COOPERATIVE SPECIALIZED INFERTILITY RESEARCH CENTER PROGRAM

COOPERATIVE SPECIALIZED INFERTILITY RESEARCH CENTER PROGRAM is sponsored by National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). This program supports multidisciplinary research projects and/or cores focused on clinical and preclinical research activities related to infertility.

NIH Guide: COOPERATIVE SPECIALIZED INFERTILITY RESEARCH CENTER PROGRAM NIH GUIDE, Volume 24, Number 10, March 17, 1995 Human Reproduction/Fertility Biomedical Research, Multidiscipl Clinical Medicine, General National Institute of Child Health and Human Development Letter of Intent Receipt Date: May 15, 1995 Application Receipt Date: October 11, 1995 The National Institute of Child Health and Human Development (NICHD) invites applications from investigators willing to participate with the NICHD under a cooperative agreement in a multicenter cooperative research program termed the National Cooperative Program for Infertility Research (NCPIR).

The objective of this Program is to expedite the development of new approaches for the diagnosis and treatment of human male or female infertility.

Recognizing that the complexity of infertility research severely limits the progress that can be achieved by individual investigators working alone, the NICHD will support at least two Centers comprised of biomedical research projects and technical service core facilities that are interactively organized to conduct accelerated preclinical and clinical research and development studies on promising new leads in human infertility research.

The Centers will also serve as national resources for the career development of young scientists electing to pursue research in high priority areas of infertility research. The benefit of this activity will be to the infertile couples, their health-care providers, and the public.

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), Cooperative Specialized Infertility Research Center Program, 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). Applications may be submitted by domestic for-profit and non-profit organizations, public and private, that meet the requirements stated in this RFA.

Minority individuals, persons with disabilities, and women are encouraged to apply as Principal Investigators. The need for continuous and active communications and interactions among the awarded sites dictates that only institutions in the United States will be eligible for these Center grant awards.

The funding mechanism to be used to assist the scientific community in undertaking this Program of applied human biology research will be the National Institutes of Health (NIH) cooperative specialized center (U54) mechanism. Funding will be provided by means of cooperative agreements established between the participating Centers and the NICHD. A cooperative agreement is not an "acquisition" mechanism.

It is an "assistance" mechanism in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activities conducted by the awardee. Under a cooperative agreement, the NIH purpose is to support, stimulate, and expedite the recipient's activities by jointly being involved with them.

NIH staff work cooperatively with the award recipients in a partner role and do not assume direction, prime responsibility, or a dominant role in the activity.

Details of the responsibilities, relationships, and governance of the activities to be funded under the cooperative agreements awarded for this Program are discussed later in this document under the section "Terms The total project period for an application submitted in response to this RFA may not exceed five years. 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 the RFA are contingent upon the availability of funds for This RFA is a one-time only 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 NICHD determination in this regard will be It is anticipated that an estimated total of $3,040,000 (including indirect and direct costs) will be available for the entire program for the first year of the Program. It is planned that these funds will support at least two Center awards.

In addition to new applications received in response to this solicitation, up to two competing continuation (renewal) applications are expected to compete for these two Center awards. It has been estimated that infertility affects between 35 and 70 million married couples, who would like to have children, around the world (World Health Organization, 1988 data).

In U.S. studies described nearly 50 years ago, it was stated that 10 percent of married couples were "sterile," while the remaining 90 percent possessed varying degrees of fertility. More recent studies (National Center for Health Statistics, 1988 and 1990 data) in the U.S. have conservatively indicated that there are 2.

3 million infertile couples, about nine percent of the domestic married couple population base with wives aged 15 to 44. In addition, it has been observed that about 4. 9 million U.S. women in this age range had an impaired ability to have children.

While analyses of the U.S. population base has not found alarming increases in either the number of infertile couples or the overall incidence of infertility, physician office visits reflecting societal life style requirements for infertility services have markedly increased from 1968 (600,000) to 1988 (1,350,000) with a projected peak in 1995 approaching 1,800,000.

