COOPERATIVE MULTICENTER REPRODUCTIVE MEDICINE NETWORK

Release Date:  May 4, 1999

RFA:  HD-99-005

P.T.

National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  June 1, 1999
Application Receipt Date:  July 22, 1999

PURPOSE

The National Institute of Child Health and Human Development (NICHD) invites
applications from investigators willing to participate, with the assistance of
NICHD under cooperative agreements, in an ongoing multicenter cooperative program
designed to conduct clinical studies investigating problems in reproductive
medicine, including infertility, reproductive endocrinology, gynecology, and
andrology. The objective of this program is to facilitate resolution of these
problems by maintaining a network of sites that, by rigorous patient evaluation
using common protocols, can study large numbers of patients and can provide
answers more rapidly than individual sites acting alone.  The benefit of this
activity will be to the public: infertile couples, individuals with reproductive
diseases and disorders, and their health-care providers.

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),
Cooperative Multicenter Reproductive Medicine Network, is related to the priority
area of family planning.  Potential applicants may obtain a copy of "Healthy
People 2000" at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, units of state and local governments, and
eligible agencies of the Federal government.  The need for continuous and active
communication among sites dictates that only institutions in the United States
will be eligible to apply.  Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be a
cooperative agreement (U01, U10), an "assistance" mechanism (rather than an
"acquisition" mechanism) in which substantial NIH scientific and/or programmatic
involvement with the awardee is anticipated during performance of the activity. 
Support will be provided by a U01 award for the Data Coordinating Center and U10
awards for the clinical sites (described below). Under the cooperative agreement,
the NIH purpose is to support and stimulate the recipients' activity by
involvement in the activity and by otherwise working jointly with the award
recipients in a partner role, but it is not to assume direction, primary
responsibility, or a dominant role in the activity.  Details of the
responsibilities, relationships and governance of the study to be funded under
cooperative agreements are discussed later in this document under the section
"Terms and Conditions."

The total project period for applications submitted in response to the present
RFA may not exceed five years.  The anticipated award date is April 1, 2000.

FUNDS AVAILABLE

The NICHD intends to commit approximately $2.3 million (including direct and
facilities and administrative costs) for the entire program in FY 2000.  It is
anticipated that up to nine new and/or competing continuation grants, including
one award for the Data Coordinating Center and eight awards for Clinical Sites,
will be made in response to this RFA.  Because the nature and scope of the
research proposed may vary, it is anticipated that the size of each award will
also vary. Although the current financial plans of the NICHD provide support for
this program, awards pursuant to this RFA are contingent upon the availability
of funds and the receipt of a sufficient number of applications of outstanding 
scientific and technical merit.

At this time, the NICHD has not determined whether or how this initiative will
be continued beyond the present RFA.

RESEARCH OBJECTIVES

Background

Within the mission of the NICHD, a preeminent goal is to assure the birth of
wanted babies through studies on human fertility and infertility.  To this end,
the Reproductive Sciences Branch supports research on human fertility and
infertility, and on diseases and disorders of the human reproductive system.

Particularly in the field of infertility, but in other aspects of reproductive
medicine as well, uncontrolled, trial-and-error methods have led to undeserved
claims of effectiveness and resulted in significant costs, both human and
financial.  Even for "male factor" infertility, the female partner usually
undergoes treatment.  Few options are available for diagnosis or treatment of
clinically normal men with a sperm defect.

There are gynecologic conditions that result in significant morbidity,
particularly in women of reproductive age.  Conditions such as endometriosis,
leiomyomata uteri, abnormal uterine bleeding, pelvic floor disorders, and others
can cause pain, disruption of function in the workplace and the home, and other
problems beyond or beside effects on fertility.  Many of these conditions can
lead to hysterectomy or other major surgery.  In some cases, alternative
management strategies might have been effective, but were not understood,
accessible, or affordable.

Following a 1988 concept clearance review by a group of independent experts, an
RFA was issued in 1989 to initiate the Cooperative Reproductive Medicine Network. 
Its overall goal has been to address the need for rigorous controlled evaluation
of diagnostic and therapeutic practices in the area of reproductive health care. 
The first major trial, a protocol study comparing intrauterine and intracervical
insemination, with or without ovulation induction by exogenous gonadotropin, has
been completed and the results published (N Eng J Med 340:177-183, 1999). 
Several other Network protocol studies are currently in various stages of
enrollment or data analysis.

