NOVEL APPROACHES TO MALE FERTILITY REGULATION RELEASE DATE: October 17, 2002 RFA: HD-02-028 (Reissued as RFA-HD-08-005) National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov) Letter of Intent Receipt Date: February 12, 2003 Application Receipt Date: March 12, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Child Health and Human Development (NICHD) invites applications from investigators interested in participating with NICHD in a cooperative research program to explore novel approaches to male fertility regulation. The NICHD has identified development of novel male contraceptives as a high priority goal within its Strategic Plan http://www.nichd.nih.gov/. The aim of the program is to conduct a wide range of research, both basic and applied, with the ultimate goal of developing knowledge that may lead to clinically useful products to regulate male fertility. The proposed research involves exploration of the epididymis and testis to identify specific targets that can be exploited for fertility regulation. The RFA will support research on novel approaches to male contraception including, but not limited to, research on epididymal function, spermatogenesis, and regulation of germ cell apoptosis. RESEARCH OBJECTIVES Background Over 50 percent of pregnancies in the United States are unintended. Other than condoms, withdrawal and vasectomy, there are no male methods available for use in the United States. The NICHD has identified development of novel male contraceptives as a high priority goal within the Strategic Plan for the Institute. Toward that goal, the Center for Population Research (CPR) has held meetings internally as well as with outside advisors to develop the mechanisms that would most efficiently accomplish the task. As a result of the meetings, we have proposed a plan to bring together investigators and resources to explore novel approaches to male contraception. The ideal contraceptive should be safe and highly effective. A variety of contraceptive methods are needed to address the needs of people of different ethnic, cultural, and religious values; those with inadequate access to services; and those with changing needs related to age. Research Scope The purpose of the RFA is to identify new targets that could lead to the development of safe and effective contraceptive products for males. Research projects proposed in response to this RFA can be directed to male targets of fertility regulation, including spermatogenesis, testicular or epididymal function, and regulation of germ cell apoptosis, etc. Examples of possible projects include, but are not limited to: o Research on a particular sperm-specific target for drug design. o Development of genomic or proteomic screens designed to identify and define the functional role of proteins in spermatogenesis, epididymal, testicular, seminal or sperm function. o The characterization of a macromolecule(s) involved in spermatogenesis or sperm, epididymal or testicular function, the perturbation of which with a pharmacological agent results in reversible infertility. o Research on the nature of the sperm-testis or blood-epididymal barriers with the goal of delivering agents to specific targets involved in control of fertility. o Research on the processes of sperm maturation with the goal of defining specific targets involved in control of fertility. Guidance and Management Structure A steering committee composed of participating Principal Investigators and NICHD program staff, will meet at least once yearly. The purpose of these meetings is to assess scientific progress, identify new research opportunities, establish priorities, and discuss strategies that will accelerate the translation of preclinical findings into clinical applications. Outside consultants/experts may be asked to participate in these discussions as nonvoting advisors. Periodic workshops will be held to allow the investigators to exchange information and advice. Research Resource A program supporting phenotyping of male fertility defects in knock-out mouse models has been initiated under a separate RFA http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-01-020.html>. The support of the phenotyping facilities that are geared toward identifying mutants with impaired fertility is to help pinpoint genes involved with male fertility regulation. Investigators supported by the present RFA will have the opportunity to utilize the mutant mice developed under that program that present with male fertility defects. The gene targets identified through this research will be further characterized with respect to function and suitability for fertility regulation. The Steering Committee, as part of its annual meeting, will develop a plan for use of mutants by the investigators within this cooperative agreement. The investigators will work together to minimize overlap and to facilitate research efforts, depending upon the research goals of the various funded projects. In the event that potential products emerge from the research, further development will be carried out through the use of NICHD service contracts that conduct toxicology, formulation, and clinical trials. Use of these contracts will be directed by project officers within the Contraception and Reproductive Health Branch of NICHD to provide assistance toward obtaining FDA approval of a product for male contraception. MECHANISM OF SUPPORT The RFA will use the National Institutes of Health (NIH) Cooperative Research Project (U01) award mechanism. The NIH (U01) is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award." FUNDS AVAILABLE The NICHD intends to commit approximately $1.5 million in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund new and/or competing continuation awards in response to this RFA. Applicants may request a period of support of up to five years. Because the nature and scope of the research proposed may vary, it is probable that the size of the awards will also vary. Applicants may request a budget up to $200,000 direct costs in the first year. Although the financial plans of the NICHD 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. Depending on the number, size and quality of the applications received it is anticipated that 4-7 grants may be funded. At this time, it is not known if the RFA will be reissued. ELIGIBILE INSTITUTIONS You may submit an application if your 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. 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 or ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Minimum Application Requirements The minimal requirements for a successful applicant to this RFA are as follows: o An innovative proposal by the Principal Investigator; o Availability of the technical resources and facilities for the conduct of the proposed project, including appropriate animal facilities, if applicable; o Research environment conducive for contraceptive research; o Willingness to engage in a coordinated, cooperative research program with multiple interacting research projects. The investigators funded by this RFA are expected to work together in a cooperative manner. The Steering Committee, as part of its annual meeting, will facilitate the development of a plan for use of resources from the mouse phenotyping program (http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-01-020.html) by the members. The investigators will work together to minimize overlap and to facilitate research efforts, depending upon the research goals of the various funded projects. A response to this RFA must consist of an application that includes: o A description of the research project. o A description of the capabilities of the