Of the infertile couples seeking medical treatment for infertility, it has been estimated that up to one-half will be unsuccessful in achieving their desired outcome. Human infertility is generally accorded to female factors (40 percent), male factors (40 percent), male and female factors (10 percent) or unexplained infertility factors (10 percent). Current therapy results for male factor infertility have been discouraging.

One earlier British study reported only a 20 percent chance of a successful pregnancy within two years and no significant improvement of this chance with the use of therapeutic insemination, husband (TIH). Potential applications of assisted reproductive technology aimed at male infertility alleviation, such as Intracytoplasmic Sperm Injection have not been well researched yet.

Varicocele is a progressive disorder affecting 15 percent of pubertal boys. While evidence suggests many, but not all, of the men affected by this disorder experience infertility, the underlying pathophysiology and effective treatment approaches are not well understood. Ovulation failure has been reported to be the underlying cause for at least 25 percent of female factor infertility.

A specific cause for anovulation is usually not able to be determined. Chronic anovulation predisposes the female to infertility and compromises fecundity if not detected and treated early.

Recent findings also indicate that current ovulation inducing fertility drug treatments may carry, in certain circumstances, underappreciated risks to the female (hyperstimulation, ovarian cancer) and the child (multiple gestation, low birth weight prematurity consequences) associated with medically assisted conception procedures.

In reproductive aged females, it has been estimated that the general incidence of endometriosis is 5 to 15 percent. For women being surgically treated for infertility, the incidence is 30 to 50 percent. Among infertile females with no other known cause of their infertility, the incidence has been reported at 40 to 70 percent.

The causative role of endometriosis in infertility is poorly understood at present and optimal diagnosis and treatment of endometriosis has yet to be attained. The role of dysfunctional uterine bleeding, either in the presence or absence of uterine myomata, is not well understood with respect to infertility.

Uterine myomata occur in nearly 20 percent of all reproductive aged women, are the single most common diagnosis from gynecological hospital admissions, may be the only clinical abnormality observed in an infertile couple, and represent the most common medical indication for an often unwanted hysterectomy that prematurely ends a females reproductive option.

It is the primary objective of the cooperative research program described in this RFA to meet the nationally identified need for a coordinated infertility research program that will accelerate the translation of promising new preclinical or clinical leads into new clinical methods available to the public.

The need for accelerated basic and clinical research on the diagnostic and therapeutic aspects of infertility alleviation or cure has been extensively considered in a number of relevant reports ("Infertility: Medical and Social Choices," Office of Technology Assessment of the Congress of the United States, Publication OTA-BA-358, May 1988; "Infertility in America: Why is the Government Ignoring a Major Health Problem?

," Report of the House Committee on Government Operations, December 1989; and "Medically Assisted Conception: An Agenda for Research," Report of the Institute of Medicine of the National Research Council, 1989.)

Legislative directives included in the deliberations of the 101st U.S. Congress stressed the need to enhance support for research on the diagnostic and therapeutic aspects of infertility alleviation (Resolution HJ 173, Bill HR 2956). Such directives were restated in the respective appropriation committee reports issued by the 102nd U.S. Congress.

The NIH Reauthorization Act of 1993 issued from the 103rd U.S. Congress and enacted on June 10, 1993, as PL 103-43 (Title X. , Subtitle A. , Section 1001) authorized the Director, NICHD, to make grants or contracts for the operation of two Centers to conduct activities for the purpose of improving methods of diagnosis and treatment of infertility and to provide for the coordination of the Centers assisted under this section.

The terms of PL 103-43 acknowledge that infertility research and development problems are so complex that they can not be solved by individual investigators working alone and that "without specialized centers, promising new leads may never be translated into new methods or ever made available to the public." The operational requirements to be met by such Centers are further detailed in the subsequent section of this RFA.

The scope of the research projects expected to be pursued by a proposed Center's research plan should address studies organized with an orientation to either female factor or male factor infertility research.