Despite this and other examples of careful, modern research, there is much yet
to be done.  Only recently has the basic science base of knowledge about the
pathophysiology of common, distressing conditions begun to approach the point at
which clinical studies can use this new knowledge as a practical foundation.  The
report language accompanying both House and Senate appropriations bills for
fiscal 1999 emphasized infertility and gynecology research.

Use of the cooperative mechanism has many advantages.  The NIH staff participant
will contribute scientifically to consensus decision-making and to maintaining
balance among the participants.  In this way, the group can identify issues with
a high degree of objectivity, develop well-designed protocols, provide to
participants expert statistical consultation in experimental design and analysis,
and provide a large patient base, so that tests and treatments can be evaluated
more rapidly and with greater statistical validity than otherwise.  The
anticipated efficiency of communication among investigators and dissemination of
information to practitioners and the public would lead to more effective patient
care and to more economical use of resources.

Objectives and Scope

There are a number of controversies in Reproductive Medicine that would lend
themselves to cooperative study.  The scope includes clinical problems in
infertility, reproductive endocrinology, gynecology, and andrology.  The
following should by no means be viewed as exclusive, and are intended only as
examples:

o Assisted reproductive technology outcomes:  Patient selection, comparison of
treatment protocols to optimize live birth rates.

o Endometriosis:  Controlled trials of diagnostic methods and treatments,
examining post-treatment fertility and/or symptom reduction.

o Polycystic ovarian syndrome:  Definition, subgroups, responses to therapies.

o Leiomyomata uteri:  Controlled trials of diagnostic methods and treatments,
examining post-treatment fertility and/or symptom reduction.

o Varicocele:  Effect on fertility, benefits of surgery.

o Male infertility:  Diagnosis and treatment directed at the male.

The Network will include approximately eight clinical sites or "Reproductive
Medicine Units" (RMUs) supported by U10 awards,  and a Data Coordinating Center
(DCC) supported by a U01 award.  There will be two domains within the Network:
Infertility/Andrology and Gynecology.  "Infertility" is intended to encompass
male factor, female factor, and unknown cause.  It is anticipated that ongoing
Network activity will encompass protocols from both domains, with one RMU acting
as lead unit for each protocol.  The RMUs will recruit, evaluate and treat the
participants in any or all of the clinical studies.  The Data Coordinating Center
will have primary responsibility for data collection and management for each
trial.

A member of NICHD program staff, serving as Research Coordinator, will cooperate
with the funded Principal Investigators in designing and executing protocols to
optimize management in these areas.

Guidance and Management Structures

The Steering Committee will consist of the Principal Investigators from each RMU,
the Principal Investigator of the DCC, and the NICHD staff Research Coordinator;
a nongovernment chairperson will be designated by the Steering Committee.  A
member of the NICHD grants management staff will serve as advisor to the
Committee.  The Steering Committee will develop by consensus the protocols to be
carried out under these cooperative agreements, and will supervise the conduct
of the studies.

An independent Clinical Trials Advisory Board will advise the Steering Committee
in identifying and prioritizing research topics appropriate for study by the
Network.  Such topics would be of high public health impact, amenable to rigorous
scientific approaches, and clinically feasible.  The Advisory Board, chosen by
the NICHD with the advice of the Steering Committee, will include members with
expertise in clinical trial design, biostatistics, epidemiology, infertility,
gynecology, and andrology, as well as the Chair of the Steering Committee and the
NICHD Research Coordinator.  The Board will evaluate the overall hypotheses and
scope of planned trial protocols, and may enlist additional ad hoc scientific
and/or clinical experts as needed to conduct such evaluations.

A Data Safety and Monitoring Committee (DSMC) convened by the NICHD will have
responsibility for reviewing the safety of ongoing clinical trials and will
advise on their conduct.  The DSMC will monitor data collection and analysis by
the DCC, including any reports of adverse effects.  When appropriate, the DSMC
will conduct interim evaluations of the data with respect to the need to
terminate studies, either because the data suffice to answer the problems posed,
data collection provides support for an alternative study initiative, or because
experience has proven that the research is not feasible.

Time Sequence

It is anticipated that the program will conduct its activities according to the
following general outline:

Initially, the Advisory Board and Steering Committee will review and identify
issues of importance in reproductive medicine.  They will consider items proposed
for study by the Network from those listed above in "Objectives and Scope" and
others suggested by participating units.  Within each of the
Infertility/Andrology and Gynecology domains, the Board and Steering Committee
will rank in priority order a series of issues that are substantive, lie within
the scope of existing technical capability, lend themselves to multicenter
evaluation, involve sufficient numbers of patients to be of consequence in terms
of morbidity, and comprise significant public health needs.  In this and
subsequent activities, the Steering Committee will attempt to use electronic and
telecommunications whenever possible.

