SPECIALIZED COOPERATIVE CENTERS PROGRAM IN REPRODUCTION RESEARCH

Release Date:  August 20, 1998

RFA:  HD-98-013

P.T.

National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  January 13, 1999
Application Receipt Date: April 28, 1999

PURPOSE

The National Institute of Child Health and Human Development (NICHD) through
the Reproductive Sciences Branch (RSB) in the Center for Population Research
(CPR) provides funding for a limited number of research centers in the
reproductive sciences.  These centers provide an arena for multidisciplinary
interactions among basic and clinical scientists interested in establishing
high quality research programs in the reproductive sciences.  Applications for
these centers are sought from investigators willing to participate with the
NICHD under a cooperative agreement in a multicenter cooperative research
program.  Center investigators will be expected to work with NICHD staff in
facilitating research collaborations and interactions within and between
centers.  Such a cooperative program will form a national network that fosters
communication, innovation and research excellence with the ultimate goal of
improving human reproductive health through accelerated transfer of basic
science findings into clinical practice.

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),
Specialized Cooperative Centers Program in Reproduction Research, 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
202-512-1800).

ELIGIBILITY REQUIREMENTS

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 domestic institutions in the United States will be eligible for these
Center grant awards.

MECHANISM OF SUPPORT

The funding mechanism to be used to assist the scientific community in
participating in this Centers Program 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 and Conditions."

The total project period for an application submitted in response to this RFA
is five years.  The anticipated award date is April 1, 2000.  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 within the funding
limits available (see Description of a Center).  It is expected that NICHD
will solicit additional new or continuation center applications through annual
issuance of an RFA.  It is anticipated that at least three Centers will be
funded in each subsequent annual competition contingent upon the availability
of funds.

FUNDS AVAILABLE

It is anticipated that an estimated total of $3,000,000 (including indirect
and direct costs) will be available for the first year of the Program, which
will support up to three Centers in FY 2000.  Although this solicitation is
included in the fiscal plans for FY 2000, support for these center grants is
contingent upon the availability of funds for this purpose.  The number of
grants to be awarded is also contingent upon a sufficient number of
applications deemed meritorious enough to be considered for an award.

RESEARCH OBJECTIVES

Background

The ultimate goals of biomedical research supported by the RSB are to develop
new knowledge leading to clinical applications that will enable men and women
to control their own fertility choices with methods that are safe, effective,
inexpensive, reversible and acceptable to various population groups.  Such
research aims to develop new leads for contraception, procedures for
alleviating infertility, and fertility preserving treatments for reproductive
disorders that threaten fertility.

The present day need for the availability of contraception options acceptable
to diverse populations remains globally unmet. Among the 600 million women of
reproductive age in today's world, as many as 228 million women are at risk of
unintended pregnancy.  Up to 64 percent of all worldwide pregnancies are
unintended (mistimed or completely unwanted).  Over 50 million abortions occur
worldwide each year with minimal estimates of at least 100,000
abortion-related deaths annually.  In the U.S., 3 million unintended
pregnancies--57 percent of all pregnancies--occur annually with half resulting
in abortion as an outcome.  In half of the 1.3 million abortions occurring in
the U.S. each year, a contraception method being used failed to prevent a
pregnancy.

Families, family values, and family planning form the cultural essence and
cohesiveness of our existence as human societies. One of the most basic of
human rights--the right to procreate-- is frustrated or denied by the
occurrence of infertility in a couple desiring children.  It has been
estimated that infertility affects between 37 and 70 million married couples
around the world.  In U.S. studies described nearly 50 years ago, it was
stated that up to 10 percent of married couples were 'sterile' with the
remaining 90 percent having varying degrees of fertility.  More recent and
technically rigorous U.S. survey studies have conservatively identified that
there are about 2.3 million infertile couples, which is about 9 percent of the
domestic married couple population base with wives aged 15-44. In addition,
such studies found that about 4.9 million U.S. women in this age range had an
impaired ability to have children. At least 30-50 percent of infertility is
attributable to male factor infertility for which the pathophysiology is
either not understood at all or, at best, poorly understood.  The prognosis
for male infertility treatment outcomes is extremely poor at present.  Indeed,
whereas 80% of infertile women can be successfully treated, male infertility
can be treated in only 10-20% of such men.

