Full Text HD-95-014 NONHUMAN IN VITRO FERTILIZATION AND PREIMPLANTATION DEVELOPMENT NIH GUIDE, Volume 24, Number 21, June 9, 1995 RFA: HD-95-014 P.T. 34 Keywords: Human Reproduction/Fertility Embryology National Institute of Child Health and Human Development Letter of Intent Receipt Date: August 11, 1995 Application Receipt Date: November 10, 1995 PURPOSE The National Institute of Child Health and Human Development (NICHD) invites applications from investigators willing to participate in the ongoing multisite National Cooperative Program on Culture Conditions for Nonhuman In Vitro Fertilization and Preimplantation Development with the assistance of the NICHD through cooperative agreements (U01). The principal goal of this Program is to improve the culture conditions for mammalian oocyte and preimplantation development. In order to achieve this goal, it is expected that methods for evaluation of the quality of mammalian oocytes, eggs and preimplantation embryos in culture will continue to be an important feature of the Program. It is anticipated that a multispecies approach will also continue to characterize the Program. The ultimate beneficiaries of this Program may be people who seek medical treatment, advice, or assistance with problems of infertility, contraception, or preimplantation genetic diagnosis. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Nonhuman In Vitro Fertilization and Preimplantation Development, is related to the priority area of family planning. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). 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. Racial/ethnic minority individuals, persons with disabilities, and women are encouraged to apply. The need for continuous and active communications and interactions among sites dictates that only institutions in the continental United States will be eligible for participation. MECHANISM OF SUPPORT Funding to assist the scientific community in undertaking this Program of basic and applied science will be through the use of cooperative agreements (U01) between participating sites and the NICHD. The major difference between a cooperative agreement and a research grant is that there will be substantial programmatic/scientific involvement of the NICHD staff Research Coordinator above and beyond the levels required by the traditional program management of grants. Specifically, an NICHD staff member will cooperate with the Principal Investigators as a partner in the research and serve as Research Coordinator. The Research Coordinator will assist the recipient(s) in a cooperative way but without assuming direction, prime responsibility or a dominant role in the activity. In a cooperative agreement, which is an assistance mechanism and not an acquisition mechanism, the NIH purpose is to support, stimulate and expedite the recipient's activities through a partnership role. All recipients in this Program will agree to accept the participatory and cooperative nature of the group process. Details of the responsibilities, relationships and governance of the activities to be funded under the cooperative agreements to be awarded for this Program are discussed later in this document under Direction and Management: The Steering Committee and in Terms and Conditions of the Award. The anticipated award date is September 1, 1996. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of the awards will also vary. Awards and levels of support depend on the receipt of a sufficient number of applications of high scientific merit. Although the Program is provided for in the financial plans of the NICHD, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. This RFA is a one-time solicitation for the purpose of the present competition. At this time, the NICHD has not determined whether or how this Program will be continued beyond the present solicitation. Any future determination in this regard will be publicly announced. FUNDS AVAILABLE It is anticipated that an estimated total of $1,900,000 (including direct and indirect costs) will be available for the entire Program for the first year. It is also anticipated that up to six awards (either new and/or competing continuation) will be made with an award period of four years. RESEARCH OBJECTIVES Background The goal of this Cooperative Program is to improve the culture conditions for nonhuman in vitro fertilization and preimplantation development that are necessary for basic and applied reproductive research on mammalian gametes and preimplantation development. Indeed, nearly our entire knowledge of mammalian oocytes and preimplantation embryos depends upon our ability to culture and manipulate them in vitro. The basic and applied studies that will benefit from this Program are at the very center of mammalian, including human, reproductive biology. Some of these research topics are: 1. The mechanisms of oocyte development in vitro, fertilization, activation of development and implantation, the prevention of polyspermy, the causes and alleviation of infertility, new contraceptive leads and genetic assessment of individual oocytes, eggs or embryos; 2. the genetic and epigenetic regulation of the program of preimplantation development that is crucial for the initiation of placenta formation (i.e., trophectoderm formation) that is, in turn, the key