From the list of important issues for each domain, the Steering Committee will
generate diagnostic or treatment protocols and agree on lead units for the
protocols.  Each protocol is to be acceptable to all the participants, adequate
for appraisal of the research issues defined, and amenable to data collection in
a single format acceptable to all units.  Satisfactory controls will be
incorporated, and attention will be given to maximize the number of studies
possible with minimal data collection.  Protocol subcommittees may be constituted
to develop protocols more efficiently.

Participating RMUs will incorporate the protocols into the clinical management
of those patients selected for study.  The units will supervise the collection
of data with adequate attention to the fidelity of records and transcription and
will provide information in uniform data format for analysis.  The mode of data
transmission and analysis will be determined by the Steering Committee in
conjunction with the recommendations of the Data Coordinating Center.  Data
summaries will be provided to the Data Safety and Monitoring Committee on a
semi-annual basis, or as indicated by study development.  Format and content of
final reports and the dissemination of information to the scientific community
will be determined by the Steering Committee.

Beginning approximately six months after the start of data collection, the Data
Safety and Monitoring Committee will examine the aggregated data and make
recommendations to NICHD on the need to modify or terminate studies, as described
above.  As studies are terminated, the Advisory Board and Steering Committee will
be expected to reinitiate identification of new issues and the institution of new
protocols.

SPECIAL REQUIREMENTS

Scientific Content

The NICHD invites applications from both current members of the Network
(competing renewal applications) and from prospective members (new applications). 
Minimum requirements for applicants are as follows (see also Review Criteria and
Procedures, below):

o Requirements for Clinical Site (RMU) Applicants

1.  Participants must be based in departments providing both inpatient and
outpatient reproductive health care.

2.  The unit must have a history of previous successful clinical research, and
expertise in research design, biostatistics, and use of clinical protocols. 
Ability to enroll sufficient numbers of patients for meaningful studies should
be documented.  For competing continuations, participation in past and current
Network studies must be described in detail.

3.  The unit must be able to demonstrate past and existing excellence in
collecting and maintaining clinical data on its patients.  Applications should
state the numbers of patients seen annually for infertility overall and for the
other reproductive health diagnoses listed as examples in "Objectives and Scope,"
above.

4.  The Principal Investigator should be able to make a substantive, long-term
commitment of effort to Network responsibilities.  The unit should have physician
staff representing several areas of expertise, either based in the participating
department or available as collaborators.  At a minimum, these areas would
include Obstetrics and Gynecology, Reproductive Endocrinology (either in OB-Gyn
or Internal Medicine), and Andrology (either in Internal Medicine or Urology).

5.  An experienced research nurse must be among the key personnel, and additional
research nursing staff should be available.

6.  Laboratory facilities must be available for appropriate testing of patients
and subjects, in such areas as hematology, blood chemistry, endocrinology,
microbiology, radioimmunoassay, and semen analysis.

7.  Appropriate imaging services must be available, including ultrasound,
contrast studies, and other radiological and related techniques that may be
required to diagnose and follow the conditions under study.

8.  The unit must be prepared to participate in a cooperative manner with other
clinical centers and with the Data Coordinating Center in the delineation of
research protocols, statistical methods, uniform data formats, and data transfer.

9.  There must be firm institutional and departmental commitments to support this
cooperative study and a strong staff dedication to adhere to programs jointly
defined and to generate data of high fidelity in order to ensure success.

10.  Applications from institutions that have a General Clinical Research Center
(GCRC) funded by the National Center for Research Resources may wish to identify
the GCRC as a resource for conducting the proposed research.  If so, a letter of
agreement from either the GCRC program director or Principal Investigator should
be included with the application.

11.  Because new protocols for investigation will not be written until after
awards are made, it is not possible for new RMU applicants to propose the exact
work that they would actually carry out if funded.  Therefore, to provide peer
reviewers and NICHD staff an idea of the capabilities of the investigators, each
new applicant for an RMU must submit a "concept" protocol for a new study which
that site might expect to conduct as a participant in the Network.  The applicant
should note carefully that the "concept" study proposed may or may not actually
be performed by the Network as one of its protocols.  The proposal is requested
to serve as an indicator of the applicant's ability to participate in the
development and design of protocols for cooperative clinical investigations.  It
is anticipated that the Steering Committee and Advisory Board will include the
"concept" protocols submitted by the funded RMU sites in their consideration of
topics for actual protocols.

