HEPATITIS C COOPERATIVE RESEARCH CENTERS RELEASE DATE: August 5, 2004 RFA Number: RFA-AI-04-028 Update: The following update relating to this announcement has been issued: April 7, 2009 - This RFA has been reissued as (RFA-AI-09-025). EXPIRATION DATE: November 23, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research No. 93.848, Digestive Diseases and Nutrition Research No. 93.273, Drug Abuse Research Programs LETTER OF INTENT RECEIPT DATE: October 22, 2004 APPLICATION RECEIPT DATE: November 22, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute on Drug Abuse (NIDA) invite applications for the establishment of multi-project Hepatitis C Cooperative Research Centers (HC CRCs). The purpose of this RFA is to foster and stimulate high-quality, multi- disciplinary collaborative research that is focused on developing tools to prevent and cure hepatitis C virus (HCV) infection and disease. The goal is to generate research findings that will be directly applicable, particularly to the development of vaccines and (immune) therapeutics. This RFA calls for new approaches for the rapid utilization and validation of research findings using a combination of basic, animal model, and clinical research approaches. The HC CRCs are encouraged to engage in early translational research so as to address hepatitis C public health needs. Together, the HC CRCs will form a consortium to: 1) conduct research of direct relevance to the objectives outlined; 2) foster interactions among established hepatitis C investigators; and 3) support Pilot Projects to evaluate new promising approaches related to this RFA. RESEARCH OBJECTIVES Background At least 2% of the world’s population is infected with Hepatitis C virus (HCV); over 75% of infections never resolve, resulting in persistent virus carriage. Over time, this chronic infection can lead to liver fibrosis and, progressively, to severe and fatal diseases including liver cirrhosis and primary liver cancer. The Institute of Medicine classifies HCV as an emerging disease agent in the USA, with 1.7 million individuals already chronically infected and 30,000 more, newly infected, every year (IOM report, 1992). In the USA, the economic cost of this medical burden is estimated at approximately $1.0 billion per year. At present, in the USA, almost all transmission stems from the use of contaminated needles in intravenous drug abuse. Thus, most new infections are likely to occur among relatively young people. HCV infection resulting from intravenous drug abuse is frequently complicated by co-infection with HIV. In particular, chronic HCV infection and associated liver disease are reported to develop at a higher rate in the presence of HIV. HCV is an RNA virus which circulates as a complex mixture of related but genetically heterogeneous quasi-species. There are at least 6 distinct genotypes of HCV, which further adds to the heterogeneity and which may influence differences in clinical outcomes - such as persistence, chronic liver disease, immune responses, and the response to interferon treatment. Currently, the treatment of choice for hepatitis C is long-acting alpha interferon given in combination with the antiviral drug, ribavirin. However, there are wide differences in the response to alpha interferon depending on the genotype of HCV. The lowest response rate (only ~ 46%), is observed in patients infected with HCV genotype-1, which is the genotype most prevalent in the USA. Studies also indicate a lower cure rate among African Americans, a population group which has a significantly higher rate of chronic infection than others in the USA. The development of a vaccine to prevent infection by HCV is beset by complex problems. Immune pressure leads to continual selection, and diversification, of viral variants that escape the host defenses. In addition, HCV directly inhibits both innate and adaptive host immune responses. Even in the small proportion of infected individuals who clear the infection there is usually insufficient immunity to prevent a subsequent re-infection. On the other hand, vaccine studies in chimpanzees have shown that induction of high titers of antibodies against virus envelope proteins E1 and E2 is associated with reduced severity of liver disease. Particularly encouraging for vaccine development are findings from prospective studies in intravenous drug users, that individuals who clear an initial HCV infection are less susceptible to viral persistence following a subsequent infection. Like several other viruses, HCV has evolved multiple strategies for blocking interferon responses, simultaneously compromising both innate and adaptive immune responses against it. Current evidence indicates that broad HCV- specific T cell responses can occur in infection, and that the breadth of the response corresponds with more benign outcomes following infection. However, it is not clear what particular responses are significant in terms of protective immunity, and why the responses vary within and among, individuals. Finally, recent HCV-replicon technology now allows in vitro screening for antiviral drugs that target virus RNA replication, but not yet for those that might interfere with the subsequent steps of virus morphogenesis and with infection. The development of in vitro systems for virus propagation, and small-animal infection models, would greatly facilitate the ultimate goals of developing new therapies and vaccines against HCV. Objectives and Scope This RFA will support integrated projects to study the virus-host interactions that determine the outcome of infection, treatment associated recovery, and pathogenesis. These projects include: multi-disciplinary research for understanding mechanisms; in vivo studies for validation of in vitro findings; the use of particular patient cohorts and/or specimens from patients in clinical research relevant to these objectives; and early development and preclinical evaluation of vaccine and therapeutic strategies. Applications should address specifically one or more of the objectives listed below and may address other closely related questions. 