Investigator. o A proposed five-year research plan that presents the applicant's perception of the organization and component functions of the program. The plan should identify the applicant's knowledge, ingenuity, practicality, and commitment in organizing a project aimed at developing new male contraceptives. Meetings An annual meeting of the Investigators will be conducted and applicants are advised to include such a plan in the budget request. The purpose of the meeting is to exchange scientific information and to discuss collaborations between investigators. It is expected that the Principal Investigator will attend the annual meeting. In addition, research fellows participating in the projects should attend the meeting. For budgeting purposes, assume that the meeting will be held in Bethesda, MD. Cooperative Agreement Terms and Conditions of Award The following terms and conditions of the cooperative agreement award and details of the arbitration procedures pertaining to the scope and nature of the interaction between the NICHD and the participating awardees will be incorporated into the Notice of Grant Award and provided to the Principal Investigator and the institutional official at the time of award. The special Terms and Conditions of Award are in addition to, not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 42 CFR Parts 74 and 92, and other HHS, PHS and NIH grant administration policies. The administrative and funding instrument used for this program is a 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 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 awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NICHD Research Coordinator. 1. Awardee Rights and Responsibilities Awardees have primary authorities and responsibilities to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of their studies. The primary responsibilities of the awardees are to: o Define the research objectives; o Design the necessary research protocols; o Conduct specific studies; o Analyze and interpret research data; o Modify protocols as required; o Interact with the FDA concerning clinical investigations; o Provide information to the NICHD Research Coordinator concerning progress. Awardees will retain custody of and primary rights to their data and intellectual property developed under the award subject to current government policies regarding rights of access as consistent with current HHS, PHS, and NIH policies. 2. NICHD Staff Responsibilities NICHD Research Coordinator: The NICHD Research 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. The responsibilities of the NICHD Research Coordinator will include the following: o Assist in setting research priorities and in avoiding unwarranted duplication of effort; o Serve on the Steering Committee as a voting member; o Review and comment on critical stages in the research program before subsequent stages are implemented; o Assist in the interaction between the awardee and the FDA, investigators at other institutions, and potential commercial sponsors; o Retain the option to recommend additional research endeavors within the constraints of the approved research and negotiated budget; NICHD Project Officer: NICHD will appoint a Project Officer, apart from the Research Coordinator, who will: o ensure that all regulatory, fiscal and administrative matters are handled according to NIH guidelines; o will evaluate requests for additional funds or for rebudgeting; o carry out continuous review of individual projects to evaluate progress; o serve as a non-voting advisor to the Steering Committee; o perform other duties required for normal program stewardship of grants. 3. Collaborative Responsibilities Overall coordination of the Program, consistent with the stated intent of the RFA, will be provided by a Steering Committee consisting of the Principal Investigators of each of the awarded grants and the NICHD Research Coordinator. The NICHD Project Officer and a member of the NICHD grants management staff will serve as nonvoting advisors to the Committee. The Steering Committee meetings will be convened at least once yearly. The purpose of these meetings is to assess scientific progress, identify new research opportunities, establish priorities, and discuss strategies that will accelerate the translation of preclinical findings into clinical applications. Outside consultants/experts may be asked to participate in these discussions as nonvoting advisors. 4. Arbitration Process When agreement between an awardee and NICHD staff cannot be reached on scientific/programmatic issues that may arise after the award is made, an arbitration panel will be formed. The arbitration panel will consist of one person selected by the Principal Investigators on the Steering Committee, one person selected by the NICHD, and a third person selected by both NICHD staff and the Principal Investigators. The decision of the arbitration panel, by majority vote, will be binding. The special arbitration procedure in no way affects the right of an awardee to appeal adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: encouraged. The opportunity to clarify any issues or answer questions is welcome. Direct your questions about scientific/research issues to: Diana Blithe, Ph.D. Contraception and Reproductive Health Branch, National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8B13, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6990 FAX: (301) 480-1972 Email: blithed@nih.gov Direct your questions about peer review issues to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1485 FAX: (301) 402-4104 Direct your questions about financial or grants management matters to: Kathy Hancock Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17M, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5482 FAX: (301) 402-0915 Email: kathy.hancock@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NICHD 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: Diana Blithe, Ph.D. Contraception and Reproductive Health Branch, National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8B13, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6990 FAX: (301) 480-1972 Email: blithed@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using 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 301-435-0714, E-mail: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: The application should address the items listed above under SPECIAL REQUIREMENTS/Minimum Application Requirements. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03, MSC 7510 Bethesda, MD 20892-7510 Rockville MD 20852 (for express/courier service) APPLICATION PROCESSING: Applications must be received by the application date listed at the heading of this RFA. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NICHD. 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 NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o 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 and assigned a priority score o Receive a second level review by the National Advisory Child Health and Human Development Council REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 12, 2003 Application Receipt Date: March 12, 2003 Peer Review Date: May 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: Scientific merit (as determined by peer review) Availability of funds Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND 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 is 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. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.864, Population Research, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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