While analyses of the U.S. population base have not found alarming annual
increases in the overall number of infertile couples or the overall prevalence
of infertility, significant age-related increases in infertility coupled with
delayed childbearing in the contemporary couple population base have been
found in such studies.  Physician office visits reflecting current societal
life style requirements for infertility services have markedly increased from
1968 (600,000) to 1988 (1,350,000) with a projected U.S. peak estimated for
1995 approaching 1,800,000.  Of the infertile couples seeking treatment for
infertility, it has been estimated that up to one- half will be unsuccessful
in achieving their desired outcome.  In concert with the increased medical
assistance sought, U.S. infertility service costs have risen to exceed a
billion dollar annual medico-economic impact in the U.S.

Reproductive disorders affecting fertility are associated with significant
morbidity and a degree of mortality in some specific instances that cannot be
ignored.  During the past two decades, the incidence of ectopic pregnancy has
increased from 4.5 to 16.1 per 10,000 pregnancies.  The rate appears to be
particularly increasing in young women aged 15-19, perhaps in relationship to
the U.S. factors of earlier age of menarche and initiating sexual activity
leading to encountering tubal disease factors earlier. In 1989, it was
reported that 88,400 women experienced an ectopic pregnancy and 34 of them
died as a direct consequence.  While improved diagnostic procedures and early
intervention protocols have resulted in markedly reducing mortality, surviving
women are left with an 8-fold risk of reoccurrence and a 20 percent lowered
chance of ever conceiving again.

Accompanying the human costs of morbidities of reproductive tract disorders,
as noted above, are the attendant substantial costs of the U.S. health care
system involving the diagnosis, treatment, and follow-up services provided the
patients, as well as the added costs to the patient and the U.S. economy of
lost employment and family service hours.  In reproductive aged couples, the
obstructive sequelae of male accessory gland infections account for 8-12
percent of male partner diagnostic costs for fertility impairment.  In
reproductive age females, it has been estimated that the general incidence of
endometriosis is 5 to 15 percent.  The incidence of endometriosis in females
being surgically treated for infertility is known to be 30 to 50 percent. 
Among infertile females with no other known cause of their infertility, the
incidence of endometriosis has been reported at 40 to 70 percent.  A diagnosis
of severe endometriosis often leads to hysterectomy-associated treatment.
While the causative role of endometriosis in infertility remains poorly
understood and its optimal diagnosis and treatment remain a goal--not an
accomplishment--of contemporary medicine, the morbid impact of the associated
pelvic pain has significant human cost and national economic costs.

Similarly, the role of dysfunctional uterine bleeding, either in the presence
or the absence of uterine leiomyomata (fibroids), is not well understood
despite its common occurrence and decades of research.  It is a significant
factor in noncompliant contraceptive use or discontinuance and, therefore, in
the unintended pregnancy problem.  Uterine myomata occur in nearly 20 percent
of all reproductive age women, are the single most common diagnosis from
gynecological hospital admissions, may be the only abnormality observed in an
infertile couple, and represent the most common medical indication for an
unintended and often unwanted hysterectomy that prematurely ends a female's
reproductive options.

Polycystic ovary syndrome (PCOS) is a major cause of female infertility, other
reproductive system, and other tissue and organ system morbidities. 
Identified more than 60 years ago by Stein and Leventhal, the etiology of PCOS
remains misunderstood despite 60 years of research.  This insidious disease is
currently the most common endocrine disorder of women of reproductive age. 
Recent prevalence rate estimates suggest at least 10 percent of the
reproductive aged population of U.S. women suffer the full blown syndrome of
hyperandrogenism, chronic anovulation and polycystic ovaries.  Also poorly
understood is the pathogenesis of premature ovarian failure which affects 2-4%
of reproductive aged women.

