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DIET, EPIGENETIC EVENTS, AND CANCER PREVENTION RELEASE DATE: April 30, 2004 PA NUMBER: PA-04-099 EXPIRATION DATE: April 30, 2006, unless reissued. Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Cancer Institute (NCI) (http://www.nci.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.393, 93.396 THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanisms of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The NCI invites applications for new R01, R21, and R03 grants which are focused on research leading to the elucidation of mechanism(s) by which dietary factors influence epigenetic processes as well as increasing the understanding of these processes in cancer prevention. The objective is to encourage collaboration between nutrition and epigenetic experts to study bioactive food components with cancer preventative properties, and to examine key epigenetic events in cancer processes (i.e., carcinogen metabolism, cell division, differentiation, apoptosis) so that investigators can begin to establish linkages between epigenetics, methylation pattern, and tumor incidence/behavior. It is anticipated that the information gained will provide guidance for the development of dietary intervention strategies for cancer prevention. RESEARCH OBJECTIVES Background Cancer is a manifestation of both abnormal genetic and epigenetic events. Epigenetic events represent important mechanism(s) by which gene function is selectively activated or inactivated. DNA methylation is the covalent addition of a methyl group to the 5 position of cytosine within CpG dinucleotides and is a fundamental process that not only modulates gene expression, but also is key to regulating chromosomal stability. Fluctuations in the degree of CpG island methylation are key to regulating functional promoters by modifying the binding of transcription factors and methyl-DNA binding proteins. A variety of regulatory proteins including DNA methyltransferases, methyl-CpG binding proteins, histone-modifying enzymes, chromatin remodeling factors, and their multimolecular complexes are involved in the overall epigenetic process. Since epigenetic events are susceptible to change, they represent excellent targets to explain how environmental factors, including diet, may modify cancer risk and tumor behavior. Abnormal DNA methylation patterns are a hallmark of most cancers, including those of high prevalence in the United States, i.e., colon, lung, prostate, and breast cancer. Preclinical and clinical studies provide intriguing evidence that part of the anticancer properties attributed to several bioactive food components, encompassing both essential and non-essential nutrients, may relate to DNA methylation patterns. There are four ways in which nutrients may be interrelated with DNA methylation. The first is that nutrients may influence the supply of methyl groups for the formation of S-adenosylmethionine (SAM). The second mechanism is that nutrients may modify utilization of methyl groups by processes including shifts in DNA methyltransferase activity. A third plausible mechanism may relate to DNA demethylation activity. Finally, the DNA methylation patterns may influence the response to a nutrient. Global hypomethylation, accompanied by region-specific hypermethylation, is a common characteristic among tumor cells. Stress, including that resulting from dietary methionine/choline, folate, zinc, and/or selenium inadequacies, as well as excessive alcohol intake, can lead to global DNA hypomethylation. Interestingly, the continuous feeding of a diet deficient in choline and methionine is recognized to lead to global DNA hypomethylation and cause hepatocellular carcinomas in rats in the absence of any exogenous carcinogen. While limitations in the supply of methyl groups appear to be a common mechanism, available data suggest that other factors determining DNA methylation, including DNA methyltransferase (Dnmt), may be influenced by bioactive food components. Increased selenium concentrations have been found to inhibit Dnmt1 activity and protein expression in vitro. Consistent with these data, selenium deficiency leads to increased Dnmt1 protein expression in vitro. Recently, a polyphenol occurring in green tea, epigallocatechin-3-gallate (EGCG), has been reported to inhibit Dnmt1 activity as well as affect CpG demethylation and reactiviation of methylation-silenced genes in esophageal cancer cells. The ability of such widely differing dietary components as selenium and EGCG to influence Dnmt1 activity suggests that other dietary factors may also influence methyl utilization and ultimately modify DNA methylation patterns. Neonatal exposure to the phytoestrogens coumestrol and equol has been found to lead to specific gene hypermethylation in the c-H-ras proto-oncogene in pancreatic DNA. Data indicating that consumption of high fiber diets is accompanied by a reduction in estrogen receptor methylation in colon tissue from healthy subjects has also been reported. Hypermethylation of the promoter CpG islands is recognized to contribute to the loss of function of several tumor related genes, including estrogen receptor (ER). Overall, several studies illustrate that bioactive food components other than essential nutrients can influence DNA methylation processes. Epigenetic events occurring in utero can lead to persistent changes in gene expression and can be modified by the diet. For example, the diet provided to female mice of two strains during pregnancy modified the offsprings' hair coat color (increased agouti versus yellow) and DNA methylation patterns. Expression of the yellow hair color in these mice is recognized to be controlled by hypomethylation of the agouti long terminal repeat (LTR), which was hypermethylated by dietary supplementation of the maternal diet with zinc, methionine, betaine, choline, folate, and vitamin B12. Expression of this yellow coat color is linked with increased risk of obesity, diabetes, and cancer. While long-term health implications remain to be determined, these studies demonstrate that feeding a methyl-supplemented diet to the mice increased levels of DNA methylation in the agouti LTR and increased the proportion of agouti to yellow mice. It should be noted that this effect occurred with control diets that are considered adequate for meeting nutritional needs. These data point to the likelihood that in utero