and Human Services (HHS)
EXPIRED
INTEGRATED PRECLINICAL/CLINICAL PROGRAM FOR TOPICAL MICROBICIDES RELEASE DATE: June 9, 2003 PA NUMBER: PAR-03-137 ( This PAR has been reissued as RFA-AI-07-001) (see clarification NOT-AI-03-051) LETTER OF INTENT DATE: August 22, 2003, August 23, 2004, 2005 APPLICATION RECEIPT DATE: September 23, 2003, 2004, 2005 EXPIRATION DATE: September 24, 2005, unless reissued. National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) National Institute of Child Health and Human Development (NICHD) (http://www.nichd.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. 93.865, Center for Research for Mothers and Children THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of this PA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators (PIs) o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) invite multi-project, multi-disciplinary applications whose goal is to advance safe, novel topical microbicides and microbicide combination strategies that prevent the sexual transmission of HIV, from preclinical to clinical studies. For the purposes of this Program Announcement (PA), topical microbicides are defined as vaginally or rectally applied biomedical products with or without contraceptive activity that safely inactivate HIV or prevent HIV infection or spread from initial target cells. The Integrated Preclinical/Clinical Program for HIV Topical Microbicides (IPCP-HTM) described in this PA links research with product development and initial clinical evaluation by supporting diverse research activities from multidisciplinary groups spanning discovery and preclinical development through early clinical trials. The previously released RFA entitled "Microbicide Preclinical Development Program" (HD-00-018) to advance the discovery and preclinical development of novel microbicides has been integrated into this PA and will not appear separately. Applications that aim to further an innovative topical microbicide may propose to initiate research at one of the following points: (1) discovery and preclinical development of a lead microbicide candidate/combination, (2) preclinical development research that transitions to iterative clinical/laboratory research directed toward optimization of the microbicide candidate/combination during the award period, or (3) iterative clinical/laboratory research in which a pilot clinical trial will be implemented within the first year of award. In combining these activities into a single PA, the IPCP-HTM provides a spectrum of research opportunities for collaborative groups pursuing any aspect of the discovery and development of new topical microbicides. Applications are required to include a component(s) (a research project and/or a core) headed by and derived from the private sector. Responsive applications will advance microbicide development with innovative microbicide research. Excluded from this PA is research on, or development of, marketed spermicidal products. Also excluded from this PA is research on, or development of, sulfated/sulfonated polymers or surfactants when advanced as the sole active ingredient in a microbicide candidate. Research on sulfated/sulfonated polymers or surfactants as components of combination microbicides will be considered responsive. RESEARCH OBJECTIVES Background In the absence of a fully effective HIV vaccine, topical microbicides represent an important potential strategy for preventing the transmission of HIV through sexual intercourse, the predominant mode by which HIV is transmitted worldwide. In particular, the number of women with HIV infection and AIDS has been increasing steadily worldwide and according to the World Health Organization (WHO), 19.2 million women are living with HIV/AIDS worldwide, accounting for almost 50 percent of the 42 million adults living with HIV/AIDS. The vulnerability of women of all ages for acquiring HIV infection - including older, postmenopausal women as well as adolescents - demands the development of safe, effective and acceptable female-controlled chemical and physical barrier methods, including topical microbicides, to reduce HIV transmission. In addition, recent statistics from several major cities in the U.S. show an increase in unsafe sexual practices as indicated by an increase in sexually transmitted diseases. Yet no safe and effective anti-HIV topical microbicide is currently available. Only products containing the surfactant, nonoxynol-9 (N-9), have advanced to efficacy trials. Results from these trials of vaginal N-9-containing products have indicated that N-9 does not provide protection against the sexual transmission of HIV. The safety and effectiveness of 6 additional candidate microbicides will be evaluated in trials scheduled to start in 2003. However, 4 of these are representative of the same class of active agent and one is a surfactant. Research is continuing into other diverse products; candidate microbicides currently under investigation include products that kill or inactivate HIV nonspecifically, those that inhibit HIV entry and cell fusion, and those that inhibit post-fusion events early in the viral replication cycle. The nonspecific candidate products fall predominantly into the category of surfactants and detergents, whereas most products targeted against specific steps in the HIV life cycle have been developed exclusively as potential therapeutics. In addition, no combination of microbicides has yet been evaluated in animal or human trials. Specifically, research needs to be conducted on the use of combinations of microbicides to determine if protective efficacy of the products is increased when microbicides with two or more different mechanisms of action are used together. Furthermore, topical strategies to safely enhance or stimulate naturally occurring healthy mucosal defense mechanisms