It is becoming increasingly apparent that some conditions of male and female
infertility may be genetically based.  In males, there is considerable
evidence from breeding studies and gene knockout experiments in animals that
mutation of over 100 separate genes results in infertility.  More limited
studies in humans show that a number of inherited diseases are associated with
abnormal sperm morphology and function.  These data suggest that a significant
number of men with infertility may have one or more mutations that predispose
to their condition.  However, it is not currently possible to determine which
men have genetic infertility.  Similarly, it is estimated that 15-20% of human
pregnancies are chromosomally abnormal as a result of division errors during
oocyte meiosis or early embryonic cleavage.  Such errors not only are the
leading cause of birth defects, but may be the single most important factor
contributing to human infertility.

Recognizing that the interactive needs of basic and clinical research
necessary to address the above and related problems may be so complex that
they cannot be solved by individual investigators working alone without the
intellectual and fiscal resources of a cooperative specialized center program,
it is the intention of the RSB, contingent upon the availability of funds, to
initiate and maintain organized, multi-component reproductive extramural
research programs of high quality that focus on topics deemed to be of high
priority and significance because of their critically important relationship
to the mission of the RSB.

Objectives

The objectives of this Centers Program are to support specialized reproductive
research programs of high quality, and to facilitate and accelerate the
translation of promising new preclinical or clinical leads into clinical
practice.  The RSB believes that the partnership developed between program
staff and the award recipients through use of the cooperative agreement
mechanism maximizes the ability of the RSB to promote, facilitate, and assist
the research conducted by the awarded centers.

This RFA is specifically designed to stimulate the reproductive sciences
research community to organize and maintain research-based centers of
outstanding quality that, serving as national research resources, form a
cooperative network with NICHD that fosters communication, innovation and high
quality reproductive research.  Such networking as afforded by the cooperative
nature of this Centers Program will ensure that the reproductive research
community remains in the forefront of the development and utilization of new
technologies which can be used to treat and ameliorate reproductive disorders,
as well as to identify novel leads for fertility regulation.

Research Scope

The Specialized Cooperative Centers Program in Reproduction Research (SCCPRR)
is composed of research-based center grants designed to support interactive
groups of research projects and supporting core service facilities.  The
research activities included in these center grants must comprise, by
definition, a multidisciplinary approach to biomedical problems addressing the
specific research topic areas announced in this RFA (see below). These centers
may have more than one theme, focus, or emphasis, but all of the subprojects
involved must be responsive to one or more of the specific research areas of
reproduction supported by the RSB.  Furthermore, the translational objective
of this Program requires that one of the subprojects be entirely or
predominantly clinical.

The following is a list of topics that are considered to be responsive to the
research mission areas of the RSB. Additionally, these topics identify areas
where research at the basic/clinical interface is deemed essential to the
potential development of new leads or approaches to fertility control, as 
well as of diagnostic tools and procedures for the detection, treatment and
effective management of reproductive disorders that impact on reproductive
competence.

Reproductive Biology and Physiology-gametogenesis, including nuclear and
cytoplasmic mechanisms that direct germ cell mitosis and meiosis, and somatic
cell-germ cell interactions which support gametogenesis; folliculogenesis,
including studies addressing intraovarian control of follicle selection and
atresia by growth factors, cytokines and their respective binding proteins and
receptor antagonists; luteogenesis and luteolysis, including intraovarian
mechanisms which control luteal life span; fertilization; early embryogenesis
during the pre- to peri-implantation period; implantation, including
cell-to-cell interactions regulating implantation.

Reproductive Endocrinology - fundamental mechanisms of hormone synthesis,
secretion, regulation and action in the context of reproduction, including
intrapituitary mechanisms governing gonadotropin secretion, and intraneuronal
mechanisms and glial-neuron interactions controlling pulsatile GnRH secretion;
identification of elements and factors controlling gene transcription, and
identification of signaling molecules and pathways mediating hormone action;
interaction of the immune and neuroendocrine systems in controlling fertility;
mechanisms by which nutritional modification alters the hypothalamo-pituitary-
gonadal endocrine axis.

Reproductive Medicine - pathophysiology, diagnosis and treatment of male or
female infertility with particular emphasis on defining those conditions which
are genetically based; relation of endometriosis to infertility, treatment of
benign gynecologic diseases; improvement of existing and development of new
approaches for assisted reproduction.