nutrient exposures can lead to genomic imprinting in the offspring and potentially modify cancer risk. Emerging evidence indicates that various chromatin states such as histone modifications (acetylation and methylation) and nucleosome positioning (modulated by ATP-dependent chromatin remodeling machines) determine DNA methylation patterning. Histone modifications have recently generated a great deal of excitement in epigenetic research, culminating in the histone code hypothesis. Evidence suggests that butyrate may mediate gene expression by encouraging interactions between a DNA binding protein and a histone acetyltransferase. The zinc-finger binding protein-89 (ZBP-89), a DNA-binding protein that binds GC-rich sites, has been found to mediate butyrate gene expression of p21waf1. The proposed model of p21waf1 promoter activation by butyrate is thought to be through promotion of p300 (a histone acetyltransferase) and ZBP-89 interaction with the subsequent recruitment of Sp1 to the complex. More probing studies are needed to characterize additional gene-specific acetylation changes brought about by bioactive food components. Objectives and Scope This initiative is designed to promote innovative preclinical and clinical research to determine how diet and dietary factors impact DNA methylation and other epigenetic processes involved in cancer prevention. Although much evidence exists that dietary components are linked to cancer prevention, the specific nutrients and sites of action remain elusive. Diet, in fact, has been implicated in many of the pathways of cancer, including apoptosis, cell cycle control, differentiation, inflammation, angiogenesis, DNA repair, and carcinogen metabolism. These are also processes that are likely regulated by DNA methylation and possibly other epigenetic events that impact gene function. The objective of this initiative is to continue to address the following issues: how bioactive food components regulate DNA methylation or other epigenetic events for cancer prevention, how bioactive food components might alter DNA methylation or other aberrant epigenetic events and restore gene function, and how these components might circumvent or compensate for genes and pathways that are altered by epigenetic events. Another important aim of this initiative is to encourage collaborations between nutrition and epigenetic/ DNA methylation experts to study bioactive food components with cancer-preventative properties and to examine key epigenetic events in cancer processes (e.g., carcinogen metabolism, cell division, differentiation, and apoptosis) in order to begin to establish linkages between epigenetics, methylation patterns, and tumor incidences/behaviors. Thus, it is expected that each application demonstrate experience in nutrition and cancer prevention as well as DNA methylation or epigenetics. Studies should also link phenotypic changes to epigenetic alterations induced by specific essential and non-essential nutrients. The resulting information will be critical for optimizing effective dietary intervention strategies for cancer prevention. Investigators may choose from the full range of clinical and preclinical approaches. The focus should be on how individual dietary components influence DNA methylation and other epigenetic events and how this correlates with phenotypic change. Very little information currently exists about gene-specific changes in DNA methylation as influenced by bioactive food components; furthermore, very little information exists to adequately evaluate the specificity of individual nutrients, the impact of intakes/exposures, and any acclimation with time and/or tissue specificity. This initiative encourages the submission of novel approaches to unravel relationships between DNA methylation and other epigenetic events, diet, and cancer prevention. A variety of technologies to assess DNA methylation sequences may be utilized. These can be broadly classified into techniques that measure the overall content or distribution patterns of 5-methylcytosine (i.e., methylated CpG island amplification, methylation-sensitive restriction fingerprinting, differential methylation hybridization, and Restriction Landmark Genomic Scanning) and those that examine known gene sequences (i.e., methylation-sensitive single nucleotide primer extension, and combined bisulfite restriction analysis). The use of genetically engineered animal models, including transgenic or gene knockouts, is appropriate. Molecular resources such as gene databases and bioinformatics may also be used to expedite identification of gene-specific methylation targets. The following study topics are relevant examples for the development of R01, R21, and R03 grant applications in response to this PA. These examples are not meant to be all-inclusive. o Gene/region-specific changes in DNA methylation and histone acetylation/methylation caused by excesses and limitations in bioactive food components or calories. o Relationship between dietary induced global DNA hypomethylation and gene- specific hypermethylation. o Relationship between diet induced changes in DNA methylation and histone acetylation/methylation and control of gene function. o Temporality in DNA methylation patterns as influenced by bioactive food components. o Bioactive food component regulation of DNA methylation and epigenetic processes, i.e., methylenetetrahydrofolate reductase, methionine synthase, DNA methyltransferases, demethylases (or various demethylation processes), methylcytosine-binding proteins, histone methyltransferases, histone aceyltransferases and deacetylases. o Linkages between DNA methylation or other epigenetic pattern as a result of environmental exposures, including low-dose radiation, and the anticancer properties of bioactive food components. MECHANISMS OF SUPPORT This PA will use the NIH Investigator-initiated Research Project Grant (R01), the NIH Exploratory/Developmental grant (R21), and the NIH Small Grants Program (R03) as award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. An R21 applicant may request a project period of up to 2-years with a combined budget for direct costs of up $275,000 for the 2-year period. For example, the applicant may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of the project. Normally, no more than $200,000 may be requested in any single year. For R03 applications, the total budget may not exceed $100,000 in direct costs for the entire project and the direct costs in any one-year for R03 grant applications must not exceed $50,000. The total project period for R03 applications submitted in response to this announcement may not exceed 3 years. The R21 and R03 grants are not renewable. Investigators are encouraged to seek continued support after completing an Exploratory/Developmental Grant project or a Small Grant project through a Research Project Grant (R01). This PA uses just-in-time concepts. It also uses the modular and non-modular budgeting format (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 budget format. Otherwise, follow the instructions for non-modular budget research. Otherwise follow the instructions for non- modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. 