1. Elucidate the mechanisms and key steps by which HCV deregulates and evades the host immune response at the time of initial infection and during chronic infection, e.g., the role of HCV proteins in blunting the innate immune response, inhibiting dendritic cell maturation, or setting up an anergic state. 2. Identify early determinants of spontaneous clearance of infection, including specific T-cell and B-cell responses, as compared with, and in contrast to, lack of clearance. 3. Examine the role of immune responses associated with delayed and more benign outcomes of chronic HCV following multiple exposures to virus, e.g., in intravenous drug users, as compared to aggressive and severe outcomes. 4. Elucidate the role of host factors (including genetic) and viral factors in the establishment and rate of progression of chronic infection and their interactions with each other. 5. Construct prototype vaccine candidates to induce specific immune responses to HCV - identified through human clinical studies, and predicted to be important in viral clearance - and evaluate these responses in appropriate in vitro and in vivo model systems. 6. Devise cell-culture systems for the synthesis of complete, infectious particles, and determine their potential usefulness for research and development. 7. Identify, test, develop and use HCV animal models, including surrogates, to evaluate neutralizing antibodies, and as screening systems for new antiviral agents. 8. Identify and define a receptor / receptor complex for HCV. Clinical Studies To address objectives 1-4 effectively and to determine the clinical relevance of any observations, it is necessary, in parallel, to undertake clinical studies in well defined cohorts of patients in whom HCV infection, clearance or persistence, and the progression of liver disease can be meaningfully and systematically studied, with particular reference to immunological parameters. Such patient cohorts include, but may not be limited to, those infected during intravenous drug abuse, minority populations who may be more susceptible to chronic infection and liver disease, those who show poor response to interferon therapy, and those co-infected with HIV. Therefore, applications for studying questions 1-4 in ”Objectives and Scope” must contain an integrated, scientifically related, clinical project. Exclusions This RFA is not intended to support basic molecular studies on the replication of HCV RNA or HCV protein expression, or their regulation, unless such studies are demonstrated to relate directly to the purposes of this RFA, as outlined. Studies involving the use of genomic or proteomic technologies will only be considered if a credible and logical plan is presented for analyzing and applying the results to furthering the objectives of this RFA. In addition, clinical trials for new drugs or vaccine candidates will not be supported under this RFA. However, research questions that are best addressed by studying clinical specimens from or in patients in defined populations or cohorts are especially encouraged. CRC Research Component: A CRC must consist of two or more related, multidisciplinary projects utilizing molecular biological and immunological approaches. These approaches may include experiments using animals such as mice, macaque monkeys and chimpanzees. Each project must be led by a Project Leader. These projects may or may not be within the same institution. The CRC Director must be the Project Leader at the applicant organization, and will have responsibility for the scientific direction, coordination, and administrative management of the CRC. Scientific Core: Scientific core facilities/resources may be proposed if they will be utilized by at least two of the research projects. Resources include reagents (e.g., antibodies, peptides, etc.), special technology and databases. Scientific cores should be well justified and clearly non- duplicative of other services or facilities available to the CRC investigators. If appropriate to the particular CRC, repositories for cells, tissues, reagents, or large data sets may be funded as Core Facilities. In this case, applications should include methods to obtain, protect and archive relevant clinical and family history information. Administrative Core: An Administrative Core is required for the management of the CRC program. The Administrative Core should include plans for organization, decision-making, periodic evaluations within the CRC, and data sharing. An Administrative Core budget should be included to provide for the required support staff, preparation of manuscripts for publication, telecommunications, and travel for participation in annual meetings of the CRCs (see SPECIAL REQUIREMENTS section below for annual meetings). MECHANISM OF SUPPORT This RFA will use the NIH multi-project cooperative agreement (U19), an "assistance" mechanism, rather than an "acquisition" mechanism. The applicant will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is June 30, 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. The NIH U19 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. 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/archive/grants/policy/nihgps_2003/index.htm. Applicants for U19 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available via the WWW at http://www.niaid.nih.gov/ncn/grants/multibron.htm. FUNDS AVAILABLE The participating ICs intend to commit approximately $6,400,000 in FY 2005 to fund 5 to 7 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for total costs of up to $1,250,000 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 ICs 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. Funding for the Development Program for Pilot Projects is in addition to the total costs. Details on the Development Program are provided in the “SPECIAL REQUIREMENTS” section below. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. 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 institutions/organizations o Foreign institutions are not eligible to apply, but may be part of a collaborative arrangement. 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 1. Steering Committee The HC CRC Program Directors and the NIAID Scientific Coordinator will constitute the Steering Committee for this research program, with responsibility for reviewing progress and future plans, revising the research focus if appropriate, and developing collaborative efforts among the awardees. The Steering Committee and the Project Leaders will meet at least annually at the NIH in Bethesda, Maryland (or at a site designated by the NIAID Scientific Coordinator), and will hold quarterly conference calls to facilitate interaction and collaboration across CRCs. The first such meeting will be held shortly after award and will be scheduled by the NIAID Scientific Coordinator. At this meeting, a Steering Committee Chair will be selected from among the non-Federal members. Funds for the travel to the annual meetings for the Program Directors, Project Leaders and other key CRC scientific staff should be included in the Administrative Core budget. 2. Development Fund (DF) for Pilot Projects The NIAID has established a CRC DF to respond to unanticipated scientific needs and opportunities. The goal of the DF is to provide some opportunity for exploring novel and promising ideas related to the overall objectives of this RFA – to develop methods or resources to enhance basic and clinical research, to follow up on new observations and hypotheses, to initiate risky projects with high potential benefit, or to stimulate collaborative efforts. Under the DF, an additional $225,000 will be available for Pilot Projects to a maximum of $75,000 each in direct costs. Each Pilot Project will be funded for up to 3 years to cover partial salary and research costs. Indirect Costs will not be allowed for Pilot Projects. Pilot Projects are not part of the CRC application; therefore, budgets for Pilot Projects should not be included in the application. At the initial meeting of the CRC Directors, the Steering Committee will select one of the CRC Directors to serve as the DF Administrator. The DF Administrator will appoint a Scientific Review Committee - which includes the Steering Committee and additional expert(s) from the scientific community as may be appropriate - to establish criteria for the evaluation of proposed Pilot Projects, and to solicit, review and select applications for funding. NIAID approval will be required for the appointment of the Scientific Review Committee and the final selection of projects for funding. If the quality of applications received is not deemed to be sufficiently high, NIAID may decide not to fund any of the projects. Approved projects need not necessarily be carried out at one of the HC CRCs; however, all Pilot Projects supported must relate to the specific objectives of this program. Continued support after the first year will be dependent on review of satisfactory progress. A separate progress report on each developmental project must be included in the annual report of the CRC. 3. Clinical Component In order to undertake basic and clinical approaches in a complementary and synergistic manner, HC CRCs will need access to well-characterized and diverse patient samples, as well as clinical experience with populations representing different disease stages, transmission modes, racial/ethnic background, co- factors, etc. All applicants are encouraged to include research utilizing well defined patient cohorts to address clinical questions and to make correlations with laboratory observations. Applications addressing one or more of objectives 1-4, as defined under “Objectives and Scope,” must include a clinical component. For such studies, detailed proposals, including study objectives, study design, population, clinical sites, and data analysis plan must be presented in the application. NIAID encourages: 1) collaborative arrangements with ongoing studies or clinical care settings capable of providing the crucial patient populations, specimens and information; and 2) the use of General Clinical Research Centers (GCRC) facilities supported by the NIH National Center for Research Resources as a resource for conducting research. If existing studies/cohorts or GCRC facilities will be used, letters of collaboration or agreement from the study Principal Investigator or GCRC Program Director respectively must be included in the application. 4. Sharing of Resources Restricted availability of unique research resources upon which further studies are dependent can impede the advancement of research and delivery of medical care. NIH policy expects investigators to make unique research resources readily available for research purposes to qualified individuals within the scientific community when they have been published [NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps/); Principles and Guidelines for Recipients of NIH Research Grants and Contracts on obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html)]. Accordingly, biomaterials and other patentable research resources (e.g., genetically encoded reporters, vectors, embryonic cell lines, etc.) produced in projects funded by this RFA are expected to be made available and distributed to the broader scientific community. Intellectual Property Rights NIH is interested in ensuring that the research resources developed through this RFA become readily available to the research community. With regard to patentable research results, such as genetically encoded reporters, cell lines, and vectors, the NIH expects