Since this list is not meant to be all-inclusive, prospective applicants
preparing either a competing new or continuation center grant application are
encouraged to discuss program relevancy issues with the program staff contact
cited under INQUIRIES in this RFA.  However, applicants should note that the
research scope of this RFA does not include studies in the area of
reproductive oncology or reproductive epidemiology or studies dealing with
post-implantation pregnancy and parturition.  These topic areas are outside
the purview of research areas supported by the RSB, and, therefore, will be
deemed nonresponsive to this RFA.  In addition, 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.  It is also not intended for the Centers to
conduct large clinical trials.

Guidance and Management Structures

Overall coordination of the Centers Program consistent with the stated
objectives set forth in the RFA (see Objectives) will be done by a Steering
Committee consisting of all Center Principal Investigators and an NICHD staff
Research Coordinator from the RSB, CPR.  The Steering Committee will employ a
consensus decision process to guide the Centers Program in evaluating the
progress of member Center programs, their proposed new research initiatives
within the general scope of the approved program, the need for collaborations
either within or outside the Center network, and the need to redirect certain
efforts of member Centers due to either sufficient data acquisition to permit
conclusion, the acquisition of data supporting an alternative study initiative
or experience proving that the proposed research is no longer feasible.

In addition to the Steering Committee, smaller cooperative groups will be
formed that consist of research components of member centers having common
research interests addressing a specific basic and/or clinical research
problem.  These research focus groups will perform coordinated research
activities as recommended by the Steering Committee.  In turn, progress of the
focus groups will further guide the Steering Committee in decision-making
regarding changes in specific research directions, translational activities,
and new research initiatives.  The research focus group will consist of an
NICHD staff Research Coordinator from the RSB, CPR, and Key Investigators of
the relevant subproject and/or Core Directors.

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

Description of a Center

The minimal requirements for a Center described in this RFA are as follows
(see sections on Review Criteria and Procedures and Award Criteria below):

o  Each center will propose a research plan that is responsive to the
objectives of the Centers Program set forth in the RFA (see RESEARCH
OBJECTIVES).

o  Each center will support at least three research subprojects that
thematically address one or more research areas listed under Research Scope. 
It is required that at least one subproject be entirely or predominantly
clinical in nature.  For this Centers Program, the definition of clinical can
involve patient studies or use of cultured human cells or tissue.  Although
not required, it is strongly encouraged that at least one basic science
subproject be in a similar scientific area as the clinical subproject in order
to facilitate transfer of information from bench to bedside. Alternatively, a
project may be proposed that incorporates both basic and clinical approaches
to a particular problem.

o  An administrative core unit which provides oversight to the Center that is
located at the grantee institution, and is accessed only by budgeted center
subprojects and cores.

o  A competent and experienced Principal Investigator who is committed to and
directly involved in research dealing with mammalian reproduction;

o  Availability of competent and experienced scientific experts to direct
individual research projects or cores associated with the proposed Center;

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  As appropriate, access to inpatient and outpatient reproductive health care
units providing adequate numbers of patients for clinical research projects
that require patient participation [Applications 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].

Optional components of the Center organization include the mix of subprojects
and cores to be included in the Center.

o  The Principal Investigator may choose to organize the Center using
collaborations of projects within the same institution.  Alternatively,
Centers may seek to maximize their scientific expertise and research
capabilities by including in the application a subproject and/or a technical
service core to be supported at other institutions through subcontracted
consortium arrangements.  No more than one consortium subproject and one
consortium core service facility will be permissible in each Center.

o The Principal Investigator may choose one of two center structure options
regarding access to technical service core facilities.

Closed Access Structure - In this center structure, administrative and all
technical service cores will be utilized by budgeted center subprojects only. 
Consistent with NICHD guidelines for establishment of core facilities,
utilization by three subprojects is required to justify a core technical
service facility.  Percent utilization by any one of the three subprojects
justifying the core cannot exceed 50 percent or be less than 5 percent.  The
percent utilization of additional subprojects requiring core services can be
less than 5 percent. Costs necessary to use a particular core facility can be
incorporated into the budget of the core unit, and not in the budgets of the
research subprojects per se.  No internal charge back system would be
required.

