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DISABLING INNATE IMMUNE EVASION: NEW ATTENUATED VACCINES RELEASE DATE: July 2, 2004 RFA: RFA-AI-04-023 EXPIRATION DATE: November 24, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research LETTER OF INTENT RECEIPT DATE: October 26, 2004 APPLICATION RECEIPT DATE: November 23, 2004 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 Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this RFA is to solicit research projects focused on new approaches for vaccine development. Research supported and conducted by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, strives to understand, treat and ultimately prevent the myriad infectious, immunologic, and allergic diseases that threaten millions of human lives. The NIAID Division of Allergy, Immunology, and Transplantation (DAIT) and the Division of Microbiology and Infectious Diseases (DMID) support extramural research to control and prevent diseases caused by virtually all infectious agents. This RFA program is focused on the NIAID Category A, B, and C pathogens, which are listed at http://www.niaid.nih.gov/biodefense/bandc_priority.htm. RESEARCH OBJECTIVES The scientific focus of this program is the human innate immune system as a target for immune evasion by NIAID Category A, B, and C pathogens. The immediate and long-range objectives of the program are to identify and modify microbial and viral innate immune evasion genes for the generation of avirulent or attenuated strains suitable for vaccine development. The program will fund pre-clinical and clinical studies but will not support clinical trials. For NIH definitions of clinical research and clinical trials, see http://grants.nih.gov/grants/funding/phs398/section_3.html#a_definitions. Background To assess the state of research on the evasion of innate immunity by pathogens, the NIAID recently convened two expert panels to define knowledge gaps and to identify scientific opportunities. In 2002, an expert panel on Immunity and Biodefense addressed the immunological aspects of biodefense preparedness research, and in 2003 a panel on Antiviral Innate Immunity addressed viral infection, innate immunity, and mechanisms used by viruses to overcome these defenses. This research solicitation is based, in part, on recommendations from these panels, and will support a cooperative research program that targets innate immune evasion mechanisms used by NIAID Category A-C pathogens with the goal of developing novel disease prevention strategies. Innate immunity is an evolutionarily ancient form of protection against microbial intruders. With the introduction of an antigen-specific adaptive immune system in vertebrate animals, innate immune systems began to co-evolve with the new mechanisms of protection against infection, to create distinct but interrelated and complementary roles for each arm of immunity within a vertebrate species. Innate immune mediators activate antigen-nonspecific host defense mechanisms that generally inhibit, but do not totally prevent infection. Innate immune mediators also play immunoregulatory roles that affect the onset, magnitude, duration, and reactivation or memory of antigen- specific T and B cell responses. Collectively, these properties of innate immune activation constitute “adjuvanticity” and they are essential for immediate host defenses as well as for the robust and long lasting protection induced by vaccines. Because innate immune responses can retard infection and promote long term immune memory in the adaptive immune system, virulence factors have evolved in many pathogens to neutralize or evade innate immune mediators. Examples include decoy receptors that block the activity of cytokines, chemokines, or Toll-like receptors and other proteins that can inhibit the activity of interferon-alpha, a potent host-derived anti-viral cytokine. Although attenuated live pathogen vaccines are generally more effective than killed pathogen or subunit vaccines, a sufficient degree of attenuation must be attained to make live vaccines safe for human populations. This process is time-consuming and often unsuccessful when approached in an empirical manner. In contrast, an alternative strategy to achieve this goal is the rational design of attenuated strains via the selective deletion (or disabling) of innate immune evasion genes. To be effective, such a strategy must preserve immunodominant T and B cell epitopes and adjuvanticity of the parent strain such as the induction of T cell costimulatory proteins or the cytokine IL-12. Recent advances in immunology and microbial genetics make this novel approach feasible, and early results are encouraging. For example, the influenza NS1 protein inhibits interferon-alpha, an innate immune mediator, increasing the severity of influenza infection. As tested in mice, selective inactivation of the gene encoding NS1 yields a highly attenuated strain that protects against wild type influenza in challenge models. Many proteins of Category A-C pathogens are thought to block interferon-alpha effects including: the NS proteins of the Rift Valley Fever virus; the VP35 protein of Ebola; the V, W, and P proteins of the Nipah virus; and the poxvirus E3L protein. The E3L gene, found in all poxviruses, is required for lethal vaccinia infection in mice and its deletion results in an attenuated virus. Although not yet tested, the inactivation/deletion of the genes encoding this, or other interferon blocking proteins, either alone or in combination with the inactivation/deletion of genes encoding other innate immune evasion proteins, might lead to novel attenuated strains suitable for further development as vaccines. Research Objectives This program will support research that focuses on rational approaches to selectively disable innate immune evasion genes relevant to the pathogenesis of Category A, B, or C organisms, while maintaining the adjuvanticity and immunogenicity of attenuated strains. The ultimate goal is to develop and validate novel approaches to vaccine design that are applicable to multiple pathogens. HIV/AIDS research is excluded from this RFA. Clinical trials will not be supported under this program, although work with human samples is encouraged. For the NIH definition of clinical trials, see http://grants.nih.gov/grants/funding/phs398/section_3.html#a_definitions. In order to be considered responsive to the RFA, each application MUST include BOTH Research Areas outlined below: Research Area 1 includes a research plan for the selective modification of one or more specific NIAID Category A, B, or