NONINVASIVE MEASUREMENT OF IRON BY MAGNETIC RESONANCE IMAGING RELEASE DATE: October 22, 2002 RFA: DK-03-007 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) National Institute of Biomedical Imaging and Bioengineering (NIBIB) (http://www.nibib.nih.gov) LETTER OF INTENT RECEIPT DATE: January 20, 2003 APPLICATION RECEIPT DATE: February 19, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) 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 Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) invite Research Grant Applications (R01 or R21) for projects that have the potential to improve the utility of magnetic resonance imaging as a method for quantitative determinations of tissue iron, especially in liver, heart and brain. A quantitative means of measuring body storage iron that would be non-invasive, safe, accurate and readily available, would improve the diagnosis and management of patients with iron overload, including hereditary hemochromatosis, thalassemia major, sickle cell disease, aplastic anemia, myelodysplasia and other disorders. Magnetic resonance imaging potentially provides a useful and widely available technique for examining the three- dimensional distribution of excess iron in the body, but further research is needed to develop a way to make measurements quantitative. Small businesses are encouraged to respond to a parallel RFA DK-03-009 (see http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-03-009.html) of identical scientific scope that uses the SBIR and STTR mechanisms. RESEARCH OBJECTIVES Background The body iron burden is a principal determinant of clinical outcome in all forms of systemic iron overload, whether from transfusion (for thalassemia major, sickle cell disease, aplastic, myelodysplastic, or other refractory anemias), from increased dietary iron absorption (hereditary hemochromatosis and other forms of primary iron overload), or both (refractory anemia with increased ineffective erythropoiesis). Accurate assessment of the body iron is essential for managing iron-chelating therapy in transfused patients to prevent iron toxicity while avoiding the adverse effects of excess chelator administration. In hereditary hemochromatosis, determination of the magnitude of body iron stores permits identification of individuals who would benefit from phlebotomy therapy from among those at genetic risk for the disease. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) organized an international workshop on the non-invasive measurement of iron on April 17, 2001, to assess the current state of the science and to identify areas needing further investigation. The workshop participants concluded that additional work was needed to develop better quantitative means of measuring body storage iron that would be non-invasive, safe, accurate and readily available to improve the diagnosis and management of patients with iron overload. Currently, biomagnetic susceptometry (SQUID) provides the only non-invasive method for measurement of tissue iron stores that has been calibrated, validated and used in clinical studies. However, the complexity, cost and technical demands of the liquid-helium-cooled superconducting instruments required at present have restricted clinical access to the method. Magnetic resonance imaging was identified as an existing, widely available technology that, with further research, potentially could answer that need. Among conclusions reached, the workshop participants recommended further investigation of magnetic resonance imaging as a method for quantitative determinations of tissue iron, especially in liver, heart and brain. Detailed information on the workshop is available at the NIDDK website: http://www.niddk.nih.gov/fund/other/iron/index.html Subsequently, an article summarizing the workshop and its recommendations has been published (Brittenham GM and Badman DG, Noninvasive Measurement of Iron: Report of an NIDDK Workshop, Blood First Edition Paper, prepublished online August 29, 2002; DOI 10.1182/blood-2002-06-1723; http://www.bloodjournal.org/cgi/reprint/2002-06-1723v1.pdf) Under physiologic conditions, the concentration of iron in the human body is carefully regulated and normally maintained at about 40 mg Fe/kg body weight in women and about 50 mg Fe/kg in men, distributed between functional, transport and storage compartments. Iron overload arises from a sustained increase in iron supply over iron requirements and develops with conditions in which the regulation of intestinal iron absorption is altered (hereditary hemochromatosis, refractory anemia with ineffective erythropoiesis), bypassed (transfusional iron overload), or both. Regardless of the cause, progressive iron accumulation eventually overwhelms the body's capacity for safe sequestration of the excess, resulting in a variety of pathologies. The prognosis in patients with iron overload is influenced by many factors (Harmatz P, et. al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood. 2000; 96:76-79). While ferritin and hemosiderin iron almost surely are not the species directly responsible for the adverse effects of iron, the overall magnitude of storage iron accumulation seems to be a principal determinant of clinical outcome in all forms of systemic iron overload. The reference method for evaluating the extent of body iron excess in systemic iron overload is measurement of the hepatic storage iron concentration (Brittenham GM, et. al., Noninvasive methods for quantitative assessment of transfusional iron overload in sickle cell disease, Semin Hematol. 