Open Access Structure - In this center structure, budgeted center subprojects
as well as research projects external to the center (e.g., R01, R29, R03, P01
subproject) may have access to technical service cores.  However, special
consideration must be given to justification of a technical service core
facility and the formal establishment of an effective charge back system for
all technical service cores.  For each core service facility, at least one of
the three projects used to justify a core must be a budgeted center subproject
while the remaining project(s) used in justifying the core must be externally
funded NICHD projects administered by the RSB.  Percent utilization by any
internally budgeted center subproject or externally-funded RSB project used to
justify a particular core facility cannot exceed 50 percent or be less than 5
percent.  An additional seven federally-funded, peer-reviewed external
research projects addressing program-relevant research areas of the RSB can
access the core up to 100 percent of its service capacity.  The 50/5 percent
utilization requirement applies to this group of external projects.  Centers
must establish an internal management policy for evaluating the acceptability
of proposed RSB program relevant external projects to access the core
facilities.  Approval of requests for core access privileges for external
projects which would replace those described above must be made to RSB Program
Staff who then will evaluate the extent to which the project is relevant to
RSB mission research areas (see Research Scope), and render a decision
accordingly.

If centers choose to operate in an open access format, costs necessary to
utilize a particular core facility by budgeted center subprojects must be
incorporated into the budget of the subproject and not the core budget in
order to accommodate participation in the required charge back system.  Core
budgets will be justified and evaluated based on its access by budgeted center
subprojects and external, program-relevant research projects as described
above.  Above and beyond this arrangement, technology-based core units can
offer services to additional external projects addressing any area of research
regardless of funding source only on a full  payback (fee-for-service or in
kind) basis.  However, additional funds necessary to provide services to these
external projects (e.g., technical support, supplies, etc.) must come from
sources other than the center funding, such as the supply budgets of the
external projects wishing to access the core facilities.  In choosing to
configure a center in an open-access center structure, the Principal
Investigator must have in place and adequately described in the application
management policies which ensure that budgeted center subprojects are given
highest priority in receiving services provided by the core.

Centers choosing to configure in an open-access center format may propose one
or more technical service cores that will be utilized exclusively by budgeted
center subprojects.  These centers may, therefore, have a mix of open or
restricted access technical service cores.  On the other hand, administrative
cores in open center structures may be accessed only by budgeted center
subprojects.

Once an award is made, centers configured as a closed-access center structure
may, at a later time, choose to convert to an open access center structure by
requesting such conversion in writing to the
NICHD.

Irrespective of the organizational mix selected by the Principal Investigator,
each research subproject or core proposed for inclusion in the Center must be
described independently using the PHS 398 application format as described in
the document "Suggested Format for NICHD U54 Grant Applications," which is
available from the program staff listed under INQUIRIES.  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 than in
an appendix.

SPECIAL REQUIREMENTS

Terms and Conditions of Award
Cooperative agreements are assistance mechanisms and are subject to the same
administrative requirements as grants.  The following Terms and Conditions 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 Branch in accordance with HHS, PHS, and NIH grant
administration requirements.

1.  The purpose of these cooperative agreements is to support a coordinated
research program of specialized centers pursuing high quality reproductive
research with the ultimate goal of facilitating and accelerating translation
of basic science knowledge into clinical applications which can be used to
regulate fertility or diagnose and treat infertility or reproductive disorders
that impact on fertility.

The primary authorities and responsibilities of the awardees are to
participate cooperatively with the Steering Committee in the following
activities:

o  Pursuit of research objectives consistent with the research scope of the
RFA and research approved during the initial peer review;
o Conduct experiments and collect the resulting data;
o Analyze, interpret and present results and plans to the Steering Committee
for approved activities;
o Publish results, conclusions, and interpretation of the studies.

The awardees will agree to: 1) accept the coordinating role of the Steering
Committee which includes evaluating objectives and research goals of the
Centers Program, and recommending modification, deletion or addition of
protocols within the Centers Program; 2) follow any common protocols in which
they participate for multicenter projects that are approved by the Steering
Committee; and 3) accept the cooperative nature of the group process,
including the establishment, where appropriate, of smaller collaborative
groups comprised of interacting subprojects and/or cores focused on a
particular reproductive research topic area.