prerequisite for successful embryo transfer, implantation and the establishment of pregnancy; and 3. the initiation and maintenance of normal mammalian embryo development into blastocysts, as well as the production and culture of healthy oocytes and eggs that are capable of fertilization and full development. Owing to new technology and broad interest, there exists an opportunity for rapid progress on these critical problems of mammalian reproductive biology. This progress will depend upon the use of more efficient in vitro techniques for the study of mammalian gametes and preimplantation embryos. This is the case for many gene transfer experiments, twinning experiments, and a multitude of experiments on the genetic assessment, morphology, physiology, biochemistry and molecular biology of oocytes and eggs and on embryo development from fertilization through implantation. In applied science, in vitro procedures are widely used in commercial endeavors, such as producing twins of valuable animals and improving the commercial qualities of livestock for food production. Knowledge gained from the animal studies is considered to be a vital step in making improvements in human in vitro fertilization, preimplantation development, and embryo transfer. Those who use in vitro fertilization, oocyte and preimplantation development and implantation as model systems for reproductive toxicology studies also need in vitro systems that produce high quality oocytes, eggs and embryos. Sensitivity of these systems to drugs and radiation may be much different in culture media that support growth better than the previously and currently used media. A far-reaching benefit of this Cooperative Program will be the improvement of conditions for the production and genetic assessment of genetically engineered embryos leading to the establishment of animals that could be used in many biomedical experiments, including models for human diseases. It is also expected that the results of the Cooperative Program will provide a better understanding of the general principles of nutrition with regard to the interaction of the preimplantation embryo with the maternal environment. Unfortunately, the culture conditions in current use bear little resemblance to in vivo conditions, our understanding of nutritional requirements and basic principles of oocyte and embryonic metabolism and nutrition are practically nonexistent, and oocytes, eggs and embryos raised under these conditions are inferior. This inferior development may be responsible for defects in fertilization, in the implantation process or during postimplantation development, resulting in limited success of embryo transfer experiments. Despite the fact that numerous successful pregnancies have followed from in vitro procedures, the efficiency and therefore the cost-effectiveness could be greatly improved by increased basic knowledge expected from the results of this Cooperative Program. This would be especially true in the case of in vitro fertilization and embryo transfer for humans, domestic livestock and of nonhuman primates, but also for small laboratory animals. Thus, there are both basic and applied science needs for improvement of culture conditions for successful in vitro reproductive procedures for a variety of mammalian species. The ongoing Cooperative Program was established by NICHD more than eight years ago. During that time, significant improvements have been made in the culture conditions for the production of higher quality mammalian oocytes and eggs that are capable of fertilization and subsequent development. Significant progress has also been made in solving the problem of in vitro "blocks" for preimplantation development for several mammalian species. We are just beginning to make correlations between superior culture media, improved development and the regulation of specific gene expression that may be used as one of the criteria for embryo quality. It is clear that there is a continuing need for major improvements in the quality of in vitro-raised oocytes and embryos for mammals and that these improvements will be critical for successful, cost-effective in vitro fertilization and subsequent development in vitro and in vivo. This Program has been enriched by the multispecies approach that has been a consistent feature. This is important since the potential beneficiaries include not only human reproductive technology and other biomedical applications, but also reproduction in agricultural species, endangered species and others. Objectives The objectives of this ongoing Program continue to be to improve the culture conditions for mammalian oocytes and preimplantation embryos. Implicit in making improvements in culture conditions is to know when improvements have been made by demonstrating that higher quality oocytes or embryos have been produced. For this Program, then, it is essential to be able to evaluate the quality of individual mammalian oocytes and preimplantation embryos by a number of parameters during and after in vitro development. The need for these assessments has always been a part of this Program and may include morphological assessments, biochemical assessments, metabolic assessments, genetic assessments and molecular assessments. Of course, these should also include the generation of live