HEPATITIS C: NATURAL HISTORY, PATHOGENESIS, THERAPY AND PREVENTION RELEASE DATE: January 6, 2003 (see amendment NOT-DK-03-003) RFA: DK-03-011 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) National Cancer Institute (NCI) (http://www.nci.nih.gov/) National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/) National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov/) National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov/) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov/) LETTER OF INTENT RECEIPT DATE: March 11, 2003 APPLICATION RECEIPT DATE: April 15, 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 Where to Send Inquiries o Letter of Intent o Submitting an Application o Specific instructions for R21 applications 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), National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of Allergy and Infectious Diseases (NIAID), and National Institute on Drug Abuse (NIDA), invite grant applications for both basic and clinical research in the areas of pathogenesis, natural history, therapy and prevention of hepatitis C. According to the National Health and Nutrition Examination Survey (NHANES) of 1988–1994, 3.9 million Americans were infected with hepatitis C, and of this group, 2.7 million are estimated to have chronic infection. These estimates likely under represent the true prevalence of HCV infection since NHANES was a population-based household survey that excluded several groups with a substantially increased prevalence of infection, such as persons who are incarcerated, homeless, or institutionalized due to disability or mental illness. HCV is the most common blood-borne infection in the United States. HCV transmission occurs primarily through exposure to infected blood. Transmission risk factors include injection drug use, blood transfusion prior to 1992, solid organ transplantation from infected donors, unsafe medical practices, occupational exposure to infected blood, birth to an infected mother, multiple heterosexual partners, and high-risk sexual practices. High HCV seroprevalence rates (from 15 to 50 percent) have been observed in specific subpopulations, such as the homeless, incarcerated persons, veterans being followed at Veterans Affairs Medical Centers, and hemophiliacs, with the highest rates (70 percent to 90 percent) reported in injection drug users. In the general population, persons aged 40 to 59 years have the highest prevalence of HCV infection, and in this age group, the prevalence is highest in African-Americans (6.1 percent). Because of the high rate of persistent infection long-term complications of chronic HCV infection are projected to increase in the next 15 years. Acute hepatitis C leads to chronic infection in approximately 75 percent of cases. Age at the time of infection appears to be an important contributing factor, spontaneous remission occurring more frequently in younger infected individuals. Chronic hepatitis C is often asymptomatic and can be mild; but in 20 percent of patients, the chronic infection leads to progressive liver disease and ultimately cirrhosis and end stage-liver disease. These conditions increase the risk of developing hepatocellular carcinoma (HCC). There is little evidence that the risk of progression of liver disease is affected significantly by virologic factors, including viral levels in the serum, viral genotype, and quasispecies diversity. However, many host factors have been found to increase this risk, including older age, male gender, and an immune suppressed state, such as HIV co-infection. Environmental factors that may complicate or worsen the course of chronic hepatitis C are alcohol, iron overload, obesity, nonalcoholic fatty liver disease, schistosomal co- infection, hepatotoxic medications, and possibly environmental contaminants. The incidence of HCV-related liver cancer is continuing to rise in the United States and worldwide, in part because of the increasing numbers of persons who have been chronically infected for decades, the presence of comorbid factors, and the longer survival of persons with advanced liver disease due to improved management of complications. Although significant advances have been made in the development of treatments for chronic hepatitis C, their efficacy is not universal, and outcome of treatment is considerably affected by viral and host factors. In optimally selected patients, the best current therapies are effective in 40 to 50 percent of cases infected with viral genotype 1 and in 70 to 80 percent of those infected with genotype 2 and 3. Thus, the focus of the RFA is to elucidate the mechanism(s) responsible for the acute and chronic injury caused by hepatitis C, define the factors that determine the course and long-term outcome of chronic infection, including a search for markers of fibrosis progression, and establish the basis for resistance to the current therapeutic regimens followed by focused efforts to improve the response rate with better and less toxic drugs. Since the most effective way to prevent the liver disease caused by hepatitis C is through the development of a preventive vaccine, this RFA also supports the submission of applications that aim at generating a vaccine for hepatitis C. RESEARCH OBJECTIVES A recent NIH Consensus Development Conference entitled "the Management of Hepatitis C: 2002"(http://consensus.nih.gov/cons/116/116cdc_intro.htm) summarized the current knowledge about hepatitis C and made recommendations