applicants who respond to this RFA to develop a plan addressing if, or how, they will exercise their intellectual property rights while making available to the broader scientific community research resources produced in projects funded under this RFA. This is expected to include an elaboration of the applicant’s anticipated plans to generate, or not generate, patents and/or exclusive or non-exclusive licensing of biomaterials and other patentable subject matter created in projects funded under this RFA. This plan should be consistent with the applicant’s institution’s policies on intellectual property rights. Applicants are reminded that funding recipients must not enter into any agreements with third parties that are inconsistent with the terms and conditions of their NIH award, if awarded, and must revise any agreements with third parties that are inconsistent with the terms and conditions of an NIH award to remain in compliance with such NIH award. The majority of transfers to not-for-profit entities should be implemented under terms no more restrictive than the Uniform Biological Materials Transfer Agreement (UBMTA). In particular, recipients are expected to use the Simple Letter Agreement (SLA) provided at http://www.ott.nih.gov/policy/rt_guide_final.html, or another document with no more restrictive terms, to readily transfer unpatented tools developed with NIH funds to other recipients for use in NIH-funded projects. If the materials are patented or licensed to an exclusive provider, other arrangements may be used, but commercialization option rights, royalty reach- through, or product reach-through rights back to the provider are inappropriate. Similarly, when for-profit entities are seeking access to NIH- funded tools for internal use purposes, recipients should ensure that the tools are transferred with the fewest encumbrances possible. The Simple Letter Agreement may be expanded for use in transferring tools to for-profit entities, or simple internal use license agreements with execution or annual use fees may be appropriate. Applicants also are reminded that the grantee institution is required to disclose each subject invention to NIH within two months after the inventor discloses it in writing to grantee institutional personnel responsible for patent matters. The awarding institute reserves the right to monitor awardee activity in this area to ascertain if patents or patent applications on protocols, cell lines, vectors, or other patentable subject matter are adversely affecting the goals of this RFA. As noted earlier, Principles and guidelines for recipients of NIH research awards on obtaining and disseminating biomedical research resources can be found at http://www.ott.nih.gov/policy/rt_guide_final.html. 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 the multi- project cooperative agreement (U19) 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 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 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; and the DMID Policies and Guidance for Data and Safety Monitoring at http://www.niaid.nih.gov/dmid/clinresearch/. Award of a cooperative agreement does not constitute approval for initiation of human subjects research. HC CRC investigators will be required to develop and conduct all studies involving human subjects using Good Clinical Practice Standards as defined and published by the International Conference on Harmonization (ICH) and adopted by the FDA (Federal Register Vol.62 No. 90 (5/9/97) ICH protocol requirements outlined in part 6 of the ICH Harmonized Tripartite Guideline for Good Clinical Practice website http://www.ich.org or at http://www.mch.com/doctors_caregivers/research/Forms/ICH% 20Guidlines%20for%20Research%20Protocols.pdf 2. Awardee Rights and responsibilities (http://www.fda.gov/oc/gcp/guidance.html). Prior to study initiation, NIAID staff will review all studies involving human subjects at two stages. The first stage will be a review of the research concept and the second review will be during protocol development. Both stages will be reviewed for scientific content, design, safety, feasibility, statistical, and regulatory compliance. Use of the NIAID protocol template, found at the International Clinical Studies Support Center website (http://icssc.org/rel_links.htm#templates), is encouraged. 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 below. It is the primary responsibility of the awardee Program Director to clearly state the objectives and approaches of the research, to plan and conduct the research stipulated in the application, and to ensure that the results obtained are analyzed and published in a timely manner. NIAID may periodically review and generate internal reports from data and progress reports developed under this cooperative agreement. The data obtained will, however, be the property of the awardee. Awardees will retain custody of and have primary rights to data collected under this award, subject to Government rights of access consistent with current U.S. Department of Health and Human Services(DHHS), Public Health Service(PHS) and National Institutes of health (NIH) Policies. 3. NIAID Staff Responsibilities NIAID staff assistance will be provided by the Hepatitis Program Officer in the Enteric and Hepatic Diseases Branch, Division of Microbiology and Infectious Diseases, who will serve as the NIAID 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, particularly with regard to the following aspects: Participation as a member of the HC CRC Steering Committee and attendance at annual Steering Committee meetings; Participation as a member of the Scientific Review Committee to evaluate and select Pilot Projects for funding; Overall design of studies, especially those undertaken jointly by the HC CRC’s linkage to special populations; NIAID staff will also facilitate liaison with existing NIAID contracts and interaction with other investigators within and outside the HC CRCs for: vaccine production; data collection and analysis; HCV reagent repository; resource and reagent sharing; HCV sequence database; and pedigreed specimen exchange. The NIAID Scientific Coordinator will serve as a liaison/facilitator between the awardee, pharmaceutical and biotechnology companies, and other government agencies (e.g., the U.S. Food and Drug Administration (FDA), the U.S. Department of Agriculture, the Centers for Disease Control and Prevention) and will serve as a resource for 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. It is 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 NIAID Scientific Coordinator. 