RFA-AI-01-008: ACUTE INFECTION AND EARLY DISEASE RESEARCH PROGRAM

Department of Health
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ACUTE INFECTION AND EARLY DISEASE RESEARCH PROGRAM Release Date: February 22, 2001 RFA: RFA-AI-01-008 National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov/) Letter of Intent Receipt Date: August 16, 2001 Application Receipt Date: October 10, 2001 PURPOSE The Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), solicits applications for the competitive continuation of a program to study the pathogenesis of acute/early HIV infection in adult humans, and to develop and evaluate the impact of therapeutic interventions at this early stage of HIV disease. This program was initiated under PAR-96-060, Acute Infection and Early Disease Research Network. There are seven current cooperative agreement (U01) awardees, six clinical units and a coordinating center. The goal of this initiative is to maintain a program of five to seven HIV Acute Infection and Early Disease Research Units and one Statistical and Coordinating Center, through cooperative agreements (U01). Each awarded unit will perform innovative, integrated, investigator-initiated pathogenesis and clinical research on acute and early HIV infection and will place emphasis on performing collaborative multi-unit research projects as part of the Acute Infection and Early Disease Research Program (AIEDRP). The multi-unit structure is required in order to enroll sufficient numbers of these difficult-to-identify acutely HIV- infected subjects for study. 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 Request for Applications (RFA), Acute Infection and Early Disease Research Program, is related to one or more of the focus areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Foreign institutions are not eligible to apply as primary grantees, however, foreign institutions are encouraged to participate as part of a domestic application. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the 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. 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. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed later in this document under the section, 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. FUNDS AVAILABLE The estimated total funds (direct and Facilities and Administrative (F&A) costs) available for the first year of support for all awards (competitive renewal and new) made under this RFA will be $11.7 million. In Fiscal Year 2002, the NIAID plans to fund approximately 5-7 units and 1 Statistical and Coordinating Center. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. RESEARCH OBJECTIVES BACKGROUND In the US, the incidence of HIV is approximately 40,000 cases per year, and the worldwide incidence is estimated to be 5.4 million cases per year. While there is accumulating data that HIV infection can be effectively blocked with appropriate perinatal therapy and post-exposure prophylaxis, once HIV infection is established in the human host a predetermined chain of events is set into motion. Acute HIV infection is associated with extremely high levels of viremia, rapid seeding of viral reservoirs, and significant perturbations of cytokine production and host immune defenses. Yet, the clinical presentation of acute HIV infection can range from an asymptomatic infection to a non-specific mononucleosis-like syndrome. An enhanced understanding of acute HIV infection is critical to furthering our knowledge of HIV pathogenesis and natural history. Elucidation of factors important in transmission may be useful for identifying new mechanisms to prevent the spread and establishment of HIV infection. Study of viral reservoirs established early during acute infection and the viral dynamics in these reservoirs may also help suggest new interventions to eliminate the spread of HIV and new therapeutic mechanisms and targets by which to suppress viral replication. Study of the immune system responses from the acute through the early stages HIV infection may lead to significant improvements in our ability to slow the rate of HIV disease progression and prolong survival. Antiviral and/or immunological interventions during acute/early infection may have dramatic impact upon disease progression and survival. For example, early treatment with antiretroviral therapy does much to preserve immune system function. Following patients throughout the course of HIV infection, beginning at the time of acute infection, may provide additional insight into the natural history of the disease. Identifying the prevalence of HIV resistance in acutely infected patients may provide additional insight into the epidemiology of HIV. The epidemiology of acute HIV infection has complicated the HIV research community’s ability to access this population that is one of the most difficult to identify, enroll, and follow. Therefore, it is important to identify investigators and sites that can access this population and, in turn, utilize it to perform state-of-the-art clinical and basic science HIV research. In FY97, six units were awarded grants to establish the AIEDRP. A seventh unit was funded in FY98. Much of the work in the early years of the AIEDRP has focused on the development of an infrastructure, the establishment of common data requirements, and the development of clinical and pathogenesis trials. Shortly after the formation of the AIEDRP, the investigators established a statistical center to develop and maintain a common database for the AIEDRP. Continuation of the AIEDRP is needed to extend the research begun through the multiple projects and to expand on the collaborative studies that may validate results that may with potential relevance for a broader patient population. Additional information about the current AIEDRP may be found at the group"s Web site (http://www.aiedrp.org/). RESEARCH SCOPE AND OBJECTIVES This initiative will support innovative, integrated pathogenesis and clinical research of acute and early HIV infection in human subjects age 13 years and older. For the purpose of this RFA, working definitions of acute and early HIV infection are