regarding management and therapy. The Conference also provided key recommendations of areas for future research studies on the epidemiology, natural history, pathogenesis treatment and prevention of acute and chronic HCV infection and its sequelae, in all affected populations. Research Areas of Focus for this RFA 1. Characterization of the mechanisms of viral replication, chronicity of infection, and resistance to host-determined antiviral factors as well as administered antiviral agents: Definition of the viral replication cycle from entry though production of new virions, including definition of key viral functions, analysis of structure- function relationships of viral enzymes/proteins, host-cell interactions and mechanisms both in vitro and in vivo. Identification of the molecular mechanism(s)and predictor(s) of sustained response to antiviral therapy and characterization of mechanisms of non- responsiveness and development of resistance to therapy. Determination of the impact of genetics and co-factors, e.g., other viruses and their therapies, drug and alcohol use, metabolism errors, etc., on viral replication and its response to anti-viral therapies. 2. Characterization of the host's immune responses to infection: Definition of the immunological phenomena that accompany the early natural history, i.e., acute infection and the first 5 years of chronic infection. Studies on the mechanisms by which HCV evades the immune system and sets up chronic infection as well as studies on the mechanisms for maintenance of chronic infection. Characterization of the mechanisms of protective immunity, the specific epitopes of HCV involved in protective immune responses, and surrogate markers of protective efficacy. Characterization of the factors that are deficient in protecting against reinfection. Definition of protective as well as injurious cellular mediated immune- responses and the balance between them. Identification of immunological mechanisms associated with chronic infection, as well as how these are modulated by co-infections with hepatitis B virus (HBV), human immunodeficiency virus (HIV) and other viral agents. Assessment of the effects of drug and alcohol use on immunological mechanisms associated with recovery from hepatitis C as well as evolution to chronicity. Characterization of the unique role of the intrahepatic immune system in determining the course and outcome of HCV infection, as well as the role of modulating factors on this system. 3. The understanding of the pathogenic mechanisms and disease progression: Definition of viral and host factors that contribute to the pathogenesis of HCV infection and to each of the stages of disease progression: acute infection, chronic infection, progression of fibrosis, evolution to cirrhosis and development of HCC. Identification of biomarkers for disease progression, as well as non-invasive markers for fibrosis, cirrhosis and cancer. Characterization of the impact of factors such as age, race/ethnicity, and gender and co-factors such as HIV, immune suppression, environmental factors, obesity, drug and alcohol use on the establishment of the disease as well as the mechanisms by which they contribute to progression of chronic liver disease. Definition of the mechanisms for spontaneous recovery from chronic infection with HCV. Characterization of the molecular pathogenesis of cancer secondary to HCV infection. Studies on the pathogenesis of clinical and biochemical manifestations of both hepatic and extrahepatic disease, including cryoglobulinemia, glomerulonephritis, keratoconjunctivitis sicca, and arthritis. Studies on the molecular and cell biologic mechanisms by which hepatitis C causes symptoms of fatigue. Analysis of the molecular basis for efficacy of novel drugs and active and passive immune-therapies. 4. The development of research resources and approaches to characterize the pathophysiology of HCV infection: Development of fully permissive tissue culture systems that supports the viral life cycle. Development of characterized, representative small animal models: to support experimental studies of the pathogenesis of HCV from infection through cancer, in liver and extra-hepatic organs and to evaluate the safety and efficacy of proposed antiviral therapies, immunotherapies, and disease-based therapies and vaccines to prevent or eradicate disease including HCC. 5. The development of novel vaccines and therapies against HCV. Development of vaccines using conventional as well as innnovative approaches to inducing humoral and cellular immune responses to HCV. Evaluation of efficacy of novel vaccines in animal models of HCV infection. Development of molecular approaches to therapy of hepatitis C, including use of antisense molecules, siRNAs, and gene therapeutic approaches. Development of small molecules with activity against HCV and related viruses that might be later evaluated in man. MECHANISM OF SUPPORT This RFA will use NIH R01 and R21 award mechanism(s). As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, R01 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 2003. The exploratory/developmental grant (R21) mechanism provides short-duration support for preliminary studies of a highly speculative or innovative nature which are expected to yield, within the 2 year time frame, sufficient information upon which to base a well-planned and rigorously defined series of further investigations. Projects will be limited to $100,000 direct costs per year and