offspring after in vitro development that would prove that an oocyte or embryo has full developmental potential. Scope The scope of the Program will include research on improved culture conditions and assessment of quality for: o mammalian oocytes developing in vitro; o fertilization in vitro; and o preimplantation embryos developing in vitro. Studies on fertilization may be included in proposals only if that is part of a project in which the primary emphasis is upon oocyte development and/or preimplantation development in vitro. Of particular interest will be studies with continuum capabilities, i.e., those in which oocytes are raised in vitro, fertilized in vitro, resultant embryos developed in vitro and transferred to the female reproductive tract for further development. This enables one to study the quality or the results of oocyte manipulation of an individual oocyte in the context of future developmental potentialities of that oocyte. It is recognized that most applicants will not have that full capability, but it is anticipated that capability will exist within the Program. For oocyte and preimplantation embryo studies, it is desirable to have the capability to conduct comparisons between in vivo and in vitro-raised oocytes and embryos. The protocols will be approved, developed and/or modified by the Steering Committee (see Direction and Management, below) through a consensus process. The Program is expected to have the following features: o Different sites that emphasize the study of different aspects of the culture environment and utilize different species; some sites may study micronutrients, some may emphasize macronutrients, and some will study other aspects of the environment. This underscores the need for coordination and communication. o Some investigators may focus strongly on the establishment of endpoints, that is the evaluation of the quality of individual oocytes or embryos raised in vitro, using various possible assays, including morphological, biochemical, metabolic, genetic or molecular assays and that may include spatial and temporal displays of gene expression. o Principles obtained from research on one species can be rapidly tested in other species. o Approaches will be determined and prioritized. o Some sites will place more emphasis on oocyte development, others on preimplantation development, but the goals of improved quality of oocytes and embryos and the production of live offspring will be an important feature. o Detailed experimental designs will be established in order to maximize chances of success and to facilitate statistical analysis. o Progress reports will be transmitted to the cooperating sites and NICHD. o Results will be analyzed and disseminated. o Meetings will be held at least three times each year to discuss progress and future plans. Direction and Management: The Steering Committee Planning and implementation of the study will be done by a Steering Committee consisting of the Principal Investigators from each of the participating sites, one NICHD staff member from the Reproductive Sciences Branch who will serve as Research Coordinator, and an independent chairperson. To ensure impartiality, the independent chairperson will be a scientist of national stature who is not participating as a Principal Investigator and who is mutually acceptable to the participants. The Steering Committee will meet at least three times per year. The purpose of these meetings will be to share scientific information, assess scientific progress, identify new research opportunities, exploit opportunities for collaboration within the Program and with outside scientists when appropriate, establish priorities that will facilitate the translation of basic research findings to the many beneficiaries of this work, and to conduct other business of the Program. SPECIAL REQUIREMENTS The NICHD invites applications both from current members of the Cooperative Program (competing continuation applications), and from prospective members (new applications). The minimal requirements for applicants are as follows (See also REVIEW CONSIDERATIONS below): o Competent, experienced principal investigators who are committed to this problem and who are willing to cooperate with the other Principal Investigators and the NICHD Research Coordinator; o access to properly managed animal colonies with breeding capabilities; o demonstration of the capability of producing and evaluating sufficient numbers of oocytes, eggs or embryos for sound statistical analysis; o experience with in vitro oocyte development, in vitro fertilization and/or preimplantation development followed by embryo transfer; o excellent technical resources necessary for conduct of the experiments; and o evidence of departmental and institutional support and commitment. Terms and Conditions of Award Cooperative agreements are assistance mechanisms subject to the same administrative requirements as grants. The special Terms and Conditions of Award are in addition to, not in lieu of, otherwise applicable OMB administrative guidelines, HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on HHS regulations at 42 CFR Part 74 and 92. The NIH Information for Management and Planning Analysis and Coordination (IMPAC) system and indirect cost award procedures will apply to cooperative agreement awards in the same manner as for grants. Business management aspects of these awards will be administered by the NICHD Grants Management Office in accordance with HHS, PHS, and NIH grant administration requirements. 