C pathogen genes that encode molecules functioning in innate immune evasion. If the applicant has previously modified a specific NIAID Category A, B, or C pathogen gene, materials documenting this work may be provided in lieu of the experimental plan, provided the applicant proposes to test the same modified strain as a vaccine candidate as outlined in Research Area 2. In this case, the approach and results should be fully described. AND Research Area 2 must include an experimental plan to demonstrate both the attenuation (i.e. reduced growth and virulence) and retention of immunogenicity and adjuvanticity of the gene-modified strain(s). The use of human cell lines, fresh cellular isolates, or tissues is highly encouraged whenever possible for in vitro studies. Suitable small or large animals may be used as in vivo models of human infection and immune protection. In all cases, the usefulness and human relevance of the in vitro or in vivo models should be addressed, and the possible extrapolation of results to human in vivo infection and vaccination should be discussed. IF THESE REQUIREMENTS ARE NOT MET, THE APPLICATION WILL BE CONSIDERED NON- RESPONSIVE AND WILL BE RETURNED TO THE APPLICANT WITHOUT REVIEW. NIAID will accept applications focused on one or more Category A-C pathogens, as long as the proposed budget matches the scope of the project. The same review criteria will be used for all pathogens and application parts and the final score will reflect the overall evaluation of the proposal. MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01), an "assistance" mechanism, rather than an "acquisition" mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. The applicant will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation and any future unsolicited, competing- continuation application 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 July, 2005. Applications submitted in response to this RFA that do not receive an award may be revised and submitted in the future as NEW R01 investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. The NIH U01 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". The total project period for applications submitted in response to this RFA may not exceed five years. At this time, the NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if the investigator is 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 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 FUNDS AVAILABLE The NIAID intends to commit a total of approximately $6M in FY 2005 to fund 5 to 10 new grants in response to this RFA. An applicant may request a project period of up to 5 years. 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 NIAID 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 The applicant may submit (an) application(s) if the 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. SPECIAL REQUIREMENTS Applicants’ Knowledge and Expertise Each application must propose a research and development project whose ultimate goal is to develop a vaccine specific for an NIAID Category A, B or C pathogen. Because the success of the research solicited by this RFA will rely on a strong synergism between the fields of innate immunity and microbial pathogenesis, applications are required to include individuals who will contribute BOTH in-depth knowledge in immunology AND expertise in the biology of the pathogen under study. Each application will include ONE Principal Investigator who is an expert in at least one of these two scientific fields; co-investigators and/or postdoctoral fellows with in-depth understanding of the other research area should be included as key personnel. APPLICATIONS THAT DO NOT MEET THIS REQUIREMENT WILL BE CONSIDERED NON- RESPONSIVE AND WILL BE RETURNED TO THE APPLICANT WITHOUT REVIEW. Milestones Applications must define the proposed project goal, yearly milestones for each project, and a schedule or timeline for achieving milestones and goals. The outline for the milestones should be provided in a chart format (e.g. GANNT chart) in PHS 398 Form at the end of the experimental plan. It is recognized that milestones may require revision and re-negotiation during the course of the project period. Release of each yearly funding increment by NIAID will be based on a NIAID review of progress towards achieving the previously agreed upon milestones. Annual Workshop Principal investigators will be expected to participate in an annual workshop organized by NIAID Program Staff in order to: assess progress; discuss positive and negative results; arrange for the sharing of materials including reagents and techniques; identify new research opportunities; and establish research collaborations so that the program will have a maximum impact on the development of improved human vaccines for NIAID Category A-C pathogens. Travel funds for the principal investigators and other key personnel should be budgeted for this purpose. COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator as well as the institutional official at the time of award. These special Terms of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is cooperative agreement (U01), an "assistance", rather than an "acquisition", mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIAID Scientific Coordinator. 1. Monitoring Clinical Studies Although clinical trials are excluded from this program, clinical studies using human samples are encouraged. When clinical studies are a component of the research proposed, NIAID policy requires that studies be monitored commensurate with the degree of potential risk to the study subjects and the complexity of the study. An updated NIAID policy was published in the NIH Guide on July 8, 2002 and is available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The full policy, including terms and conditions of award, is available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf. 2. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA and for performing the scientific activity. Specifically, awardees have primary responsibility as described in the SPECIAL REQUIREMENTS SECTION of this RFA which specifies the applicants’ knowledge and expertise, the submission of project milestones, the participation to an annual workshop, and the adherence to Public Law 96-517 (the Bayh-Dole Act of 1980), 35 U.S.C. Secs. 200-212, 37 C.F.R. Part 401, and 45 C.F.R. parts 6 and 8) safeguarding Institutions' rights in inventions made under this funding mechanism and the reporting requirements for such inventions. 