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
NIH policies.

2.  The degree of programmatic involvement of the Research Coordinator is as
follows:

o  Participating in the overall coordination of the Centers Program with the
Steering Committee.  This includes efforts to improve and strengthen inter-
and intra-center cooperation amongst the research projects of the Centers,
particularly as it pertains to translational research activities within and
between centers.  As a means of improving inter-center cooperation, the
Research Coordinator will directly participate in the activities of the
smaller collaborative groups established by the Steering Committee comprised
of subprojects and/or cores focused on a particular reproductive research
topic area.  The Research Coordinator will also assist the research efforts of
the Centers Program by facilitating access to fiscal and intellectual
resources provided by industry, private foundations and NIH intramural
scientists.  The Research Coordinator will, as required, help reprogram
research efforts, including options to modify or terminate them, by mutual
consent between the Centers 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  Interacting with each individual center awardee evaluating objectives and
research goals of that particular center, 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 this process and not direct it. The Research Coordinator will also
provide assistance in reviewing and commenting on all major transitional
changes of an individual center's activities prior to implementation to assure
consistency with required goals of the Centers Program.

o  Retaining the option to recommend the withholding of support from a Center
subproject or core materially failing to meet the technical performance
requirements established by the Centers Program. This includes identifying
jointly with participants of the Steering Committee the need to add additional
research subprojects or service cores to Centers or to phase out a Center
subproject or core when performance standards have not been met; and

o  Participating, where warranted, in data analyses, interpretations, and the
dissemination of study findings to the research community and health care
recipients including co- authorship of the publication of results of studies
conducted by the Centers.

3.  Overall Coordination of the Centers Program consistent with the stated
intent of the RFA will be done by a Steering Committee consisting of the
Principal Investigators from each of the participating Centers and one NICHD
staff member from the RSB, CPR, NICHD, who will be the Research Coordinator. 
A member of the NICHD grants management staff will serve as a nonvoting
advisor to the Committee.  A chairperson for the Steering Committee will be
chosen by a majority vote of the Principal Investigators.  The Steering
Committee meetings will be convened at least once per year.  The purpose of
these meetings is to share scientific information, assess scientific progress,
identify new research opportunities and potential avenues of collaborations
such as with industry, private foundations and/or NIH intramural scientists,
establish priorities that will accelerate the translation of preclinical
findings into clinical applications, reallocate resources and conduct the
business of the cooperative research program.  In anticipation that some
centers will have common research interests that address a specific basic
and/or clinical research problem, it is envisioned that research focus groups
will be formed to conduct coordinated research activities recommended by the
Steering Committee.  The Steering Committee will approve multicenter protocols
on specific research activities.  As needed, the Steering Committee will
develop a publication policy regarding joint authorship of research reports
derived from such collaborative efforts.

4.  Arbitration

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 Investigator, 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 policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"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 the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address:  https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 13, 1999, a letter of
intent that includes: 1) a descriptive title of the proposed research; 2) the
name, address, and telephone number of the Principal Investigator; 3) the
identities of other key personnel and participating institutions along with
the tentative titles of the respective subprojects; and 4) 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. Louis V. DePaolo at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

Contents of Applications

A response to this RFA should consist of an application that includes:

o  A description of a Specialized Center in Reproduction Research consisting
of multiple individual research subprojects, an Administrative Core and, if
applicable, one or more technology- based core service facilities.  For
suggested formatting instructions see the document, "Suggested Format for
NICHD U54 Grant Applications," available from the program staff listed under
INQUIRIES.

o  A description of the capabilities of the Center to meet or exceed the
minimal requirements stated below (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 basic and
clinical studies in the reproductive sciences.  The research plan for the
Center and all component subprojects must address the "Research Scope"
described earlier.

o The stated willingness of the Principal Investigator to cooperate in a
coordinated cooperative program involving multiple Centers with the objective
of developing research project and/or service core interactions between
Centers.

o  Substantive evidence of departmental and institutional support for and
commitment to the proposed Center.