have not been sufficiently exploited. Thus, there is a critical need to promote the discovery and development of safe, novel microbicides and combinations and to provide support for translational studies to advance new candidates and combinations that have proven safe in preclinical studies into early clinical trials. This PA will support multi-project, multi-disciplinary research groups, whose goal is to advance topical microbicides and microbicide combination strategies from discovery through preclinical development to clinical studies, to assemble the diverse scientific expertise and ancillary resources needed to translate basic discoveries to innovative applied entities. Scope The purpose of the IPCP-HTM is: (1) to encourage discovery and preclinical development of lead topical microbicide candidates and combinations, and (2) to foster translation of safe, new microbicides/combinations from preclinical studies to pilot clinical studies. The ultimate goal of this research is the development and exploratory clinical evaluation of new and potentially effective microbicides for the prevention of HIV sexual transmission. Such research is expected to increase the array of approaches and availability of potential candidates and combinations suitable for evaluations of safety and effectiveness in human clinical studies. In line with this objective, the PA will support diverse and creative microbicides/combinations with sound scientific rationale that are new and innovative or understudied. The PA provides a continuous spectrum of research opportunities - from discovery and preclinical development to pilot clinical studies - for interdisciplinary research groups to conduct. Examples of microbicide candidates of interest to the IPCP-HTM include, but are not limited to: o Development of combination microbicides containing a cocktail of active agents with diverse mechanisms of action, including those addressed below; o Discovery of novel microbicides including but not limited to: small molecules, metal and chelating agents, proteins, glycans, natural products, agents controlling pH, and bacterial and live vectors that may target viral or host elements essential for (i) HIV entry, including attachment, receptor engagement or fusion; (ii) early post-entry events in the HIV life cycle prior to and including reverse transcription, such as uncoating or translocation of the pre-integration complex into the nucleus; and/or (iii) HIV capture by, and dissemination from, initial target cells; o Development of microbicides that enhance or stimulate naturally occurring healthy mucosal defense mechanisms; and o Development of innovative virucidal agents that inactivate infectious HIV-1 particles or HIV-1-infected cells without causing host cell toxicity. Preclinical Research The preclinical component of the IPCP-HTM supports discovery and preclinical development of topical microbicides and combination microbicide approaches. A new microbicide or combination should have relevance and future application to clinical evaluation. As part of an integrated approach to the critical path development of a specific candidate product and advancement into pilot clinical trials, applicants are encouraged to incorporate research in areas of microbicide development that are largely underexplored e.g., (1) formulation science, (2) development of new and/or improved ex vivo (e.g., tissue explants) and in vivo animal models for evaluating the safety and efficacy of new microbicides, including models for reproductive toxicity, and (3) design and evaluation of delivery systems. To be considered responsive to this PA, IND-enabling safety and other preclinical studies must comply with Good Laboratory Practice (GLP) regulations, as well as production and manufacture of microbicide products according to Good Manufacturing Practice (GMP) regulations,. A successful group proposing preclinical studies would move a candidate microbicide, or combination, from discovery through advanced preclinical development such that at completion of the 4-year award period it would be poised for clinical evaluation. Applicants seeking to transition from preclinical to clinical research during the award period are required to detail the discrete goals and measurable milestones considered necessary to enter the clinical phase. These goals and milestones should also include plans and a timetable for obtaining the required institutional and government approvals [Institutional Review Board (IRB), Office of Human Research Protection (OHRP), FDA]. The peer review group will review the appropriateness of the goals and milestones. Funding of the final 2 years of the grant will be contingent upon successful completion of negotiated milestones and the feasibility of clinical testing within the funding period as determined by a mid-point review of progress to date (see Special Requirements). Clinical Studies The clinical portion of the IPCP-HTM should exploit interdependent, iterative clinical/laboratory research designed to evaluate and optimize a microbicide. Research in the areas of identification/evaluation of markers and/or methodologies to establish product use compliance and assessment of state-of- the-art technologies to measure bio-adhesive and bio-dispersion characteristics may be included as part of an integrated approach to advance a specific microbicide candidate. Examples of other scientific areas appropriate for pilot clinical studies include, but are not limited to, evaluation of pharmacokinetics and tissue distribution of the proposed microbicide candidate, evaluation of the safety and acceptability of a novel delivery system, and preliminary evaluation of potential activity on viral load (if relevant to the proposed mechanism of action) recovered in vaginal and rectal mucosal specimens. Proposals