Although it is anticipated that the overall NCPIR cooperative research program may be expanded by one or more Centers in the future, to accommodate a broadened range of studies, the two Centers to be awarded from this RFA are expected to be oriented toward either research on the early diagnosis and/or therapy of those female factors that most contribute to infertility (endometriosis, ovulatory dysfunction, uterine dysfunction) or those male factors associated with ineffective sperm production (quality or quantity) or function.

Research proposals for projects or cores directly involving human in vitro fertilization and/or embryo transfer must be in compliance with NIH policies for such research and should not, therefore, include efforts or activities that create human embryos solely for research purposes.

As a cardinal principle, the current Center organization should consist of multidisciplinary projects and/or cores capable of interacting in a coordinated, cooperative fashion. Each Center should organize its overall research plan to include a mix of primary clinical and closely adjunctive preclinical research activities.

Applicants should note that it is not the intent of this cooperative research program to fund a collection of diverse, noninteractive projects. Awards will not be made for applications with research activities focused exclusively on basic research or clinical research. It is not intended for the Centers to conduct epidemiological research or large clinical trials.

Applicants should particularly note that the NICHD currently supports a separately established cooperative research program, called the Reproductive Medicine Clinical Trial Network (RMN) for conducting national clinical research trials of experimental protocols and it is not the intent of the present NCPIR cooperative research program to support additional large-scale, long-term clinical trials.

It is anticipated, however, that progress achieved by the NCPIR Centers may lead to collaborating interactions with the existing RMN group. The scope of the Centers requested in the present RFA is expected to include a program of applied human biology involving clinical research projects and requisitely adjunctive preclinical projects and/or cores that may prove translational in moving research progress from the bench into the clinic.

Within the requirement for a minimum of three funded projects to constitute a Center award, an applicant's research plan might, for example, include a set of clinical research projects and related animal model projects to study infertility-related aspects of endometriosis.

Alternately, an applicant's research design strategy may include projects involving clinical and preclinical animal investigations of several different types of infertility-associated ovulation failure. Another orientation might be toward male spermatogenesis failure. Yet another orientation of scope might encompass comparative clinical and preclinical experimental evaluations of in vitro fertilization and embryo transfer protocols.

Research proposals for projects or cores directly involving human in vitro fertilization and/or embryo transfer must be in compliance with NIH policies for such research and should not, therefore, include efforts or activities that create human embryos solely for research purposes. These examples are only indicative of general strategy designs and should not be taken as an inclusive or exclusive preference of the NICHD.

Guidance and Management Structures The National Cooperative Program for Infertility Research (NCPIR) will include two Centers supporting an aggregate of up to ten to twelve research projects and two or more technical service cores. At least one clinical project and an administrative core will reside in the sponsoring department of the grantee institution awarded a Center grant.

As the Centers may be consortium-based, other research projects may be resident at domestic U.S. institutions other than the grantee institution.

A Steering Committee consisting of the investigators responsible for each project, the Principal Investigator of each Center, an NICHD staff Research Coordinator, and a nongovernment chairperson designated by the Steering Committee will assist and guide the conduct of the research performed by the Centers. A nonvoting member of the NICHD grants management staff will serve as an advisor to the Committee.

The Steering Committee will employ a consensus decision process to assist the Centers in evaluating the progress of Center projects, proposed new research initiatives, the need for extra-Center collaborations and the need to redirect certain Center efforts due to either sufficient data acquisition to permit conclusion, the acquisition of data supporting an alternative study initiative or experience proving that proposed research is no longer feasible.

Further details of the guidance and management structures and processes may be found in the Terms and Conditions section below.

The minimal requirements for the Centers described in this RFA are as follows (see also Review Criteria and Procedures below): o Competent and experienced principal investigator who is committed to and directly involved in human infertility research; o Availability of competent and experienced scientific experts to direct individual research projects or cores associated with the o Availability of the technical resources and facilities necessary for the conduct of the experiments; o Access to properly managed animal facilities for projects conducting animal studies; o Access to inpatient and outpatient reproductive health care units providing adequate numbers of patients for clinical research projects (Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research.