All applicants must document their ability to meet or exceed the minimum
requirements as set forth in the 'Description of a Center.'  This specifically
includes understanding of and commitment to the cooperative nature of this
Program.

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.

Submission Procedures

The research grant application form PHS 398 (rev. 5/95) is to be used in
applying for these awards.  Applications kits are available at most
institutional offices of sponsored research and may be obtained from the
Division of Extramural Outreach and Information Resources, National Institutes
of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, email: GRANTSINFO@nih.gov.

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. 5/95) 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, SPECIALIZED COOPERATIVE CENTERS PROGRAM IN REPRODUCTION RESEARCH, and
number, RFA HD-98-013, must be typed on line 2 of the face page of the
application form and the YES box must be checked.

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:

Scott Andres, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03
Bethesda, MD  20892-7510
Rockville, MD 20852 (for express/courier service)

Applications must be received by April 28, 1999.  The Center for Scientific
Review (CSR) will not accept any application in response to this RFA 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. 
The NICHD will not accept for review competing new or continuation
applications that have been revised more than one time.  If a revised
competing continuation application is not selected for funding, the applicant
institution may then only submit a new, substantially different application.

Budgets

Applications from new center sites may not request more than $750,000 in
direct costs for the first year, with incremental increases not exceeding
three percent in each subsequent year. For currently existing RSB-supported
center sites, direct costs requested for the first year can be either $750,000
or 120 percent of the direct costs awarded for the final competitive segment
year of the preceding project period as stated in the Notice of Grant Award,
whichever is higher.  A submitted application exceeding the budgetary limits
specified above will be returned to the applicant unreviewed.

In the event that an application submitted in response to this RFA is not
funded, one revision of the application will be accepted in response to a
subsequent RFA.  Budgets for revised applications must be submitted in accord
with the recommendations of the peer review group who evaluated the initial
submission unless a different budget has been approved in advance by the
NICHD.  If a revised competing continuation application is not selected for
funding, the applicant institution may then submit only a new, substantially
different application that will be subject to the direct cost limit of
$750,000.

Principal Investigators should request travel funds to support their
participation in the annual Steering Committee Meeting, and Key Investigators
of budgeted center subprojects should request travel funds to support
participation in either the Steering Committee Meeting or a research focus
group meeting.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR  and
responsiveness to the RFA by NICHD staff.  Incomplete applications will be
returned to the applicant without further consideration.  Any application that
does not meet the minimum requirements as set forth in the 'Description of a
Center' section of this RFA will be considered unresponsive to the RFA and
returned to the applicant.  This includes, but is not limited to, an
evaluation by NICHD staff of the program relevancy of the proposed research
subprojects and external projects being proposed to access core facilities.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NICHD in accordance with the review criteria stated below.  As part of the
initial merit review, a process may be used 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
determined to be noncompetitive by the review committee will be withdrawn from
further consideration, and the principal investigator will receive a summary
statement reflecting the reviewers' evaluation.  Applications judged to be
competitive will be further discussed and assigned a priority score.  They
will then receive a second level review by the National Advisory Child Health
and Human Development Council (NACHHD).

Applications submitted in response to this RFA and judged to be competitive
may also receive a site visit as part of the review process.  However,
applicants should ensure that their applications are complete and can stand on
their own.

Review Criteria

The scientific and technical merit peer review focuses on three areas:  (1)
review of the component research subprojects; (2) review of the core units,
and (3) review of the overall center as an integrated effort.

1.  Component Research Subproject Criteria:

The review criteria for the component research subprojects are:

1.  Component Research Subproject Criteria:

o Significance:  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

o Approach:  Are the conceptual framework, design (including composition of
study population), methods, and analyses adequately developed, well-
integrated, and appropriate to the aims of the project?  Does the applicant
acknowledge potential problem areas and consider alternative tactics?

o Innovation:  Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

o Investigators:  Is the Key Investigator and collaborators, if any,
appropriately trained and well suited to carry out this work?  Is the work
proposed appropriate to the experience level of the key investigator and other
researchers (if any)?  Is the Key Investigator committed to devote the
required time and effort to the subproject and the Center?  Please comment on
the willingness of the Key Investigator to work and collaborate with other
Center Programs as appropriate and with NICHD assistance in the manner
summarized in this RFA.