2001;38:37-56). Total body iron stores can be measured by quantitative phlebotomy, but this approach cannot be used in transfusion- dependent patients with iron overload and is generally acceptable only if the procedure provides therapeutic benefit. The measurement of plasma ferritin provides an indirect estimate of body iron stores, but the usefulness of this measure is limited by the many common clinical conditions in which the plasma ferritin is not a reliable indicator of body iron. While liver biopsy with chemical analysis of tissue iron content provides the most quantitative direct measure of iron status generally available, the discomfort and risk of the procedure limits its acceptability to patients and precludes its frequent use in serial observations. Magnetic Resonance Imagining (MRI) uses the magnetic properties of the body to provide detailed three-dimensional images of any structure or tissue. With MRI, tissue iron is detected indirectly by the effects on relaxation times of ferritin and hemosiderin iron interacting with nearby hydrogen nuclei. The interactions are complex, involving factors such as tissue hydration, the water diffusion coefficient within the tissue, the distribution of iron and water within the tissue examined, the number of iron atoms per molecule of ferritin and hemosiderin (called the loading factor) and, because ferritin iron and hemosiderin iron have different effects on both T1 and T2 (Vymazal J, Urgosik D, Bulte JW. Differentiation between hemosiderin- and ferritin- bound brain iron using nuclear magnetic resonance and magnetic resonance imaging. Cell Mol Biol (Noisy-le-grand). 2000;46:835-842), the relative proportion of these two iron storage materials. Conventional MRI measurements are affected by the instrument used, the applied field strength, the repetition time used in the imaging sequence, the method used to analyze the relaxation curves, and other technical aspects of the measurement procedure. Comparison of absolute signal intensities from one MRI unit to another is unreliable because of substantial intermachine variation (Bonkovsky HL, et. al., Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology. 1999;212:227-234). In the absence of a theoretical understanding of the effects of iron on MRI, empirical efforts to estimate hepatic iron concentrations have used a variety of instruments, magnetic field strengths, imaging sequences (spin-echo, gradient recalled-echo), and parameters (T1 and T2 relaxation times, and signal intensity ratios as measured in proton, T1-, T2- or T2*-weighted images) but no standard or generally accepted method has been adopted for clinical application. To date, MRI has been more useful as a screening technique for the detection of marked iron overload than as a means for quantitative measurement. In particular, with increasing iron concentrations, the signal intensity of the liver is reduced to such an extent that discrimination between different concentrations becomes impossible (Angelucci E, et. al., Limitations of magnetic resonance imaging in measurement of hepatic iron. Blood. 1997;90:4736-4742), at least with current technology. Additional recent publications on both theoretical and practical efforts to develop non-invasive methods for measurement of tissue iron are presented in the article by Brittenham and Badman, referenced above. Research Goals and Topics At present, MRI provides a means of probing the three-dimensional distribution of excess iron in the body, but further efforts are needed to make measurements quantitative. The following are examples of basic and clinical research that could be addressed in the application of MRI to the measurement of tissue iron: o improve understanding of the contribution of ferritin and hemosiderin iron to magnetic resonance effects to guide development of optimal methods for measuring relaxation times and susceptibility, o improve techniques for data acquisition, choice of field strength, selection of timing parameters, reduction of noise, identification of region of interest and selection of analytic methods; o devise phantoms and/or other means for calibrating and validating iron concentration detected by magnetic resonance imaging that could enhance standardization between different laboratories; o develop new methods for non-invasive measurements of iron deposition in the heart, in endocrine tissue, and in specific areas of the brain to determine the role of abnormalities of brain iron in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases, mitochondrial disorders and Parkinson's disease. o determine whether a dual field approach, used by some for MRI measurement of brain iron with promise of greater accuracy than conventional single-field images, can be applied to assessment of liver iron. o investigate the most appropriate magnetic resonance method for determining relaxation times and susceptibility. o determine which data acquisition method is best with selected timing parameters. o develop improved methods of selecting a region-of-interest. o examine the mechanistic contribution of iron in iron-containing materials (e.g. ferritin and hemosiderin) to magnetic resonance relaxation, to be able to select the optimum measurement field strength and methods. These topics are suggestions for further research, only, and investigators are encouraged to develop and propose other lines of investigation relevant to the purposes of the RFA. MECHANISM(S) OF SUPPORT This RFA uses the National Institutes of Health (NIH) research project grant (R01) award mechanism. Pilot studies, using the R21 mechanism, will be considered, if limited in scope and duration. The total requested project period for an R01 application submitted in response to this RFA may not exceed four years for full-scale R01 projects, and two years for R21 pilot studies. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Future unsolicited competing continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats. (See http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. FUNDS AVAILABLE The NIDDK intends to commit approximately $1,000,000 in FY 2003, and the NIBIB intends to commit approximately $250,000, to fund 4 to 7 new grants submitted in response to this RFA. An applicant may request a project period of up to four 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 NIDDK 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. At this time, it is not known whether this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) 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. Among the types of expertise potentially useful in this research may be investigators active in the development of non-invasive measures of iron, scientists and engineers interested in improving MRI technology, clinicians who care for patients with iron disorders, and experts in the physics and chemistry of iron and in iron metabolism. Projects proposing collaborations among such individuals are particularly encouraged. SPECIAL REQUIREMENTS In order to be responsive to this RFA, applications must focus on studies that could lead to improved quantitative MRI measurements of body iron in target organs (brain, heart, liver, endocrine organs) of iron overloaded individuals. Applications addressing alternative technologies will not be eligible for consideration and will be returned to the applicant. Upon initiation of the program, the NIDDK and NIBIB will sponsor annual meetings to encourage the exchange of information among investigators who participate in this program, perhaps in conjunction with other related Institute-sponsored programs. In the preparation of the budget for the grant application, applicants should include travel funds for the one meeting each year to be held in Bethesda, Maryland. Applicants should also include a statement in the applications indicating their willingness to participate in such meetings. 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: David G. Badman, Ph.D. Hematology Program Director National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 621 MSC 5458 Bethesda, MD 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: db70f@nih.gov John W. Haller, Ph.D. Health Scientist Administrator National Institute of Biomedical Imaging and Biomedical Engineering National Institutes of Health 6707 Democracy Blvd., Suite 920 Bethesda, MD 20892-2077 Telephone: (301) 451-4780 FAX: (301) 480-4973 Email: hallerj@mail.nih.gov o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm.752, MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: fc15y@nih.gov o Direct your questions about financial or grants management matters to: Ms. Aretina Perry-Jones Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 745 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8862 FAX: (301) 480-3504 Email: ap19s@nih.gov Pamela L. Mayer Grants Management Analyst National Institute of Biomedical Imaging and Biomedical Engineering 2 Democracy Plaza, Suite 900 Telephone: 301-451-4791 FAX: 301-480-4974 Email: mayerp@mail.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC 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: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm.752, MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: fc15y@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. ADDITIONAL R21 APPLICATION PROCEDURES All application instructions outlined in the PHS 398 application kit are to be followed, with the following requirements for R21 applications: 1. R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" concepts, with direct costs requested in $25,000 modules, up to the total direct costs limit of $250,000 per year. 2. Although preliminary data are not required for an R21 application, they may be included. 3. Sections a-d of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures. 4. R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 15 page limit of items a-d of the research plan SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. 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: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two (2) additional copies of the application and five (5) sets of appendices must be sent to: Francisco Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm.752, MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: fc15y@nih.gov 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 NIDDK. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. 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 (IC) 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 Diabetes and Digestive and Kidney Diseases Advisory Council and the National Advisory Council for Biomedical Imaging and Bioengineering. 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 application's 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? (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? (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)? (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 BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 20,2003 Application Receipt Date: February 19, 2003 Peer Review Date: June/July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA Criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance Nos. 93.849 and 93.286 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)(or other authorizations) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm (cite other relevant policies) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 (cite other relevant regulations). 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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