In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application); o A research environment conducive to the training of new investigators in infertility research; o Willingness to cooperate in a coordinated cooperative research program involving two or more Centers with multiple interacting research projects, and if required, service cores; o Substantive evidence of departmental and institutional support for and commitment to the proposed Center.

A response to this RFA should consist of a proposal that includes: o A description of a National Center for Infertility Research (NCIR) consisting of multiple individual research projects and, as justified, one or more core service facilities.

For suggested formatting instructions see the document, "Suggested Format for NICHD U54 Grant Applications," available from the program staff listed o A description of the capabilities of the Center to meet or exceed the minimal requirements stated earlier (see DESCRIPTION OF A CENTER o A proposed five-year research plan that presents the applicant's perception of the Center's organization and component functions.

This plan should demonstrate the applicant's knowledge, ingenuity, practicality, and commitment in organizing a multiproject research infrastructure for conducting studies aimed at developing new approaches to the diagnosis and/or therapy of human infertility. The research plan for the Center and all component projects must address the "Research Scope" described earlier.

For the 02 through 05 years of the overall Center research plan, the plan should include (for peer review evaluation) at least one and no more than two "New Program Development" (NPD) research projects directly related to the overall research emphasis of the Center, which will provide up to $75,000 total cost per annum to new investigators who have not been the Principal Investigator of a funded NIH (or comparable) research project grant award.

The initial NPD project(s) should be presented as a two-year research project by a named new investigator. NPD project investigators may be resident at either the grantee or a participating consortium institution.

For each successfully competed NPD project, the NICHD will include a full four years of budgeting support to permit renewal of a continuing project or replacement by a new NPD project in accord with the consensus decision process of the NCPIR Steering Committee.

Optimal components of the Center organization include the mix of local and external projects or cores to be included in the Center as o Principal investigators may consider organizing the Center to attack a problem from different disciplines using collaborations between institutions via consortium subcontract arrangements for projects at other institutions.

Centers may thus seek to maximize their scientific expertise and research capabilities by including in the application new projects or technical service cores to be supported at other institutions through subcontracted consortium o The Principal Investigator may choose to organize the Center using collaborations of projects within the same institution.

o The Principal Investigator of the Center may wish to incorporate into the application a highly relevant individual NIH research project, which is currently ongoing and deemed appropriate for transfer into the Center.

Such a project may be fully presented in the Center application as a renewal project and, contingent upon the review outcome, become eligible for funding through the Center upon relinquishment of the prior awarded project.

Irrespective of the organizational mix selected by the Principal Investigator, each research project or core proposed for inclusion in the Center must be described independently using the PHS 398 application format as described in Appendix A of this RFA. For the individual projects or cores, the page limits stated in the PHS 398 instructions must be followed.

The overall Center application must also use the PHS 398 format to provide at the beginning of the application an overall summary of the Center's organization and cumulative aggregate budgeting for the various budgetary categories.

In both instances, all essential information for the evaluation of the application must appear in the body of the application rather Terms and Conditions of Award The following terms and conditions of the award, and details of the arbitration procedures pertaining to the scope and nature of the interaction between the NICHD and the participating Centers will be incorporated into the Notice of Grant Award and provided to the Principal Investigator as well as 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 purpose of these cooperative agreements is to establish new methods for the diagnosis or therapy of human infertility.

2. Planning and implementation of the studies will be done by a Steering Committee consisting of the Principal and Project Investigators from each of the participating Centers, one NICHD staff member from the Reproductive Sciences Branch, CPR, NICHD, who will be the Research Coordinator and Collaborator, and a nongovernment Chairperson, who will be a nonvoting member, as designated by the Steering Committee.

A member of the NICHD grants management staff will serve as a nonvoting advisor to the Committee. The Steering Committee meetings will be convened at least twice yearly.

The purpose of these meetings is to share scientific information, assess scientific progress, identify new research opportunities, establish priorities that will accelerate the translation of preclinical findings into clinical applications, and conduct the business of the cooperative research program. 3.