as follows: Acute HIV Infection: o Detectable plasma HIV RNA or detectable HIV p24 antigen with a negative ELISA, or detectable ELISA with a negative or indeterminate Western blot (indeterminate Western blot as defined by the Centers for Disease Control and Prevention (CDC)) Early HIV Infection: o A positive ELISA with a positive detuned assay, (Detuned assay is defined as a less sensitive HIV EIA, such as the Abbott Laboratories, 3A11-LS EIA assay) or o A positive ELISA and Western blot with a documented negative serologic test within the past 12 months The initiative will support single-unit and multi-unit clinical research on HIV pathogenesis, therapeutic interventions, and factors that influence response to interventions. In addition, the initiative will support a central Scientific Planning Committee and a Statistical and Coordinating Center to direct and support multicenter collaborative research studies. Initial observations on pathogenesis and treatment are often conducted in small pilot studies. In order to validate the preliminary results of these novel studies, a larger number of subjects will be needed. The investigators of the AIEDRP are expected to collaborate extensively with other AIEDRP investigators in order to achieve this goal. Furthermore, in order to understand the long-term safety and efficacy of early therapeutic interventions, the AIEDRP must maintain long-term follow-up of individuals diagnosed with acute and early HIV infection. Each unit will be comprised of basic and clinical scientists, and will include one or more sites, coordinated under the direction of a Principal Investigator, and each unit will be part of the AIEDRP. The structure of the AIEDRP and funding are not linked to a specific experiment or clinical trial. Thus, this mechanism has the potential for considerable flexibility in resource allocation that will facilitate the rapid testing of hypotheses about the pathogenesis of HIV infection and of early-phase clinical interventions. AIEDRP Units In order to address the scientific needs of the initiative, each unit should: o Identify, accrue and retain acute/early HIV positive individuals for pathogenesis studies and clinical trials. This requires strong linkages with, and intense screening from, unique referral sources such as sexually transmitted diseases (STD) clinics, emergency rooms, blood banks, and primary care centers, as well as close collaboration with centers and investigators studying existing natural history cohorts. The projected enrollment of each AIEDRP unit should be at least 30 to 50 patients per year. Of the total number of subjects, approximately 10 subjects per year should be acutely infected. Applications may include studies on ways to improve detection and recruitment of newly infected individuals. o Conduct independent and collaborative (both through the AIEDRP and with non-AIEDRP investigators) studies of the in vivo pathogenesis of early HIV disease. o Evaluate and optimize therapeutic interventions in small, focused clinical studies and in larger collaborative studies involving two or more units, perform extensive virologic and immunologic evaluations that will provide new insights into the pathogenesis of acute/early HIV infection and the potential effectiveness of therapeutic approaches. The identification and use of existing resources (such as the Adult and Pediatric AIDS Clinical Trials Networks (AACTG and PACTG), HIV Prevention Trials Network (HPTN), Adolescent Medicine Trials Network (ATN), and the Centers for AIDS Research (CFAR)) should be extensive. The banking and storage of specimens for later analyses and for use in collaboration with investigators outside the AIEDRP is encouraged. o Participate actively in AIEDRP activities, through regular participation in, and contributions to, the Scientific Planning Committee, and by participation in multi-unit evaluation (Phase I/II and Phase II clinical studies) of novel therapeutic interventions and large controlled pathogenesis-related studies in acute infection and/or early HIV disease. o Contribute data to a common database for cross-study analyses and long-term follow-up. Scientific Planning Committee A Scientific Planning Committee (SPC) will be established to foster, coordinate, and facilitate collaborative activities within the AIEDRP. The composition and specific responsibilities of the AIEDRP SPC are noted below. Statistical and Coordinating Center AIEDRP units should support their own local biostatistical collaborators. The central Statistical and Coordinating Center (SCC) will provide biostatistical collaboration for multi-unit research protocols and, in rare cases and at the direction of the SPC, for those units without such resources. The SCC also will provide central data management support for core AIEDRP data and will support network administrative functions (operational support). A. With respect to biostatistical collaboration, the SCC will: o Provide biostatistical collaboration in the design and analysis of clinical and basic science studies, whether single- or multi-unit, when requested by the unit investigators. o Facilitate interactions among local unit biostatistical groups so that the entire AIEDRP may benefit from specific statistical expertise of any one of the local groups. B. A core dataset, representing fundamental clinical and laboratory data, will be collected in a standardized way with common data forms in the context of all clinical study protocols within AIEDRP. This dataset will facilitate future meta-analyses of data across protocols to study the safety and benefit of interventions of acute and early HIV infection and also will form the basis for creation of a long term AIEDRP cohort. With respect to the core dataset, the SCC will: o Collaborate with site investigators to identify the standard data items comprising the core dataset and collection instruments, and training in their use. o Provide central management, data editing, and quality control of the core dataset. o Provide the AIEDRP investigators with summaries of the core data as needed for quality control, study planning, and analysis purposes. C. The SCC will