RFA-HD-00-018: MICROBICIDE PRECLINICAL DEVELOPMENT PROGRAM

Department of Health
and Human Services (HHS)

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MICROBICIDE PRECLINICAL DEVELOPMENT PROGRAM Release Date: November 7, 2000 RFA: HD-00-018 National Institute of Child Health and Human Development (http://www.nichd.nih.gov) National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) Letter of Intent Receipt Date: December 18, 2000 Application Receipt Date: March 30, 2001 PURPOSE The National Institute of Child Health and Human Development (NICHD) and the National Institute of Allergy and Infectious Diseases (NIAID) invite applications to conduct research on the discovery and preclinical development of novel microbicides, with or without contraceptive activity, for prevention of sexual transmission of HIV-1. For the purpose of this RFA, all novel microbicides for prevention of sexual transmission of HIV-1 that are based on virus inactivation or prevention of viral infection of susceptible cells will be termed microbicides. The preclinical activities supported through this RFA will target both new agents and products already identified as having potential for microbicide development. The program project grants funded through this initiative will be established to advance the development of novel microbicides with or without contraceptive activity. Each program project will consist of: (1) a Principal Investigator, who is responsible for the scientific and administrative aspects at his/her institution, including the Administrative Core, (2) three or more independent Research Projects, each directed by a Project Leader, and (3) Support Core(s) directed by Support Core Leader(s) that provide essential facilities or services to the Research Projects. Since the majority of the women infected with HIV-1 in the United States are African-American or Hispanic, these studies will be relevant to the reduction of health disparities in minority populations. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to several priority areas. Potential applicants may obtain "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, 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 for these grants, but components of a program project may be located at foreign sites. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. For further information regarding the application, contact the Program Staff listed under INQUIRIES. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) program project grant (P01) award mechanism. Responsibility for the planning, direction, and execution of the proposed projects will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed four years. The P01 supports broadly based multidisciplinary research programs that have a well-defined central research focus or objective. An important feature is that the interrelationships among the individual projects will result in a greater contribution to the overall program goals than if each project was pursued independently. The program project grant requires a minimum of three interrelated individual research projects that contribute to the overall program objective. The application may request support for certain common core resources. Complete guidelines for the NICHD Program Project Grant are available at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. These guidelines must be followed in preparing applications in response to this RFA. FUNDS AVAILABLE The NICHD and NIAID intend to commit approximately $3.0 million each in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2001 to fund six to eight new grants in response to this RFA. An applicant may request a project period of up to four years. Budgets for direct costs in excess of $750,000 in the first year, excluding F & A costs on consortium arrangements, will be accepted for review only with prior approval of the Program Staff listed under INQUIRIES, below. Annual budgets for Years 02 to 04 should not exceed the first year budget plus a three percent yearly increase. Because the nature and scope of the research proposed might vary, it is anticipated that the size of awards also will vary. Although the financial plans of the NICHD and NIAID provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background Human immunodeficiency virus type-1 (HIV-1) infection is spreading most rapidly among women, especially among young women and women of color. Worldwide, the vast majority of new HIV infections in women now occur through heterosexual transmission. There is a need to identify new and effective microbicides that, when administered vaginally or rectally, can prevent sexual infection with HIV and other sexually transmitted pathogens. This RFA encourages the discovery and preclinical development of novel or under-explored microbicides, with or without contraceptive activity, to prevent sexual transmission of HIV. The active participation of industry is encouraged, which will allow that segment of the scientific community to contribute both intellectual and material resources. The interaction of academic and non-profit research institutions with industry and the Government will facilitate subsequent development and marketing of the new products. Objectives and Scope The purpose of this RFA is to expand the range of novel microbicide candidates suitable for advancement into late stage preclinical development and clinical trials by encouraging the discovery and preclinical development of under- explored or novel microbicidal products, with or without contraceptive activity, to prevent the sexual transmission/acquisition of HIV. Applicants should utilize innovative approaches to prevention based on knowledge of HIV etiology and pathogenesis. Specific approaches may target a wide range of topics. Projects based on targeted interruption of HIV replication and attachment are encouraged. Analogs or combinations of non-detergent products that have previously been entered into clinical trials may be considered responsive. However, HIV therapeutic compounds, which have not been developed previously as microbicides, could be modified in accordance with section b below. Each program project grant consists of three or more research projects (see SPECIAL REQUIREMENTS, below) and is centered on the discovery and preclinical development of a microbicide candidate. Generic examples of