3. NIAID Staff Responsibilities NIAID staff assistance will be provided by a NIAID Program Officer from the Division of Allergy, Immunology, and Transplantation (DAIT), who will serve as NIAID's Scientific Coordinator. The NIAID Scientific Coordinator will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. During performance of the award, the NIAID Scientific Coordinator, with assistance from other scientific program staff who are designated based on the research topic and their relevant expertise, may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources (e.g., determining where a particular reagent can be found); coordinating or participating in the collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications. The NIAID Scientific Coordinator will serve as a liaison/facilitator between the awardee, pharmaceutical and biotech industries, and other government agencies (e.g. USDA, CDC) and will serve as a resource of scientific and policy information related to the goals of the awardee's research. However, the role of NIAID will be to facilitate and not to direct the activities. The Chief of Regulatory Affairs, DAIT, NIAID, will be responsible for providing guidance and assistance in the development, assembly, and submission of all required regulatory documents, e.g., those regarding the use of investigational vaccines or drugs, to the Food and Drug Administration. It anticipated that decisions in all activities will be reached by consensus and the NIAID staff will be given the opportunity to offer input into this process. The manner of reaching this consensus and the final decision-making authority will rest with the Principal Investigator. An NIAID Program Official will be assigned to perform normal program stewardship responsibilities for this award. The Program Official may serve as the Scientific Coordinator. 4. Collaborative Responsibilities NIAID Staff will provide expertise in technology and resource development, availability, and application; development, design, and implementation of studies with human samples; policies and procedures for the protection of human subjects; and will serve as liaison to other NIH-sponsored programs to facilitate collaboration and coordination. 5. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and I/C may be brought to arbitration. An arbitration panel will be composed of three members – one chosen by the awardee, a second member selected by the IC, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. 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 questions about scientific/research issues to: Francesca Macchiarini, Ph.D. Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases Room 3070, MSC-6601 6610-B Rockledge Drive Bethesda, MD 20892-6601 Telephone: 301-496-7551 FAX: 301-480-2381 Email: fm46w@nih.gov o Direct questions about peer review issues to: Thomas Hiltke Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3254, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: 301-402-6891 FAX: 301-402-2638 Email: th247q@nih.gov o Direct questions about financial or grants management matters to: Kim Coats Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2243, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: 301-451-4576 FAX: 301-480-3780 Email: kc127b@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 NIAID 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: Thomas Hiltke Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3254, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: 301-402-6891 FAX: 301-402-2638 Email: th247q@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. 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 additional exact copies of the grant application and all five sets of any appendix material must be sent to: Thomas Hiltke Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3254, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 BETHESDA, MD 20817 (for express mail/courier service) Telephone: 301-402-6891 FAX: 301-402-2638 Email: th247q@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 NIH 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. 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 Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAID. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration or review. 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 NIAID in accordance with the review criteria stated below. 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 Advisory Allergy and Infectious Diseases Council 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 the following 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 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. 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. 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 $500,000 or more 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. (See instructions and URL to policy in the Federal Citations, below.) 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: October 26, 2004 Application Receipt Date: November 23, 2004 Peer Review Date: April, 2005 Council Review: May, 2005 Earliest Anticipated Start Date: July, 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Programmatic 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. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 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 or state why this is not possible http://grants.nih.gov/grants/policy/data_sharing. 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 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. 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. This policy announcement is 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. 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 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. 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 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 Catalogue of Federal Domestic Assistance at http://www.cfda.gov/ in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research and No. 93.856, Microbiology and Infectious Diseases Research. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The NIH Grants Policy Statement is available at http://grants.nih.gov/grants/policy/policy.htm. This document includes general information about the grant application and review process; information on the terms and conditions that apply to NIH Grants and cooperative agreements; and a listing of pertinent offices and officials at the NIH. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. 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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