, validation, and/or extrapolation from adult trials of biomarkers of diagnosis, prognosis, and of disease activity. o Identification, development, validation, and/or extrapolation from adult trials of biomarkers of efficacy or toxicity. o Study of treatment effects on additional outcome variables not included in the parent trial. o Use of non-invasive measures of organ function (e.g., functional MRI, magnetic resonance spectroscopy, ultrasound, PET) to identify, characterize, and validate diagnostic biomarkers, intermediate surrogate endpoints, and prognostic biomarkers. o Development of genetic biomarkers and genetic databases using samples and data from trial subjects. o Study and validation of biomarkers used in clinical practice, including markers of disease severity that reflect underlying pathogenesis. o Application of cDNA microarray technology for the development of biomarkers in pediatrics. o Identification and validation of natural history biomarkers that may predict clinical outcome in the absence of therapy. o Estimation of the magnitude of treatment effect on validated adult biomarkers that reflect underlying pathogenesis. o Characterization of the effect of developmental stages in the concentration, activity or other quantifiable measurement of a biomarker. o Development of statistical methodology to establish the validity of surrogate endpoints in pediatrics. o Study of related biomarkers (e.g., biomarkers of inflammation) to determine the most specific and valid measurement of or ascertain whether a composite marker provides a more accurate estimate of underlying pathogenic mechanisms than the individual biomarkers. o Identification and development of biomarkers that can be used in combination with or substitute for severity of illness scoring systems that are inadequate for stratification of patients according to disease severity or for estimation of a treatment effect. o Linking of pharmacokinetics and pharmacodynamic methods to biomarker applications in pediatrics. o Identification and/or validation of osteopenia biomarkers in relation to child development and their correlation to drug effects. o Biomarkers to assess immunoresponsiveness in children at different developmental stages. o Development of biomarkers for pain assessment in young infants that are more sensitive and specific than current pain scales and can be used to determine drug effects accurately. o Applications in pediatrics of echocardiographic and ultrasonographic biomarkers including brachial artery flow mediated dilatation. o Applications in pediatrics of neuroimaging and neurophysiological biomarkers to monitor disease progression, effects of therapeutic interventions, or complications o Development of biomarkers that reflect appropriate neurodevelopmental status from infancy through adolescence with respect to any domain of the developmental process: motor, sensory, cognitive, and behavioral assessment. Research Focus This PA does not seek applications that propose research that merely identifies associations or the development of methodology or instrumentation. The major emphasis of this PA is on mechanistic studies using ongoing pediatric clinical trials at the participating Institutes. Studies needed to develop biomarkers or clinical endpoints such as development of instrumentation should be integrated into the proposed research program. Proposed biomarkers or surrogate endpoints must be biologically plausible, specific with limited interpatient variability, and exhibit significant changes in activity, concentration or other appropriate quantitative measurement in response to treatment (effectiveness biomarkers) or in relation to severity and/or recurrence of a disease. Proposed new clinical endpoints must also be validated in relation to clinical outcome and must be compared to clinical endpoints currently in use. The distinguishing feature of the ancillary studies sought in response to this PA is the requirement for the resources of a clinical trial. Prospective applicants for this PA 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. All ancillary study applications MUST include a letter or statement documenting that the patients, samples, data, and/or materials are available from the parent clinical trial and that the proposed ancillary study has the approval of the parent study’s organization/leadership. Applicants must submit a time line in their application demonstrating that the ancillary study can be completed within a reasonable time. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECT 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 read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH-defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of 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, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available at: http://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. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES Applicants are strongly encouraged to contact program staff listed in INQUIRES, below, with any questions regarding their proposed projects. Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained 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, email: GrantsInfo@nih.gov. Applications are also available on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the Institute staff that the Institute will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. Application Instructions 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 NIH 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. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS398 application instructions.) 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 http://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. o Under Personnel, list ALL 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 F & A) 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 all 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: http://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. Submission Instructions The title and number of the PA 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 five 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be reviewed for completeness by the Center for Scientific Review (CSR). Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second-level review by the appropriate National Advisory Council or Board. 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 likely 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. o 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? o 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? o Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o 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)? o 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, in accordance with NIH policy, all applications will also 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 will also 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 or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. Written documentation of approval from a trial’s Principal Investigator and the parent’s study organization/leadership must be provided prior to funding. INQUIRIES Inquiries 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 Catherine C. Cowie, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 691, MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8804 FAX: (301) 480-3503 E-mail: cowiec@extra.niddk.nih.gov Barbara Linder, M.D., Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 699, MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: linderb@extra.niddk.nih.gov Judith M. Rumsey, M.D. Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7175, MSC 9643 Bethesda, MD 20892-9643 Telephone: (301) 443-1692 FAX: (301) 402-4740 E-mail: jrumsey@box-j.nih.gov Giovanna M. Spinella, M.D. Neurogenetics and Development National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2132, MSC 9527 Rockville, MD 20892-9527 Telephone: (301) 496-5745 FAX: (301) 402-1501 E-mail: gs41b@nih.gov Direct inquiries regarding fiscal matters to: Mary E. Daley Grants Management Branch National Institute of Child Health and Human Development Building, Room 8A 17 Bethesda, MD 20892- 7510 Telephone: (301) 496-1305 FAX: (301) 402-0915 E-mail: md74u@nih.gov Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-6885 E-mail: dt21a@NIH.GOV Karen Shields Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3625 Rockville, MD 20892-9527 E-mail: ks26n@NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.865, 93.848, 93.242, and 93.853. 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 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 Health Systems Agency review. The PHS strongly encourages all grant 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, and 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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