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 as well as to the institutional official at the time of award. These procedures will be in addition to the customary programmatic and financial negotiations which occur in the administration of grants. 1. The Steering Committee The planning and implementation of the study will be done by a Steering Committee consisting of the Principal Investigators from each of the participating sites, one NICHD staff member from the Reproductive Sciences Branch who will serve as Research Coordinator, and a nonvoting, independent chairperson who is acceptable to the participants and who is a nongovernment employee. The Steering Committee will meet at least three times a year. The purpose of these meetings is to share scientific information, assess scientific progress, identify new research opportunities, exploit opportunities for collaboration within the Program and with outside scientists when appropriate, ensure the rapid dissemination of the findings, establish priorities that will facilitate the translation of basic research findings to the many beneficiaries of this work, and to conduct other business of the Program. 2. Awardee Responsibilities and Rights The primary responsibilities of the awardees are: o Determine experimental approaches o Design protocols o Conduct experiments o Analyze and interpret the results o Present results and plans at Steering Committee meetings o Publication of results o Modify, delete or add protocols o Accept and participate in the cooperative nature of the group process. Awardees will retain custody of and primary rights to their data developed under the award, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. 3. The degree of programmatic/scientific assistance by the NICHD staff Research Coordinator includes: o Participation in the development of optimal approaches and protocol designs (and adjustments of protocols and approaches when needed). The Research Coordinator will assist and facilitate the process, rather than directing it. o Assistance and review of all phases of the study to assure consistency of protocol compliance, to improve and strengthen cooperation between the sites, and to help redirect efforts, if necessary. In the event of disagreement among participants, the Research Coordinator will assist in forming an arbitration panel acceptable to participants (see below). o Participation in data analyses, interpretation and publication of study results. o Identification, jointly with awardees, the need to modify or terminate a site when technical performance requirements are not met. 4. Arbitration When agreement between an awardee and NIH staff cannot be reached on scientific/programmatic issues that may arise after the award, an arbitration panel will be formed. The panel will consist of one person selected by the Principal Investigators, one person selected by NICHD staff, and a third person selected by these two members. The decision of the arbitration panel, by majority vote, will be binding. This special arbitration procedure in no way affects the right of an awardee to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. 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 subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which has been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Program staff may also provide additional relevant information concerning the policy (see INQUIRIES). LETTER OF INTENT Prospective applicants are asked to submit, by August 11, 1995, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 avoid conflict of interest in the review. The letter of intent is to be sent to: Richard J. Tasca, Ph.D. Center for Population Research National Institute of Child Health and Human Development Building 61E, Room 8B01 Bethesda, MD 20892 Telephone: (301) 496-6515 FAX: (301) 496-0962 Email: TASCAR@HD01.NICHD.NIH.GOV APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these cooperative agreements. These forms are available at most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD 20892-7762, telephone 301/710-0267. Content of Applications Applications in response to this RFA should include: o A description of the capabilities of the site to meet or exceed the minimal requirements (see SPECIAL REQUIREMENTS above). o A proposed four-year research plan that should be the applicant's perception of the study and of his/her cooperative role. This plan should demonstrate the applicant's knowledge, ingenuity, practicality, and commitment to improve the culture conditions for nonhuman in vitro oocyte development, fertilization and/or in vitro preimplantation development followed by embryo transfer. o All essential information in the body of the application rather than in the Appendix. o Current members who wish to submit competing continuation applications should prepare a renewal proposal, and are required to list significant progress they have made in this Program and indicate how they have met any special cooperative agreement terms and conditions of their awards including their interaction with other investigators