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 institutions/organizations 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 your inquiries concerning this PA 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: Sharon A. Ross, PH.D. Division of Cancer Prevention National Cancer Institute 6130 Executive Blvd., EPN Room 3157, MSC 7328 Bethesda, MD 20892-7328 Rockville, MD 20852 (for express/courier service) Telephone: (301) 594-7547 FAX: (301) 480-3925 Email: rosssha@mail.nih.gov o Direct your questions about financial or grants management matters to: Ms. Debbie Dunn Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, EPS Room 243 Bethesda, MD 20892-7150 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3154 FAX: (301) 496-8601 Email: dunned@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B;) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document 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. The title and number of this program announcement must be typed on line 2 of the face page of the application form and the YES box must be checked. SUPPLEMENTARY INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions for R21 applications: o Research Plan Items a - d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required but may be included if it is available. Please note that a Progress Report is not needed; competing continuation applications for an exploratory/developmental grant will not be accepted. o Appendix. Use the instructions for the appendix detailed in the PHS 398 except that no more than 5 manuscripts, previously accepted for publication, may be included. All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions for R03 applications: o Research Plan Items a - d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 10 pages. Please note that a Progress Report is not needed; competing continuation applications for a small grant will not be accepted. o Appendix. The appendix may include original, glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the page limits of the research plan. No publications or other printed material, with the exception of pre-printed questionnaires or surveys, may be included in the appendix. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. 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. For the NIH Exploratory/Developmental Grant (R21), applicants may request direct costs in $25,000 modules, up to a total direct cost of $275,000 for the combined 2-year award period. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of the NIH institutes or centers who have agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1. Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2. Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3. Identify, in a cover letter sent with the application, the National Cancer Institute and the staff member who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: 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) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA 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 a substantial revision of an unfunded version of an application already reviewed, but such an application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Cancer Advisory 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of these criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment 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. 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? 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? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 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)? 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below.) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below.) CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. See http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II), efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (See NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-084.html.) Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials, see http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. For additional information see NIH Guide Notice on “Further Guidance on a Data and Safety Monitoring for Phase I and II Trials” http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available at http://www.cancer.gov/clinical_trials/. SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing (http://grants.nih.gov/grants/policy/data_sharing) or state why this is not possible. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, State, and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 "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. 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. A continuing education program in the protection of human participants in research is available online at http://cme.nci.nih.gov/. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://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, in the project description and elsewhere in the application as appropriate, 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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the “Standards for Privacy of Individually Identifiable Health Information”, the “Privacy Rule,” on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on “Am I a covered entity?” Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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 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/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. 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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