establish an administrative support office to perform network administrative and operational duties. Functions of the office will include, but are not limited to: o Supporting conference calls and meetings of the SPC by coordinating the development of the agendas, scheduling calls and meeting sites, preparing conference materials, and writing and disseminating conference summaries, in addition, coordinating unit staff training for multi-unit studies. o Maintaining files of AIEDRP materials including study protocols, minutes of meetings and conference calls, reports, correspondence, safety information, abstracts, and publications. o Maintaining a directory of AIEDRP participants and distribution lists and coordinating communications. o Preparing and distributing reports and newsletters on AIEDRP activities and progress. o Conducting a visit to each AIEDRP unit early in the project period to provide training and orientation, and making follow-up visits to units requiring extra assistance during the course of the project. o At the direction of the SPC, the administrative support office will coordinate the research activities of individual research projects (for example, large, multi-unit projects and complex single unit, multi-site projects), including assistance with protocol development and distribution, and coordinating communications with regulatory and pharmaceutical representatives. SPECIAL REQUIREMENTS Each applicant should develop a scientific agenda that includes proposals for collaborative studies with other AIEDRP Units. Over the five-year funding period, the AIEDRP will increasingly emphasize collaborative studies, however, independent pilot studies may still be included as part of the scientific agenda. Multi-unit research activities of the AIEDRP will be overseen by the AIEDRP SPC. The AIEDRP will meet twice yearly to provide updates on the progress of research. One meeting will be a large meeting to review the progress being made in acute infection research and to discuss potential areas for collaborations. The second meeting may be a small meeting to focus on one or two topics that the AIEDRP investigators feel is of particular relevance to advance the work of the AIEDRP. The agenda for these meetings will be set by the SPC. 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 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" 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. 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 PIs for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the PIs and the NIAID Scientific Coordinator. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are applicable. The special terms and conditions pertaining to the scope and nature of the interaction between the NIAID and the investigators will be incorporated in the Notice of Grant Award. However, these terms will be in addition to, not in lieu of, the customary programmatic and financial negotiations that occur in the administration of cooperative agreements. 1. Monitoring Clinical Studies When clinical studies or trials are a component of the research proposed, NIAID policy requires that studies are monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. Terms and Conditions of Award will be included with awards. NIAID policy was announced in the NIH Guide on February 24, 2000 and is available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-00-003.html. 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 RFA AI-01-008 and for performing the scientific activity. Specifically, awardees have primary responsibility for: a. research design, protocol development, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis, and publication of results. All protocols and protocol amendments developed and conducted by the AIEDRP will be submitted to the NIAID Program Officer for review and approval by the DAIDS Clinical Science Review Committee (CSRC) as noted below prior to FDA submission or implementation. A formal plan for monitoring the conduct of the study is to be included in each protocol submitted for CSRC review. b. establishing a Scientific Planning Committee (SPC) with the other Principal Investigators to facilitate information exchange, foster collaboration, and coordinate activities to reduce duplication. c. proposing concepts to the SPC for collaborative pathogenesis and therapeutic studies, functioning as the scientific coordinator for protocols (Protocol Chairperson) and assuming responsibility for monitoring study performance. d. establishing mechanisms for internal quality control and monitoring. Awardees are responsible for ensuring the accurate and timely assessment of the progress of studies, including the development of procedures to ensure that data collection and management are adequate for quality control and analysis. e. preparing and submitting interim progress reports, when requested, to the NIAID Program Officer including summary data on progress of multi-unit studies. The SPC may require additional information on multi-unit studies from the individual awardees/sites. f. timely presentation and/or publication of major findings. This is essential and requires acknowledgment of NIAID support. A copy of manuscripts for work supported by this mechanism must be provided to the NIAID Program Officer. The awardee retains the rights to the data consistent with current HHS, PHS, and NIH policies, under this cooperative agreement, however, the NIAID will have access to all data and may periodically review it. g. inclusion or establishment of a Community Advisory Board (CAB) representative of the HIV-infected community in the catchment area. The site should have plans that demonstrate how the CAB will be included in the activities to substantially contribute to the success of the unit. Funds requested in the application must be made available to the CAB for reimbursement of reasonable expenses including representation at the Group meeting(s). h. The central Statistical and Coordinating Center (SCC) will provide biostatistical collaboration for multi-unit research protocols and, in rare cases and at the direction of the SPC, for those units without such