The primary authorities and responsibilities of the awardees are to participate cooperatively with the Steering Committee in the o Determine objectives and experimental approaches; o Conduct experiments and collect the resulting data; o Analyze results and interpret the results; o Present results and plans to the Steering Committee; o Publish results, conclusions, and interpretation of the studies; o Modify, delete, or add protocols within the Program Awardees will retain custody of and primary rights to their data developed under the award subject to current government policies regarding rights of access as consistent with current HHS, PHS, and The awardees agree to accept the coordinating role of the Steering Committee and the cooperative nature of the group process.

4. The degree of programmatic involvement of the Research Coordinator is as follows: o Participation in the group process setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Research Coordinator will assist and facilitate the group process and not direct it.

o Providing, as a member of the Steering Committee, assistance by reviewing and commenting on all transitional phases of the Centers' activities prior to implementation to assure consistency with required program goals and compliance with research protocol priorities. This includes efforts to improve and strengthen inter- and intra-Center cooperation amongst the research projects of the Centers as well as interactions with industry.

The Research Coordinator will, as required, help redirect program efforts, including options of modifications or terminations by mutual consent between the Program and NICHD.

In the event of disagreements among the Program participants, the Research Coordinator will assist in forming an arbitration panel as discussed below; o Retaining the option to recommend the withholding of support from a Center project or core materially failing to meet the technical performance requirements established by the Program.

This includes identifying jointly with participants the need to add additional research projects or service cores to Centers or to phase out a Center project or core when performance standards have not been met; o Participating in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted by a Center to the research community and health care When agreement between an awardee and NICHD 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 6.

Cooperative agreements are assistance mechanisms and are subject to the same administrative requirements as grants. The above special Terms of Award are in addition to, and 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 45 CFR Part 74 and 92.

Business management aspects of these awards will be administered by the NICHD Grants Management section in accordance with HHS, PHS, and NIH grant administration 7. The level of support recommended for future years is subject to negotiation and the availability of funds.

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 subject, 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 have 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, Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES.

Program staff may also provide further discussion concerning the policy.

Prospective applicants are asked to submit, by May 15, 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 subsequent applications, the information that it contains allows NICHD staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Michael E. McClure at the address listed under INQUIRIES.

All applicants must document their ability to meet or exceed the minimum requirements as set out in the DESCRIPTION OF A CENTER section and meet or exceed those in the SPECIAL REQUIREMENTS section as detailed above. This specifically includes understanding of and commitment to the cooperative nature of this Program.

Any competing renewal application should include in the progress report section a description of how the Center has met the special cooperative agreement terms and conditions of the award, including its interaction with other NCPIR Center projects and the NICHD Applications from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research, if appropriate.

If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these awards.

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, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, Additional suggestions for formatting the application into a Center grant application are provided in the document "Suggested Format for NICHD U54 Grant Applications," which is available from the program staff listed under INQUIRIES.

The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the application. 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, COOPERATIVE SPECIALIZED INFERTILITY RESEARCH CENTER GRANT, and number, RFA HD-95-008, must be typed on line 2a of the face page of the application form and the YES box must be checked. On line 2b, type U54.

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 20817 (for express mail or courier service) At the time of submission, two additional copies of the application Division of Scientific Review National Institute of Child Health and Human Development Applications must be received by October 11, 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.

Letter of Intent Receipt Date: May 15, 1995 Application Receipt Date: October 11, 1995 Initial Review Group Peer Review: February/March 1996 NACHHD Council Review: June 4, 1996 Earliest Award Date: September 1, 1996 Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by NICHD staff. Incomplete applications will be returned to the applicant without further consideration.

Any application that does not meet the minimum requirements in the DESCRIPTION OF A CENTER and SPECIAL REQUIREMENTS sections of this RFA will be considered unresponsive to the RFA and returned to the Applications that are complete and responsive to the Request for Applications 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. Evaluation of the applications will be based upon the following: 1.

Qualifications, experience, and commitment of key personnel, particularly, but not exclusively, in the area of the proposed o Scientific, clinical, and administrative abilities of the Principal Investigator and other