are limited to two years duration. These grants will not be renewable; competing continuation applications will not be accepted. Continuation of projects developed under this program will be through the regular research grant mechanism (for example, R01). This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see https://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 participating IC(s) intend to commit approximately $6 million in FY 2003 to fund 17 to 22 new and continuing grants in response to this RFA. An applicant may request a project period of up to 5 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 IC(s) 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 if 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 o Faith-based or community-based organizations 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. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Jose Serrano M.D., Ph.D. Director, Liver and Biliary Programs Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Rm. 657 Bethesda, MD 20892-5450 Telephone 301 594-8871 FAX: 301 480-8300 Email: js362q@nih.gov John S. Cole, III, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Suite 5000 Bethesda, MD 20892-7398 Telephone: (301) 496-1718 FAX: 301-496-2025 Email: jc121b@nih.gov Luiz H. Barbosa, D.V.M. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 7601 Rockledge Drive, Rm. 10146 Bethesda, MD 20817 Telephone: 301-435-0075 FAX: 301-480-0868 Email: barbosal@nih.gov Diane L. Lucas, Ph.D. Program Director National Institute on Alcohol Abuse and Alcoholism 6000 Executive Blvd., Rm. 402 Bethesda, MD 20892-7003 Telephone: 301-443-8744 Fax: 301-594-0673 Email: dlucas@nih.gov Leslye D. Johnson, Ph.D. Chief, Enteric and Hepatitis Diseases Branch Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases 6610 Rockledge Dr., Rm. 4015 Bethesda, MD 20892 Telephone: 301-496-7051 FAX: 301-402-1456 Email: ljohnson@niaid.nih.gov Tom Kresina, Ph.D. Deputy Director Center on AIDS and Other Consequences of Drug Abuse National Institute on Drug Abuse 6001 Executive Blvd., Rm. 5200 Bethesda, MD 20892 Telephone: 301-402-1913 FAX 301 594-6566 Email: tk13v@nih.gov o Direct your questions about financial or grants management matters to: Ms. Donna Huggins Grants Management Specialist National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Rm. 711 Bethesda, MD 20892-5456 Telephone: 301-594-8848 FAX: 301-480-3504 Email: dh48v@nih.gov Mr. Bill Wells Grants Management Specialist National Cancer Institute 6120 Executive Blvd. Rm. 243 Bethesda, MD 20892 Telephone: 301-496-8796 FAX: 301-496-8601 Email: ww14j@nih.gov Ms. Shelia Ortiz Grants Management Specialist Division of Extramural Affairs Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Rm. 7171 Bethesda, MD 20817 Telephone: 301-435-0166 FAX: 301-480-3310 Email: ortizs@nih.gov Mr. Judy Fox Chief, Grants Management Branch National Institute of Alcohol Abuse and Alcoholism 6000 Executive Blvd., Suite 504 Bethesda, MD 20892-7003 Telephone: 301-443-4704 FAX: 301-443-3891 Email: jsimons@nih.gov Lesia A. Norwood Grants Management Officer Grants Management Branch Division of Extramural Activities National Institute of Allergy and Infectious Disease, NIH 6700-B Rockledge Drive, MSC 7614, Room 2117 Bethesda, MD 20892-7614 (Express Zip 20817) Telephone: 301-402-7146 FAX: 301-480-3780 Email: ln5t@nih.gov Gary Fleming, J.D., M.A. Chief, Grants Management Branch National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 594-6849 Email: gf6s@nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by March 11, 2003, 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 to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes, Digestive and Kidney Diseases 6707 Democracy Blvd., Rm. 752 Bethesda, MD 20892-5452 Telephone: 301-594-8897 FAX: 301-480-3505 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 https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR R21 APPLICATIONS 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 $100,000 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 https://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 https://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: https://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, appendix material 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) 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 will 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 CSR 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 an 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 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 DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: March 11, 2003 Application Receipt Date: April 15, 2003 Peer Review Date: June/July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. 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: https://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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://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 https://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 https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 https://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 No. 93.848 (NIDDK), 93.396 (NCI), 93.839 (NHLBI), 93.273 (NIAAA), 93.856 (NIAID), and 93.279 (NIDA) 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) administered under NIH grants policies described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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