For purposes of this RFA only, it is suggested that the "concept" protocol
address one of the following topics:

1.  Procedures for improved outcome in human assisted reproductive technologies;
2.  Fertility-sparing management of endometriosis, leiomyomata uteri, or abnormal
uterine bleeding;
3.  Improved management of pelvic floor disorders or pelvic pain conditions;
4.  Role of immunologic evaluation and intervention in management of infertility;
5.  Effects of varicocele and the treatment thereof on fertility.

The choice of a "concept" topic from one domain will not necessarily prevent the
participation of an RMU in the other domain in the event that it is funded.  The
protocol should be written specifically for this Network and will be a key factor
in evaluation of the application.

The following additional characteristics are highly desirable:

1.  The applicant institution should have a computer facility and an authorized
user who is knowledgeable in computer data storage and retrieval, including
transmission via the Internet and/or World Wide Web.

2.  The site should have previous experience in multicenter clinical trials.

3.  If the specialty of the Principal Investigator is in disorders of one sex,
then the designation of a co-principal investigator with expertise in disorders
of the opposite sex will be viewed as a
strength.

o  Requirements for Data Coordinating Center (DCC) Applicants

1.  The applicant must have demonstrated prior experience as a Coordinating
Center in multi-center studies.

2.  The Principal Investigator, with other staff, must have appropriate
biostatistical, data management, and coordination expertise.

3.  The applicant must have ability to assist in designing protocols and the data
collection system, including transmission via the Internet and/or World Wide Web.

4.  The applicant must demonstrate experience in developing and monitoring
quality control.

5.  The Data Coordinating Center will report to the Data Safety and Monitoring
Committee at least every six months regarding accumulating data and the RMUs'
performance.  The application should document the ability to meet such reporting
deadlines as well as the overall timetable.

6.  The applicant must be prepared to cooperate with the RMUs and NICHD staff in
all design, collection, and analysis functions.

7.  The application must include a plan detailing methods of data receipt,
analysis, quality control, and reporting, including communications with
administrative and clinical personnel.

8.  If an institution applies for both RMU and DCC, the DCC application must
address the issue of how the DCC would maintain operational independence if both
were funded.

Terms and Conditions of Award

The following Terms and Conditions of the award, and details of arbitration
procedures pertaining to the scope and nature of the interaction between NICHD
and the participating RMUs and Data Coordinating Center, 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.

Cooperative agreements are assistance mechanisms and are subject to the same
administrative requirements as grants.  The following 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.  A  Program
Officer from the Reproductive Sciences Branch, Center for Population Research,
NICHD, separate from the Research Coordinator, will exercise normal program
stewardship.  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 Agreements is to facilitate resolution of problems in
reproductive medicine by establishing a network of units (Reproductive Medicine
Units and a Data Coordinating Center) able to study large numbers of patients and
provide conclusions more rapidly than institutions acting alone.

2. The Steering Committee will consist of the Principal Investigators from each
RMU, the Principal Investigator of the DCC, and the NICHD staff Research
Coordinator; a nongovernment chairperson will be designated by the Steering
Committee.  A member of the NICHD grants management staff will serve as advisor
to the Committee.  The Steering Committee will develop by consensus the protocols
to be carried out under these cooperative agreements, and will supervise the
conduct of the studies.

3.  An independent Clinical Trials Advisory Board will advise the Steering
Committee in identifying and prioritizing research topics appropriate for study
by the Network.  Such topics would be of high public health impact, amenable to
rigorous scientific approaches, and clinically feasible.  The Advisory Board,
chosen by the NICHD with the advice of the Steering Committee, will include
members with expertise in clinical trial design, biostatistics, epidemiology,
infertility, gynecology, and andrology, as well as the Chair of the Steering
Committee and the NICHD Research Coordinator.  The Board will evaluate the
overall hypotheses and scope of planned trial protocols, and may enlist
additional ad hoc scientific and/or clinical experts as needed to conduct such
evaluations.

4.  A Data Safety and Monitoring Committee (DSMC) convened by the NICHD will have
responsibility for reviewing the safety of ongoing clinical trials and will
advise on their conduct.  The DSMC will monitor data collection and analysis by
the DCC, including any reports of adverse effects.  When appropriate, the DSMC
will conduct interim evaluations of the data with respect to the need to
terminate studies, either because the data suffice to answer the problems posed,
data collection provides support for an alternative study initiative, or because
experience has proven that the research is not feasible.