some microbicides under development that could be the focus of research supported through this RFA are given below. This list is not meant to be all inclusive, but merely provides examples: a. products that interfere with binding, membrane fusion and/or entry of HIV such as small peptides or monoclonal antibodies, b. inhibitors of HIV replication previously developed as therapeutic products, such as non-nucleoside reverse transcriptase inhibitors, small peptides or organometallic complexes, c. naturally occurring antimicrobial inhibitors such as magainins, defensins, protegrins and secretory leukocyte protease inhibitor, d. adhesion and aggregation products that adhere to cell surfaces rendering them impervious to infection or interact with receptors on multiple virus targets resulting in viral aggregates with resulting loss of infectivity, e. other novel approaches. Any novel approach for which a strong scientific rationale is provided will be considered. A sound scientific rationale for selection of the lead microbicide candidate is strongly recommended. Further, an experimental plan is required that describes the methods and decision-making process for evaluation of the candidate microbicide. Since the intent of this RFA is the discovery and preclinical development of new microbicides, with or without contraceptive activity, with active involvement of industry and multiple collaborative partners, it will be imperative that applicants provide plans for patent coverage. Analogs or combination products of marketed detergent-containing spermicides would not be considered responsive to this RFA. Also excluded from this RFA is non-targeted random screening of potential microbicides. Furthermore, advanced preclinical development activities, undertaken according to good laboratory/manufacturing processes (GLP/GMP), such as formulation, toxicology, or scale-up for production for clinical trials, as well as clinical trials themselves, are beyond the scope of this RFA. SPECIAL REQUIREMENTS Applications submitted in response to this RFA should be prepared in accordance with the instructions presented in the NICHD Program Project (P01) Guidelines, available at http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. Required Application Components The Program Project must contain three components: An application must contain an Administrative Core unit, directed by the Principal Investigator, three or more independent Research Projects, directed by Research Project Leaders, and Support Cores as needed, directed by Support Core Leaders. These components are described below. Each application must include all components, however, one or more of the components may be located at collaborating institutions (see below). o Principal Investigator: The scientist who is designated by the applicant institution to direct the Program Project. The Principal Investigator (PI) will assume responsibility and accountability to the applicant institution and to the NICHD/NIAID for the performance and proper conduct of the Program Project in accordance with the requirements specified in this RFA. The Principal Investigator is responsible for the Administrative Core unit. o Administrative Core: A separately budgeted administrative unit that manages daily operations of the Program Project. The Administrative Core unit, under the direction of the Principal Investigator, will coordinate all the operations of the Program Project. The Administrative Core will ensure that the aims of the Research Projects are carried out by the Research Project Leaders and that Support Cores provide the necessary services to further the research aims. o Research Projects: Defined research aims for the discovery and development of novel microbicides, with or without contraceptive activity. A minimum of three Research Projects must be described in the application. Some examples of individual research projects that might be one component of an application include: 1. Characterization of the activity and toxicity of novel microbicides utilizing relevant in vitro, in vivo, and/or ex vivo laboratory models. 2. Design and development of genetically modified microbial organisms to deliver microbicides or augment the expression/activity of natural defense mechanisms of the vagina topically, such as single chain monoclonal antibodies produced by recombinant bacteria that naturally colonize the human vagina. 3. Development and use of animal models to evaluate in vivo efficacy and establish experimental proof-of-concept. 4. Structure-activity relationship studies. An example of three inter-related research projects could be: transgenic production of monoclonal antibodies, evaluation of the activity of the monoclonal antibodies, and distribution of labeled monoclonal antibody in the mouse vaginal model o Support Core(s): Separately budgeted component(s) that provides support for the research programs, for example, crystallography, mass spectrometry, biological testing, or statistical support for the studies. The most common support is likely to be in chemistry, however, pharmacokinetic support cores and animal support cores are other examples. o Research Project Leader: The individual responsible for directing one or more of the Research Projects of the Program Project. The Research Project Leader may or may not be the Principal Investigator. o Support Core Leader(s): The individual responsible for directing a support core facility. There may be one or more support cores. These cores would provide services to achieve the research goals. For the purposes of this RFA, each core must be utilized by at least two component projects at all times during the period of award. This is an exception to the NICHD P01 Guidelines stating that each core should be utilized by three or more component projects. If only one of the component projects requires proposed core support, then the required expertise, technology and/or infrastructure should be integrated within the relevant component project and the core as a separate entity eliminated. Collaborative Arrangements Two or more institutions that can demonstrate a credible plan for collaborative research may apply as a consortium. Evidence of prior collaboration and/or a plan for proposed collaborations between the investigators should be cited. A multi-institutional network application must be submitted by one