with projects focusing on new strategies that exploit pre-existing non-detergent microbicides, especially as combination microbicides, would also be considered responsive. A successful application proposing clinical studies would develop and optimize a microbicide candidate to the point of determining its merits for further clinical evaluation. A clinical application must be based on a strategy in an advanced stage of preclinical development that is suitable for evaluation in a small number (6- 12) of subjects in a pilot clinical study. [When merited by the study, a larger number of subjects may be considered; prior approval by the Program Officer (see INQUIRIES, below) is required.] Conventional Phase I through Phase III clinical trials are not supported by this Program Announcement. The application should include (1) a detailed plan of the iterative clinical and laboratory research to be conducted to optimize the proposed strategy, (2) a timetable to be followed, (3) plans for clinical studies, including a clinical concept, outline of a clinical protocol, or the clinical protocol, and (4) institutional and government approvals (IRB, FDA, OHRP), where applicable. NIAID and NICHD intend to support the following research groups through this PA: (1) groups focusing exclusively on advanced preclinical optimization and IND-directed development of new topical microbicides [i.e., appropriately synthesized and manufactured microbicide products that will undergo safety testing as per U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) guidelines], and (2) groups positioned to implement a pilot clinical study during the award period. Pilot clinical studies are defined as early Phase I studies with small numbers of participants, exclusive of formal Phase I through Phase III clinical trials. U19 applications submitted in response to this PA may not request in excess of $750,000 first-year direct costs for research involving preclinical studies, or $1,300,000 first- year direct costs, exclusive of Facilities & Administrative (F & A) costs for consortium arrangements for translational research involving clinical studies. Budgets exceeding these levels must be strongly justified and pre- approved for submission by the Program contact person listed under "INQUIRIES." Applications with budgets exceeding these levels that are submitted without prior Program approval will be returned without review. Groups proposing to transition from preclinical to clinical studies during the award period should submit a budget for each phase that reflects the limits given above. MECHANISM OF SUPPORT This PA will use the NIH Multi-project Cooperative Agreement (U19), an "assistance" mechanism, rather than an "acquisition" mechanism. 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." Essential elements of the multi-project cooperative agreement mechanism also include: (1) a minimum of three interrelated individual research projects organized around a central theme; (2) collaborative efforts and interaction among independent projects and their investigators to achieve a common goal; (3) a single PI who will be scientifically and administratively responsible for the group effort; (4) a single applicant institution that will be legally and financially responsible for the use and disposition of funds awarded; and (5) support provided, as necessary, for "Core" resources or facilities, each of which is expected to be utilized by at least two research projects in order to facilitate the research effort The level of support for clinical research under this PA may be insufficient to provide all the funds necessary to conduct the proposed clinical study. Prospective groups are therefore encouraged to develop plans to use existing infrastructure and organizational support to complement the award [including NIH-sponsored General Clinical Research Centers (GCRC), Centers for AIDS Research (CFAR), the HIV Prevention Trials Network (HPTN), the Adolescent Medicine Trials Network (ATN), the Contraceptive Clinical Trials Network (CCTN) and the Comprehensive International Program for Research on AIDS (CIPRA)]. These plans should be included in the application. The total project period for applications submitted in response to this PA may not exceed five years for applications proposing clinical research; for applications focusing solely on preclinical development, the total project period may not exceed 4 years. 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. ELIGIBLE INSTITUTIONS The applicant may submit (an) application(s) if the institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign 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 Milestones Through the Scientific Coordinator (as described in the Collaborative Responsibilities section below), NIAID/NICHD may revise the proposed and peer-reviewed milestones and negotiate acceptance of the revised milestones with the PI, as necessary, prior to award. The finalized milestones will be included in the Terms of Award. Progress will be based upon the timely completion of these milestones. Decisions regarding funding beyond 3 years for groups transitioning to clinical studies will be based on the completion of milestones in the first 2.5 years. Milestones Review At the mid-point of the grant (2.5 years), based on the preceding 2 annual reports and any additional information that the PI elects to submit at the 2.5-year anniversary, Program will determine whether the milestones have been accomplished and whether the progress as reported will allow, with high probability, initiation of a clinical study within 5 total years. The mid- point grant review will be conducted via a phone conference call or a meeting with the PI and NIAID/NICHD staff and may include members of the Scientific Advisory Panel (SAP) (as described in the