4. Collaborative Responsibilities The HC CRC Program Directors and the NIAID Scientific Coordinator will constitute the Steering Committee for this research program and will meet at least annually to review progress and future plans, revise the focus if required, and develop collaborative efforts. The NIAID Scientific Coordinator will work with the HC CRC Program Director selected to serve as the Development Fund Administrator to appoint a Scientific Review Committee; both will participate in the review and selection of applications for Pilot Projects. Special Consideration: In the event that research supported by the Cooperative Agreement results in development of a therapeutic or other medical intervention, NIAID will retain the option to cross-file or independently file an application for an investigational clinical trial (i.e., an Investigational New Drug Application [IND]) to the FDA. To facilitate this, reports of data generated by the HC CRCs or any of its members, which are required for inclusion in INDs and Clinical Brochures and for cross-filing purposes, will be submitted by the Program Director to the NIAID Scientific Coordinator upon request. Such reports will be in final draft form and include background information, methods, results, and conclusions. They will be subject to approval and revision by NIAID and may be augmented with test results from other Government-sponsored projects prior to submission to the appropriate regulatory agency. 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: Rajen Koshy, PhD Enteric and Hepatic Diseases Branch Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Room Number 4010, MSC-6603 6610 Rockledge Drive Bethesda, MD 20892-6603 Telephone: 301 402 8550 FAX: 301 402 1456 Email: firstname.lastname@example.org o Direct questions about peer review issues to: Gerald McLaughlin Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3119, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 435-2766 FAX: (301) 402-2638 Email: email@example.com o Direct questions about financial or grants management matters to: Celeste Kerner Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2253, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-6213 FAX: (301) 480-3780 Email: firstname.lastname@example.org LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Gerald McLaughlin Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3119, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 435-2766 FAX: (301) 402-2638 Email: email@example.com SUBMITTING AN APPLICATION Applicants for U19 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available via the WWW at http://www.niaid.nih.gov/ncn/grants/multibron.htm. 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 D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B 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: Gerald McLaughlin Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3119, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 BETHESDA, MD 20817 (for express mail or courier service) Applications that are not received as a single package on or before November 22, 2004 or that do not conform to the instructions contained in PHS 398 (rev. 5/01) Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be judged non-responsive and will be returned to the applicant. SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA: Applicants for U19 cooperative agreements must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available from NIAID listed under INQUIRIES via the WWW at http://www.niaid.nih.gov/ncn/grants/multibron.htm. This brochure presents specific instructions for sections of the PHS 398 (rev. 5/01) application form that should be completed differently than usual. For all other items in the application, follow the usual instructions in the PHS 398. 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. CONCURRENT SUBMISSION OF AN R01 AND A COMPONENT PROJECT OF A MULTI-PROJECT APPLICATION: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. 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. 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 general review criteria for U19 multi-project cooperative agreement applications are presented in the NIAID brochure entitled "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS” at http://www.niaid.nih.gov/ncn/grants/multibron.htm. 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 22, 2004 Application Receipt Date: November 22, 2004 Peer Review Date: March 15, 2005 Council Review: May 2005 Earliest Anticipated Start Date: June 30, 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 ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. 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 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. (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998): http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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, Transplantation Research; No. 93.856, Microbiology and Infectious Diseases Research; and No. 93.848, Digestive Diseases and Nutrition 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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