applicant organization that will receive any resultant award. The application must provide details of agreements regarding sub- contracting arrangements, coordination, and support of activities at and among participating institutions, and must demonstrate the potential effectiveness of such a sub-network for the ongoing work of the program project. Annual Meetings Due to the anticipated proprietary nature of the products under development, each Program Project will act independently of the other. The Program Project leadership will meet annually to exchange non-confidential information. The Principal Investigator for the overall grant and the Project and Support Core Leaders for each component project should plan to attend an annual two-day meeting with NIH staff in Bethesda, MD. Applications should include a request for funds to support attendance of the Principal Investigator for the overall grant and the Project and Support Core Leaders for each component project and core at the annual meetings, as well as a statement of agreement to participate in these meetings. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, telephone number, and institution of the Principal Investigator, the identities of other key personnel and participating institutions, 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 a subsequent application, the information it contains allows NICHD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Patricia Reichelderfer by December 18, 2000 at the address listed under INQUIRIES, below. 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 and compelling rationale and justification are 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 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, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available on the Internet at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. Although this RFA will not support clinical trials, some applicants may propose research projects that involve the use of human tissue. In these cases, guidelines on the protection and inclusion of human subjects in research apply. URLS IN NIH GRANT APLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained with 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. APPLICATION PROCEDURES The research grant application form PHS 398 (rev.4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, 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, E-mail: GrantsInfo@nih.gov. Application Instructions Applicants for P01 grants must follow special application guidelines in the NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998) that are available from NICHD program staff listed under INQUIRIES, below, and on the Internet at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. These guidelines contain important information on the suggested format of applications and on review criteria. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the number of this RFA, RFA-HD-00-018. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note that this is in pdf format. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and five sets of all appendices should be sent to: L.R. Stanford, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Blvd., Room 5E03, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Applications must be received by March 30, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. 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 policy is 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 Program Director and applicant institution. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR, and for responsiveness to this RFA by NICHD and NIAID staff. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Child Health and Human Development Council and/or the National Advisory Allergy and Infectious Diseases Council. Review Criteria For program projects, peer review of scientific and technical merit focuses on three areas: (1) review of the individual component projects, 2) review of the individual cores, and (3) review of the program as an integrated effort and the overall merit of the program. The review criteria to be used to evaluate applications submitted in response to this RFA are presented in APPENDIX II, GUIDELINES FOR REVIEWERS COMMENTS, of the NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998), available at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. Schedule Letter of Intent Receipt Date: December 18, 2000 Application Receipt Date: March 30, 2001 Peer Review Date: July 2001 Council Review: September 2001 Earliest Anticipated Start Date: September 29, 2001 AWARD CRITERIA Criteria that will be used to make award decisions include scientific and technical merit as determined by peer review, programmatic priorities and relevance, program balance, and the availability of funds. INQUIRIES Potential applicants are strongly encouraged to contact program staff early in application development with any questions regarding the responsiveness of their proposal to the goals of this RFA. Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and microbicide candidates known or anticipated to have contraceptive activity to: Patricia Reichelderfer, Ph.D. Contraception and Reproductive Health Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8B13G, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1661 Fax: (301) 480-1972 E-mail: pr20f@nih.gov Direct inquiries regarding programmatic issues and microbicide candidates known to lack contraceptive activity to: Roberta Black, Ph.D. Vaccine and Prevention Research Program Division of AIDS National Institute of Allergy and Infectious Diseases 6700 B Rockledge Drive, Room 4110, MSC 7628 Bethesda, MD 20892-7628 Telephone: (301) 496-8199 Fax: (301) 402-3684 E-mail: rblack@niaid.nih.gov Direct inquiries regarding fiscal matters to: Mary Ellen Colvin Grants Management Specialist Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17K, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496- 1304 Fax: (301) 402-7827 E-mail: mc113b@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.864 and 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 inter-governmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant 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 case, 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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