Collaborative Responsibilities Section of this PA). If NIAID/NICHD determines high feasibility for the grant to culminate in a human clinical study, the grantee will be funded for years 4 and 5. If NIAID/NICHD determines that progress does not demonstrate likelihood of a clinical study, the grant will be phased out by the end of 4 years, or sooner, if appropriate/feasible. Patent Coverage Since an application may include several institutions, including the private sector, complex patent situations may arise. To avoid delays related to intellectual property issues, each multi-project group is required to submit, as part of the application, a plan detailing (1) the approach agreed to by all parties for obtaining patent coverage and licensing, where appropriate, (2) a statement demonstrating acceptance of the approach signed by all parties, and (3) procedures to be followed for the resolution of legal problems that may potentially develop. Meetings and Travel All awardees will be strongly encouraged to attend a scientific conference of NIAID/NICHD Topical Microbicide Program investigators, organized by NIH and held every 12-18 months in the Washington, D.C. area. Applicants should include estimated travel expenses for one such meeting per year to the Washington, D.C. metropolitan area in the application budget. Estimated expenses for travel of the SAP members and key staff [e.g., PI, all Project Leaders (PL) etc.] should be based on one group meeting per year and should also be included in the budget. No additional travel funds will be provided to attend other domestic or foreign meetings. COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the PI 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), "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/NICHD Scientific Coordinator. 1. Monitoring Clinical Studies When clinical studies or trials 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. 2. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the PA and for performing the scientific activity. Specifically, awardees have primary responsibility as described below. All awardees are required to host for the Scientific Coordinator and other NIAID/NICHD Program staff, an annual site visit. The PI, all co-PIs, PLs and Core Leaders and the SAP (described in the Collaborative Responsibilities section below) members shall attend this meeting. An update and summary of results generated on each project shall be presented by the PI and other relevant members of the cooperative agreement. These presentations shall include summaries of all goals or milestones (refer to Special Requirements) and a description of all problems encountered that will impact on the achievement of future goals and milestones. In addition to annual site visits, the PI will be afforded the opportunity to submit in writing a mid- point progress report delineating progress on each of the stated milestones and a clear plan for the initiation of a clinical study. Any such supplemental information must be provided to the Scientific Coordinator no later than 1 month prior to the date of the 2.5-year anniversary of the grant award. 3. NIAID/NICHD Staff Responsibilities NIAID/NICHD staff assistance will be provided by a Program Officer who will serve as NIAID/NICHD's Scientific Coordinator. The NIAID/NICHD Scientific Coordinator will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. o Interacting with the PI(s) on a regular basis to monitor program progress and clinical study progress, compliance, adherence to protocol, and quality assurance in order to ensure the production of high-quality, unbiased results. Monitoring may include: (a) regular communications with the PI and staff, (b) periodic site visits for discussions with awardee research teams, (c) observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters, as well as (d) attendance at and participation in SAP meetings and/or annual site visit meetings. The NIAID/NICHD retains, as an option, periodic external review of progress. NIAID/NICHD reserves the right to independently monitor the trial to ensure adherence to regulatory requirements. Such review and monitoring may be conducted by an organization contracted by and acting on behalf of NIAID/NICHD. o NIAID/NICHD Program staff or designee will have access to and may periodically review all study protocols and data. o Serving as a resource with respect to ongoing NIAID/NICHD activities that may be relevant to the research to facilitate expeditious accomplishment of program goals and compatibility, avoid unnecessary duplication, and potentially forging collaborations that may enhance the quality and breadth of the study. o Providing substantial assistance in the design and coordination of research activities for awardees including: a. Advice on planning, management and technical performance of the investigations b. Access to and use of, when appropriate, reagents and assays, and other resources available through NIAID/NICHD contractors and awardees c. Technical advice and assistance with meeting FDA requirements for investigational agents d. Coordination of activities among awardees [for multi-institutional protocols, through participation on the SAP and with the agreements of the PI(s)] by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in preparation of questionnaires and other data recording forms; and in the publication of results e. Review and approval of protocols to insure adherence to the scope of the original proposal, peer review comments and suggestions, and for adequacy of safety, protection of human subjects, and representation of women and minorities as required by Federal regulations and NIH policies. The NIAID/NICHD Program Officer will monitor protocol progress, and may require that a protocol be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion, (b) accrual