resources. The SCC also will provide central data management support for core AIEDRP data and will support network administrative functions (operational support) 3. NIAID Responsibilities The NIAID Program Official 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. a. Monitoring of study progress, which may include: (i) periodic site visits for discussions with awardee research teams. (ii) observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters. (iii) attendance at, and participation in, the SPC and other meetings. The NIAID retains, as an option, periodic external review of progress. b. Serving as a resource with respect to other ongoing NIAID activities that may be relevant to the AIEDRP’s research and facilitating compatibility to avoid study duplication. c. Assisting substantially in the design and coordination of research activities for awardees including: (i) providing advice on the management and technical performance of the investigations. (ii) facilitating access to and use of reagents, assays, and other resources available through NIAID contractors and repositories. (iii) providing technical advice and assistance with FDA regulatory requirements for investigational agents. (iv) For multi-unit protocols and through participation on the SPC, a NIAID Representative may coordinate activities among awardees by assisting with: the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data, the preparation of data recording forms, and the publication of results. (v) The CSRC will review and approve single- and multi-unit clinical trial protocols to ensure that they are within the scope of the AIEDRP and are adequate with respect to patient safety, human subject protections, and representation of women and minorities, as required by Federal regulations. The NIAID will monitor protocol progress, and may request that a protocol be closed to accrual for reasons including: (1) accrual rate insufficient to complete study in a timely fashion, (2) accrual goals met early, (3) poor protocol performance, (4) patient safety, human subjects, and women/minority recruitment concerns, (5) study results that are already conclusive, and (6) emergence of new information that diminishes the scientific importance of the study. The NIAID will not permit further expenditure of NIAID funds for a study after requesting closure (except for patients/subjects on-study and final data analysis and reporting). (vi) reviewing and providing advice regarding the establishment of mechanisms for quality control and study monitoring for multi-center clinical trials. 4. Collaborative Responsibilities In addition to the interactions defined above, awardees and NIAID staff shall form a Scientific Planning Committee (SPC) formed by the Unit Principal Investigators or their designees, 1-2 representative(s) from the Statistical and Coordinating Center, and a NIAID representative. The AIEDRP SPC will coordinate collaborative AIEDRP activities, including multi-unit clinical projects, through e-mails, conference calls, and meetings.. The AIEDRP SPC serves to facilitate information exchange, foster collaboration, and coordinate activities to minimize duplication. Additionally, the AIEDRP should have the capability and flexibility to conduct multi-unit clinical trials involving a larger number of patients (Phase II studies) as scientific opportunities become available. The AIEDRP SPC will identify the highest priority research questions requiring multi-unit study. An initial meeting will be convened early after award by the NIAID Program Official. The final structure of the committee will be established at the first meeting. The NIAID representative(s) will have voting membership on the committee and, as appropriate, its subcommittees, but may not serve as Chair of a committee or subcommittee. The SPC should meet at least quarterly, either in person or by conference call, to: o Discuss issues related to enrollment in AIEDRP protocols. o Review and approve multi-unit concept sheets submitted by AIEDRP investigators. o Develop and approve collaborative projects. o Make decisions regarding future research directions. o Create focus groups to address specific aspects of the AIEDRP research agenda, with emphasis on multi-unit collaborative projects. o Designate a Protocol Chairperson for each multi-unit research study. o Define core data collection strategies, as well as methods and approaches to cross-study analyses. o Review publications resulting from multi-unit trials. 5. IND Responsibilities For pilot studies, either the Principal Investigator or a pharmaceutical company may file an Investigational New Drug (IND) application to the United States Food and Drug Administration. The sponsor of the IND has responsibility for the conduct of trials under that IND, which includes adhering to applicable Federal regulations. For large scale, multi-unit (Phase II) studies, NIAID will retain the option to cross-file or independently file an IND. Reports of data generated by the AIEDRP or any of its members required for inclusion in INDs and Clinical Brochures and for cross-filing purposes will be submitted by the Principal Investigator to the NIAID Program Official 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. If NIAID holds the IND for a trial, a NIAID Medical Officer or his/her designee will monitor the safety of the treatment(s) being evaluated. Regulatory responsibilities will be the responsibility of NIAID. Standard procedures (e.g., registration of sites participating in clinical trials) will apply. Interim and final reports on toxicities for all sponsored clinical trials will be routinely provided through the NIAID Program Official to the NIAID Medical Officer. In addition, when NIAID holds the IND for a trial, a DAIDS pharmacist may participate on the protocol team, consult on the pharmaceutical aspects of protocol development, and will interact with pharmaceutical companies to ensure product availability. DAIDS will not provide study agents or permit expenditure of NIAID funds for disapproved protocols. 6. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Scientific Planning Committee or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, and a third member who has expertise in the relevant area and who is selected by the two other members. The panel will review any scientific or programmatic issue that is significantly inhibiting progress. While the decisions of the panel are binding, these special arbitration procedures will in no way affect the awardee"s right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. STUDY POPULATIONS This initiative will focus on recruitment and long-term follow-up of individuals with acute and early HIV infection. Long-term follow-up will be essential to determine whether the benefits of very early intervention outweigh the risks of toxicity associated with therapy. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear, compelling rationale and justification are provided 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). The changing demographics of the HIV epidemic have led to the majority of new infections now occurring in minorities and increasingly in women, with half of new infections in the past year in the United States occurring in persons under 25 years of age. It is therefore essential that applicants develop plans to capture this group in their study population. All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at: (http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm). The revisions relate to NIH-defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and which is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. For the purpose of this RFA, participation in AIEDRP clinical research studies is open to persons 13 years of age and older. The NIH has other programs for HIV clinical research in children less than 13 years of age. Investigators may obtain copies from these sources or from Dr. Frederick Batzold, listed in INQUIRIES below, who also may provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit by August 16, 2001, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, and the number and title of this RFA. Although the letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, 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 to Dr. Hagit David at the address listed under INQUIRIES by the letter of intent receipt date listed. APPLICATION PROCEDURES Applicants are strongly encouraged to call NIAID program staff with any questions regarding the responsiveness of their proposed project to the goals of this RFA. Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov, as well as on the internet at http://grants.nih.gov/grants/forms.htm. For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number "AI-01-008" and the words "ACUTE INFECTION AND EARLY DISEASE RESEARCH PROGRAM" must be entered on the face page. On Page 2 (Key Personnel), all professional personnel and their institutional affiliations for the project must be listed, including those with no requested salary support. Each Biographical Sketch (limited to two pages) and Other Support pages should be listed at the end of the application with the Principal Investigator first, followed by other key personnel in alphabetical order. The use of tables, diagrams, organizational and flow charts is strongly encouraged. Key information submitted as appendices as detailed in the PHS 398 (Rev. 4/98) should be clearly referenced in the Research Plan section. Information submitted as appendices should be limited to essential materials in support of the application, summaries or examples of information are encouraged. Letters of support that do not formally commit to contributions to the AIEDRP should not be included. For both the AIEDRP units and the SCC, the Research Plan (Items a-d) is not subject to the page limitation in the PHS Form 398. This section of the application should not exceed 170 pages. Applications must be received by October 10, 2001. Applications not received as a single package on the receipt date or not conforming to the instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and superseded by, the special instructions below, for the purposes of this RFA), will be judged non-responsive and will be returned to the applicant. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. 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. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application that is essentially identical to one that has already been reviewed cannot be submitted in response to this RFA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided 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 mail or 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: Dr. Hagit David, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room Number 2152, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 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. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. REVIEW CONSIDERATIONS General Considerations Upon receipt, applications will be reviewed for completeness and adherence to the Special Instructions above by the NIH Center for Scientific Review and for responsiveness by NIAID staff, those judged to be incomplete or non-responsive 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 Division of Extramural Activities, NIAID in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Allergy and Infectious Diseases Council. Review Criteria The criteria to be used in the evaluation of grant applications are listed below. To put those criteria in context, the following information is contained in instructions to the peer reviewers. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that 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. A. AIEDRP Units 1. Significance: Is the proposed research of scientific, technical, and clinical significance, and based on an original concept? Do the proposed projects take advantage of unique features of the AIEDRP or make optimal use of collaborative arrangements? 