and the Research Coordinator, if appropriate. In order to respond to these requirements, current members may use up to five additional pages in the Progress Report section of their application. Budget Since the final protocol(s) for this study will not be exactly known at the time of submission of the application, the budget request should be based on the plan proposed by the applicant and should reflect the scope of the project. The requested budget should not be in excess of the amount generally requested for a regular research grant. Include estimates for staffing needs, although it is expected that some modification will be needed once the final research protocol(s) have been developed. The budget must also include estimates of travel expenses for three meetings of two days each of the Steering Committee per year. The first meeting will be a planning meeting held in Bethesda, Maryland in September 1996. Applications must be identified by typing in the RFA number, HD-95-014, and the RFA Title, NONHUMAN IN VITRO FERTILIZATION AND PREIMPLANTATION DEVELOPMENT, on line 2a of the face page of the application form and the YES box must be checked. Type U01 in Item Number 2b. In addition, the RFA label available in the PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS 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 also be sent to: Susan Streufert, Ph.D. Division of Scientific Review National Institute of Child Health and Human Development Building 61E, Room 5E03 Bethesda, MD 20892 Applications must be received by November 10, 1995. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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. Schedule Letter of Intent Receipt Date: August 11, 1995 Application Receipt Date: November 10, 1995 NACHHD Council Review: June 4, 1996 Earliest Award Date: September 1, 1996 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and for responsiveness by NICHD staff. Incomplete applications will be returned to the applicant without further consideration. Any application that does not meet the minimum requirements (see SPECIAL REQUIREMENTS above) of this RFA will be judged to be unresponsive to this RFA and will be returned to the applicant. 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, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or noncompetitive based on their scientific merit relative to other applications received in response to this RFA. Applications judged to be competitive will be discussed and assigned a priority score. Applications determined to be noncompetitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. Review Criteria In addition to the usual NIH criteria for scientific merit, evaluation of the applications will be based upon the following: 1. Qualifications, experience and commitment of key personnel o Scientific and administrative abilities of the Principal Investigator and other team members, as evidenced by pertinent publications. o Knowledge and experience in areas relevant to the conduct of the experiments proposed. o Commitment of time for the proposed study and stated willingness to work and collaborate with other sites and the NIH in the manner summarized in this RFA. 2. Protocols and Procedures o Appropriateness of the application to the objectives of the study as outlined in this RFA. o Scientific merit of the proposal. o Demonstration of cost-effectiveness through improved oocyte and/or embryo quality. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. 3. Facilities and Management o Adequacy of administrative and technical capabilities. o Adequacy of animal facilities and appropriateness of animal care management. o Institutional assurance to provide support to the study in such areas as fiscal administration, personnel management, space allocation, procurement, planning and budgeting. 4. Budgeting o Appropriateness of budget. 5. Human Subjects, Animal Welfare, Biohazards, Gender and Minorities o The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA The anticipated date of award is September 1, 1996. Applications recommended by the NACHHD Council will be considered for award based upon scientific and technical merit as determined by peer review; program balance, including in this instance, sufficient compatibility of features to enhance the likelihood of a successful collaborative Program; and availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific program issues to: Richard J. Tasca, Ph.D. Center for Population Research National Institute of Child Health and Human Development Building 61E, Room 8B01 Bethesda, MD 20892 Telephone: (301) 496-6515 FAX: (301) 496-0962 Email: TASCAR@HD01.NICHD.NIH.GOV Direct inquiries regarding fiscal matters to: Ms. Melinda Nelson Office of Grants and Contracts National Institute of Child Health and Human Development Building 61E, Room 8B17 Bethesda, MD 20892 Telephone: (301) 496-5481 FAX: (301) 402-0915 Email: NELSONM@HD01.NICHD.NIH.GOV AUTHORITY AND REGULATIONS This Program is described in the Catalog of Federal Domestic Assistance No. 93.864, Population Research. Awards are made under authorization of the Public Health Service Act, Title IV,Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routing 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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