5.  Primary authorities and responsibilities of the awardees:

o  Define objectives and approaches;
o  Plan the design and implementation of the protocols;
o  Conduct the studies;
o  Collect and analyze the data;
o  Publish the results, conclusions and interpretations of studies.
o  Modify or delete protocols; add new protocols, subject to NICHD approval.

Awardees will retain custody of and primary rights to their data developed under
the award, subject to current Government policies regarding rights of access.

The awardees agree to accept the advisory role of the Clinical Trials Advisory
Board, the coordinating role of the Steering Committee and the cooperative nature
of the group process.

6.  The degree of programmatic involvement by the NICHD Research Coordinator:

o  Assist in and facilitate the development of study protocols;
o  As a member of the Steering Committee, review and comment on each stage of the
program before subsequent stages are started, including options of modification
or termination by mutual consent between the Network and NICHD;
o  Assist in maximizing cooperation among the units, and help redirect efforts,
if necessary;
o  Retain the option to withhold support of a participating unit, if technical
performance requirements such as compliance with the protocol, meeting patient
enrollment targets, and adherence to uniform data format are not met.  Support
will be contingent upon meeting these requirements.  Alternatively, determine
jointly with the awardees the need to add clinical sites for the purpose of
increasing patient accrual.
o  Assist, through review, comment, analysis and, where appropriate, co-
authorship, in reporting results to the community of investigators and health
care recipients.

7.  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 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 clear and compelling rationale
and justification are 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 was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994, available on the web at:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html.

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/or 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: 
https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 1, 1999, 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 this RFA. 
Although a letter of intent is not required, is not binding, and does not enter
into the review of a subsequent application, the information that it contains
allows NICHD staff to estimate the potential review workload and to avoid
conflicts of interest in the review.

The letter of intent is to be sent to Dr. Donna L. Vogel at the address listed
under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms are available at most institutional Offices of
Sponsored Research and from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov.

All applicants must document their ability to meet or exceed the minimum
requirements set out in the SPECIAL REQUIREMENTS section for RMU or DCC
applications detailed above.  This specifically includes understanding of and
commitment to the cooperative nature of this program. If an applicant institution
elects to submit applications for both an RMU and the DCC, they must be separate
applications, appropriately  labeled, with different personnel and separate
budgets.

Any competing renewal application should include in the progress report a
description of how the site has met the special cooperative agreement Terms and
Conditions of the award, including its interaction with other Network sites and
the NICHD Research Coordinator.

Budget Preparation

The instructions for budget estimates provided with the research grant
application form (PHS 398, revised 4/98) should be followed.  Facilities and
administrative costs will be awarded in the same manner as for research project
grants (R01).  Budgets will be reviewed on the basis of appropriateness for the
work proposed.  Allowable costs and policies governing the research grants
programs of the NIH will prevail.  In planning the budget section of the
application, each applicant should submit budget estimates for all years
including estimates of staffing needs.

Since the details of study requirements will not be known at the time of
application, however, it is understood that requested budgets will be estimates. 
Therefore, funding levels at the time of award will be negotiated between the
grantee institutions and the NICHD.

In the first year, support should be requested for the Principal Investigators
to travel to meetings required for initial activities:  joint identification of
topics, the development of protocols, and the design of data gathering
instruments.

The first year budget should also request partial year support for new protocol
start-up costs, to begin after the  above  initial tasks have been completed, as
well as completion of studies that may have been approved during 1999 or 2000. 
A composite for all these activities might include the following:  a full-time
research nurse/study coordinator; fractional-time senior investigator;
fractional-time data entry specialist; fractional-time technician; clinical
testing expenses; travel expenses covering four meetings in Bethesda, Maryland
for the Principal Investigator; one trip each for nurse coordinator, data entry
specialist,  and technician training; and justifiable supplies and "other"
expenses.

The budget proposal for future years should include estimated costs of
participating in a study such as the proposed "concept" protocol (new
applications), or ongoing trial activities (competing applications) including
personnel costs similar to the first year, plus subject recruitment costs and
travel for the Principal Investigator to three Steering Committee meetings per
year in Bethesda.