o Environment:  Does the scientific environment in which the 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?

o Accomplishments and progress to date of the component research subprojects
in the case of competing renewal applications;

o Appropriateness of the budget for each component research subproject;

o Adequacy of animal facilities and appropriateness of animal care management
where animal work is proposed;

o Adequacy of clinical facilities and appropriateness of patient care
management where clinical work is proposed; and

o Appropriateness of plans to ensure the protection of human subjects, the
humane care and use of laboratory animals, and the environment; and

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.  (See INCLUSION
OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS).

o Adequacy of plans for including children as appropriate for the scientific
goals of the research, or justification for exclusion.  (See NIH POLICY AND
GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING
HUMAN SUBJECTS).

2.  Core Unit Criteria:

The criteria for reviewing the Core Units are:

o Qualifications, experience and commitment of key personnel in the services
provided by the core unit, as well as their ability to devote the required
time and effort in providing services to the Center;

o Accomplishments of the Core Unit in the case of competing renewal
applications;

o Appropriateness of the budget for each core unit that considers cost
effectiveness and quality control for core units;

o Appropriateness of the use of core services by the budgeted center
subprojects, and, if applicable, by external projects.

o Adequate plans for charge back and priority management procedures for
technical core units offering services to external projects.

3.  Overall Center Criteria:

The criteria for reviewing the Center as an integrated effort are:

o Overall strength of the Center in terms of the combined strength of the
research subprojects and core units, and the significance of the application
to the objectives of the Program outlined in this RFA;

o Leadership ability and scientific stature of the Principal Investigator
particularly, but not exclusively in the area of the proposed research, and
his/her ability to meet the Center's demands of time and effort;

o Specifically stated and described willingness of the Principal Investigator
to work and cooperate with other Center Programs as appropriate, and with
NICHD assistance in the manner summarized in this RFA;

o An appropriate organizational and administrative structure for effective
attainment of Center objectives that considers arrangements for internal
quality control of ongoing research, the allocation of funds, day-to-day
management, contractual agreements if applicable, and internal communication
among Center investigators;

o The institutional environment in which the research will be conducted,
including the availability of space, equipment, and subjects, if proposed;
adequacy of administrative, clinical and technical capabilities to conduct the
research proposed; physical proximity of investigators; and the potential for
interaction with scientists from other areas;

o Demonstrated commitment to the center and its objectives in terms of
providing research facilities and management support.

Schedule

Letter of Intent Receipt Date:     January 13, 1999
Application Receipt Date:          April 28, 1999
Initial Review Group Peer Review:  October/November 1999
NACHHD Council Review:             January 2000
Earliest Award Date:               April 1, 2000

AWARD CRITERIA

The anticipated date of award is April 1, 2000.  Applications recommended by
the NACHHD Council will be considered for award based on scientific and
technical merit; program balance; and availability of funds.  The NICHD will
not support more than one SCCPRR center award involving departments or
specialty units of a single grantee institution.  In order to receive funding,
an individual domestic institution's application for a Specialized Cooperative
Center Grant must have three or more related, interactive, and high quality
research subprojects that provide a multidisciplinary, yet thematic, approach
to the problems to be investigated.  At least one of the subprojects must be
clinically oriented.  Awards will not be made for applications with research
activities focused exclusively on clinical research or exclusively on basic
research or for applications or components thereof proposing epidemiological
or large scale clinical trial research.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding programmatic issues and address the letter of
intent to:

Louis V. DePaolo, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
Building 61E, Room 8B01
Bethesda, MD  20892-7510
Telephone:  (301) 496-6515
FAX:  (301) 496-0962
Email: ld38p@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 8A17
Bethesda, MD  20892-7510
Telephone:  (301) 496-5481
FAX:  (301) 402-0915
Email: mn23z@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 PHS
Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42
USC 241 and 285). These special Terms of Award are in addition to, and not in
lieu of, otherwise applicable OMB administrative guidelines 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 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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