2. Approach: Are the experimental approach and the methodology proposed to carry out the research appropriate and adequate? Specifically, the reviewers should evaluate the adequacy and feasibility of the applicant’s plans, methods, approaches and strategies to: 1) identify, screen, and recruit individuals with acute or early HIV infection that are representative of the demographics of the catchment area, 2) follow subjects for the long term and retain them in research studies, and 3) perform and quality assure laboratory assays in support of these studies. Does the applicant demonstrate the ability to enroll and retain an adequate number of subjects (in particular, acutely infected individuals), given the proposed scientific agenda? 3. Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator: Do the Principal Investigator and key staff have adequate qualifications and research experience in the area of the proposed research, specifically: 1) expertise and experience in conducting clinical research on the pathogenesis and treatment of acute HIV infection, and 2) experience in performing virology, immunology and pharmacology assays in support of state-of-the-art pathogenesis research and HIV clinical trials? Are the investigators appropriately trained and well suited to manage and direct local and AIEDRP-wide research? Are they well suited to engage in collaborative interactions with other AIEDRP investigators and with investigators external to the AIEDRP who desire to utilize AIEDRP data and specimens? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers? Has the Principal Investigator budgeted sufficient time to ensure that adequate attention is paid to these AIEDRP-wide scientific issues? 5. Environment: Are necessary resources to conduct the proposed research available? Additional Review Criteria for This RFA 6. Are the scientific goals set forth in this application feasible considering the challenges of recruitment and the predicted outcomes? Have existing AIEDRP units achieved their goals? Are the plans adequate for recruiting and following study subjects, obtaining data, and sending data to the SCC? Are the plans adequate for maintaining good relationships with community groups relevant to the AIEDRP? Are the plans adequate for participating in key AIEDRP organizational structures, such as the SPC? Are the plans adequate for working with the SCC to ensure appropriate standardization and quality control of data collected at each site? Are the site-specific plans adequate for participation in AIERDP-wide activities? 7. Is the study design adequate for the representation of women, adolescents, and/or minorities in study design? 8. Are the plans adequate for collaborative projects that might be conducted among multiple AIEDRP units and evidence of collaborations in other current or recent projects? 9. Have recompeting applicants appropriately described their qualifications based on past and present activities within the AIEDRP? Those applicants who are not currently a member of the AIEDRP should describe their participation in comparable projects (e.g., group participation, pharmaceutical studies). B. Statistical and Coordinating Center 1. Does the application provide evidence of statistical expertise that complements the goals of the AIEDRP? Does the biostatistical methodology set forth in this application represent the most relevant manner in which the data obtained from the units and from collaborators may be analyzed to advance understanding of acute HIV infection and early HIV disease? 2. Does the applicant demonstrate data management expertise including procedures for collecting and managing a database of core data from the AIEDRP clinical units? Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the AIEDRP? Is the approach for managing data appropriate and optimal? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Are the applicant"s plans adequate for providing operational support for administrative functions of the AIEDRP and particularly its Scientific Planning Committee? Has the applicant appropriately addressed the responsibility of developing the logistics necessary for the SPC to develop and coordinate the scientific agenda? 4. Is the overall SCC management plan appropriate? Are the investigators appropriately trained and well suited to perform the data management, data analyses, study design, and AIEDRP-wide coordinating roles central to the functioning of SCC? Are the experience levels of the Principal Investigator and other key personnel appropriate for the proposed work? The Initial Review Group also will examine: the appropriateness of the proposed project budget and duration, the adequacy of plans to include children (ages 13 years and above) and both genders and minorities and their subgroups as required for the scientific goals of the research, the plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and plans for ensuring the safety of the research environment. Schedule Letter of Intent Receipt Date: August 16, 2001 Application Receipt Date: October 10, 2001 Scientific Review Date: February, 2002 Advisory Council Date: May, 2002 Earliest Award Date: July 1, 2002 AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. The earliest anticipated date of award is July 1, 2002. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic (research scope and eligibility) issues to: Dr. Frederick Batzold, Ph.D. Clinical Research Management Branch/Division of AIDS National Institute of Allergy and Infectious Diseases Room 5154, MSC-7624 6700-B Rockledge Drive Bethesda, MD 20892-7624 Telephone: (301) 402-0143 FAX: (301) 480-4582 E-Mail: fbatzold@niaid.nih.gov Direct inquiries regarding review issues, address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Dr. Hagit David, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2152, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 402-4596 FAX: (301) 402-2638 E-Mail: hdavid@niaid.nih.gov Direct inquiries regarding fiscal matters to: Ms. Linda Shaw Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2125, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-6611 Fax: (301) 480-3780 E-mail: lshaw@niaid.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance No. 93.856. 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 Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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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