goals met early, (c) poor protocol performance, (d) patient safety, human subjects, and women/minority recruitment concerns, (e) study results that are already conclusive, and (f) emergence of new information that diminishes the scientific importance of the study. The NIAID/NICHD will not permit further expenditure of NIAID/NICHD funds for a study after requiring closure (except for patients/subjects on-study and final data analysis and reporting) f. Advice regarding the establishment of mechanisms for quality control and study monitoring o Making recommendations for continued funding based on: (a) overall study progress including study subject and/or data accrual, (b) cooperation in carrying out the research e.g., following SAP meeting guidance, implementation of group decisions, compliance with terms of award and reporting requirements), and/or (c) maintenance of a high quality of research that will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements. 4. Collaborative Responsibilities IPCP-HTM Group Scientific Advisory Panel Each IPCP HTM group will establish a Scientific Advisory Panel (SAP) i.e., Steering Committee of 2-3 investigators not affiliated with any of the institutions comprising the awardee(s). Membership will be determined in consultation with the Scientific Coordinator. Applicants must not name the prospective Advisory Panel members in their applications nor should prospective members be contacted by applicants prior to completion of peer review of applications. However, a proposal should include identification of the proposed expertise to be represented on the panel. The Panel will attend one or more of the IPCP-HTM group meetings each year, review the group's activities, and evaluate progress, adherence to the original time frame of activities, and the continued relevance of each project to the group's overall goals. The Panel will recommend new directions as appropriate and will provide the PI with a comprehensive written evaluation of the group's activities and recommendations after each meeting. For applications proposing a clinical component, the Panel may, at the discretion of NIAID or NICHD, also be called upon to evaluate the feasibility of initiating a clinical study per the final goals and milestones. A copy of the Panel's report is to be sent to the NIAID or NICHD Coordinator, as appropriate, within 30 days of each meeting. 5. Arbitration Arbitration. Any disagreement that may arise on scientific or programmatic matters (within the scope of the award), between award recipients and the NIAID/NICHD may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NIAID/NICHD representation not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIAID/NICHD, 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. WHERE TO SEND INQUIRIES We encourage inquiries concerning this PA 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 your questions about NIAID scientific/research issues to: Dr. Roberta Black Division of AIDS National Institute of Allergy and Infectious Diseases Room 4110, MSC-7628 6700-B Rockledge Drive Bethesda, MD 20892-7628 Telephone: (301) 496-8199 FAX: (301) 496-8530 E-Mail: [email protected] o Direct your questions about NICHD scientific/research issues to: Dr. Patricia Reichelderfer Center for Population Research National Institute of Child Health and Human Development Room 8B13G, MSC 7510 6100 Executive Boulevard Bethesda, MD 20892-7510 Telephone: 301-496-1661 FAX: 301-480-1972 E-mail: [email protected] o Direct questions about peer review issues; address the letter of intent; mail two copies of the application and all five sets of appendices to: R. V. Srinivas, Ph.D. Chief, AIDS & Related Research IRG Center for Scientific Review, NIH Room 5222, MSC 7852 6701 Rockledge Dr Bethesda, MD 20892 (Use 20817 for express mail Telephone: (301) 435-1167 FAX: (301) 435-1167 E-Mail: [email protected] o Direct questions about financial or grants management matters to: Jane Unsworth Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2128, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-6824 FAX: (301) 480-3780 Email: [email protected] 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: Dr. Roberta Black Division of AIDS National Institute of Allergy and Infectious Diseases Room 4110, MSC-7628 6700-B Rockledge Drive Bethesda, MD 20892-7628 Telephone: (301) 496-8199 FAX: (301) 496-8530 E-Mail: [email protected] SUBMITTING AN APPLICATION 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 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). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected]. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted June 27, 2003, 2004, 2005. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and five signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) Applications that are not received as a single package on the receipt date 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. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the PI and awarding institution. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a letter of intent identifying the NIAID/NICHD staff member who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the NIAID/NICHD program staff person listed in this PA at least 6 weeks before submitting the application, i.e., as applicant is developing plans for the study 2) Obtain agreement from the NIAID/NICHD staff that the NIAID/NICHD will accept the application for review and potential consideration for award; and 3) Identify in the letter of intent, the NIAID/NICHD staff member you contacted, a proposed first year budget with the number of Projects, PIs and Institution for each project, specific aims for each project, and a projected budget for the proposed funding period. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS PA: 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 PA. If an application is received after that date, it will be returned to the applicant without review. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. 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 PI 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 Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. U19 applications that are complete and responsive to this PA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Center for Scientific Review. As part of the initial merit review, all applications will: o Receive a written critique 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 second level review by an appropriate national advisory council or board. 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 ADDITIONAL REVIEW CRITERIA: In addition, the following review criteria items will be considered in the determination of scientific merit and the priority score: o The potential biomedical significance and novelty of the project. o The likelihood that the research will open new directions in the prevention of HIV sexual transmission, demonstrate a capacity to be translated to clinical practice, and merit evaluation in IND-directed clinical trials for safety and proof-of-concept. o Appropriateness of the experimental approach, development plan, and methodology proposed, including laboratory capabilities of the investigators (preclinical and/or clinical). o The PI's and PLs' commitment to devote substantial time and effort to the program. [Due to the complexity and time required to maintain a well coordinated and productive research effort, a minimum 20% (time) commitment by the PI and PLs is strongly suggested.] o The suitability of the proposed private sector component to the overall scientific objectives of the applicant; the scientific capability and commitment of the private sector component to the group's objectives and to the development of the proposed microbicide candidate; adequacy of the development plan to achieve the scientific goals of the proposed research and to move the proposed microbicide toward clinical application and toward approval of the proposed microbicide for clinical use. Each of these review criteria will be addressed and considered by the reviewers 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 a 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. In addition to (not in lieu of) the review criteria detailed in the instruction brochure (see above), review criteria specific to this PA include an evaluation of the following: For groups focusing on preclinical research: o Choice of the microbicide target or strategy, its contribution to the diversity of potential microbicides, and the likelihood that the microbicide candidate can be developed (e.g., following a prescribed preclinical development plan; selecting a clinical candidate) during the award period o Likelihood that work will progress through preclinical development during the award period, after which the microbicide candidate will be poised for clinical evaluation For groups proposing clinical research: o Adequacy and validity of the proposed discrete goals and measurable milestones for determining the readiness of the group to transition to clinical research; iterative research plan to develop and optimize the proposed microbicide candidate; general protocol design; short and long term development plans; contingency plans addressing the specific objectives; plans to guard the safety of subjects; plans to evaluate outcome even if unanticipated; and provisions to obtain the required institutional and regulatory approvals (IRB, FDA, OHRP) to conduct the clinical study o Experience of the PI and PLs in filing INDs and in the planning, design, and conduct of small pilot clinical studies in healthy individuals and/or in the conduct of topical microbicide clinical trials; availability of a GCRC, CFAR, CIPRA, HPTN clinical site, ATN site, CCTN site or other additional source of institutional support and/or statistical support; the infrastructure required for the conduct of safe and efficient clinical research; and short and long range plans that will result in the successful implementation of clinical studies during the award period In addition to evaluating the scientific merit of the application, all multi- project applications are assessed for the soundness of the administrative and organizational structure that facilitates attainment of the objective(s) of the program. Thus, the Administrative Core should detail short and long term management components of the Program, such as: communication, group meetings, sharing and transmission of information and reagents, awareness of development of other projects within the program, progress, problems and how will they be addressed, engagement of the SAP and NIAID and NICHD, as appropriate, in the group's research activities/meetings, consideration and integration of scientific input/recommendation from the SAP and NIAID and NICHD, as appropriate, into scientific direction and decision-making, timely reporting as required in the Terms of Award (provided at the time of award), and other aspects relevant to the cohesiveness and interactive nature of group activities. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. MONITORING PLAN AND DATA AND SAFETY MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (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. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance at http://www.cfda.gov/ in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research, No. 93.856, Microbiology and Infectious Diseases Research, and No. 93.865, Center for Research for Mothers and Children. 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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