The RFA label available in the PHS 398 (rev. 4/98) 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 Multicenter Reproductive Medicine Network, and number, HD-99-005, 
must be typed on line 2 of the face page of the application form and the YES box
must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7910
BETHESDA, MD 20892-7910
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application must be sent
to:

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

Applications must be received by July 22, 1999.  If an application is received
after that date, it will be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The CSR
will not accept any application that is essentially the same as one already
reviewed. This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NICHD.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  Any application that
does not meet the minimum requirements of this RFA will be considered
unresponsive to the RFA and returned to the applicant.

Applications that are complete and responsive to the requirements stated in this
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 by the
scientific review group in which applications will be determined to be
competitive or non-competitive based on their merit relative to other
applications received in response to this RFA.  Applications judged to be non-
competitive by the review committee will be withdrawn from further consideration. 
However, the Principal Investigator will receive a summary statement reflecting
the critiques of the reviewers.  Applications judged to be competitive will be
discussed and assigned a priority score, and will receive a second level review
by the National Advisory Child Health and Human Development (NACHHD) Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In the
written comments reviewers will be asked to discuss the following  aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning  the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

(1) Significance (New RMU applications only):  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?

(2) Approach (New applications only):  Are the conceptual framework, design,
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?

(3) Innovation (New applications only):  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?

(4) Investigator:  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the Principal Investigator and other researchers (if any)?

(5) 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?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their subgroups,
and children as appropriate for the scientific goals of the research.  Plans for
the recruitment and retention of subjects will also be evaluated.

o The reasonableness of the proposed budget and duration in relation to the
proposed research.

o The adequacy of the proposed protection for humans, animals or the environment,
to the extent they may be adversely affected by the project proposed in the
application.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.

Specific Additional Criteria for Review of RMU Applications:

a.  Qualifications, Experience, and Commitment of Key Personnel:

o Scientific, clinical, and administrative abilities of the Principal
Investigator and other team members;

o Knowledge and experience in areas relevant to the conduct of potential studies
utilizing clinical and laboratory evaluation of patients with reproductive
disorders;

o Commitment of staff time for the satisfactory conduct of the study;

o Experience and qualifications of team members who would be responsible for
internal coordination of data management.

b.  Protocols and Procedures

o Ability of the applicant to meet the objectives of the Network as outlined in
this RFA;

o Willingness to work and cooperate with other RMUs and the NICHD in the manner
summarized in this RFA;

o Quality of the RMU's participation in Network protocols during the current
grant period (competing renewal applicants); OR

o Quality of the proposed "concept" protocol designed to be undertaken by the
Network (new applicants only).

c.  Facilities and Management

o Adequacy of administrative, clinical, and data organizational management
facilities as described in the minimum requirements;

o Institutional assurance to provide support to the study in such areas as fiscal
administration, personnel management, space allocation, procurement, planning and
budgeting.

Additional Specific Criteria for Review of Data Coordinating Center

a.  Qualifications, Experience, and Commitment of Key Personnel:

o Scientific and administrative abilities of the Principal Investigator and other
team members;

o Experience of the Principal Investigator and other key personnel in
statistical, data management, quality control, study coordination, and
administrative aspects of multicenter clinical studies;

o Commitment of staff time for satisfactory conduct of the study;

o Understanding of the scientific objectives and design of the program, as
evidenced by discussion of design, recruitment and implementation issues.

b.  Protocols and Procedures

o Proposed data collection and monitoring system;

o Discussion of ability to meet proposed timetables;

o Willingness to work cooperatively with the RMUs and the NICHD, in the manner
summarized in this RFA.

c.  Facilities and Management

o Satisfactory facilities and supporting environment, including space and
equipment for the work proposed (any new equipment requested under this award
must be strongly justified);

o Evidence of institutional support for participation in a long-term
collaborative program.

Schedule

Letter of Intent Receipt Date:  June 1, 1999
Application Receipt Date:       July 22, 1999
Peer Review:                    October/November 1999
NACHHD Council Review:          January 25, 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, including in this instance sufficient compatibility of
features to make a successful collaborative program a reasonable likelihood; and
availability of funds.

INQUIRIES

Written, e-mail 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:

Donna L. Vogel, M.D., Ph.D.
Reproductive Sciences Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-6515
FAX:  (301) 496-0962
Email:  dv1h@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Melinda Nelson
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5482
FAX:  (301) 402-0915
Email:  mn23z@nih.gov

AUTHORITY AND REGULATIONS

This Program is described in the Catalog of Federal Domestic Assistance number
93.121, 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 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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