From: kristoff@NET.BIO.NET (Dave Kristofferson)
Newsgroups: bionet.sci-resources
Subject: NIH Guide, vol. 21, no. 41, pt. 3, 13 November 1992
Date: 12 Nov 92 18:14:29 GMT
Distribution: bionet


$$XID RFA AI9212 AI-92-12 P1O1 *****************************************

WOMEN'S INTERAGENCY HIV STUDY

NIH GUIDE, Volume 21, Number 41, November 13, 1992

RFA:  AI-92-12

P.T. 34, II; K.W. 0715008, 0740075, 0411005, 0403004, 0785035

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 11, 1993
Application Receipt Date:  February 18, 1993

PURPOSE

The Vaccine Trials and Epidemiology Branch (VTEB) of the Division of
AIDS (DAIDS) of the National Institute of Allergy and Infectious
Diseases (NIAID) invites applications for cooperative agreements for
the establishment of a Women's Interagency HIV Study (WIHS) to
investigate the clinical, laboratory, and psychosocial impact of human
immunodeficiency virus (HIV) infection in women.  The WIHS will use a
multi-site, prospective study design to gather data on the clinical,
immunological and behavioral aspects of HIV infection and disease in
women.  This study will investigate the full spectrum of clinical
disease caused by HIV infection in women.  It also will seek to
determine the immunological factors and the cofactors which may be
associated with HIV disease progression in women.

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), Women's Interagency HIV Study, is related to
the priority area of HIV infection.  Potential applicants may obtain a
copy of "Healthy People 2000" (Full Report:  Stock No.017-001-00474-0)
or "Healthy People 2000" (Summary Report:  Stock No. 017-001-10473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic non-profit and for-profit
research institutions; public and private organizations such as
universities, colleges, hospitals or laboratories; units of State and
local governments; and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

Applicants must demonstrate the capability to recruit and maintain a
minimum of 300 HIV-infected women and 75 HIV seronegative women with
high risk behaviors for HIV; the proposed study cohort should reflect
the socioeconomic, racial, and ethnic female populations infected with
HIV in the US.

MECHANISM OF SUPPORT

Successful applicants funded under this RFA will be supported through
Cooperative Agreements (U01).  This type of funding mechanism is used
when it is desired to encourage investigator-initiated research
projects in areas of special importance to the NIAID and when
programmatic assistance and involvement of NIAID staff would be
beneficial to attain the desired research goals.  This RFA represents
a single competition with a specified deadline for receipt of
applications.  Reissuance of this RFA will be dependent on the state of
science and findings at the completion of this cooperative agreement as
well as the availability of funds.

It is estimated that the total annual cost for an awardee with a study
population of 300 HIV-seropositive women and 75 HIV-seronegative women
could approach $1,000,000.  It may be advantageous for applicants
(including institutional consortia) to recruit significantly more than
the minimum number of women when it would be cost effective.  Awards
will be made annually for a period of up to four years. Continuation of
funding for each new annual budget period will be contingent on
availability of funds, and will be based on satisfactory performance in
recruitment and retention, success in protocol performance, and
scientific productivity.  Annual progress reports will be required and
will include reports on recruitment, retention, and scientific
productivity.  Funding adjustments may be made based on study
performance and changing NIAID research priorities.

FUNDS AVAILABLE

Approximately $5,000,000 will be available for funding the total costs
of the WIHS during its initial year.  The earliest possible award date
is July 1993.

The NIAID anticipates making two to five awards as a result of this
RFA.  The final number of awards to be made is dependent upon receipt
of a sufficient number of applications of high scientific merit and the
continuing availability of funds.

RESEARCH OBJECTIVES

Background

The number of cases of Acquired Immunodeficiency Syndrome (AIDS)
diagnosed in women has increased rapidly since 1985. As of December
1991, more than 21,000 cases of AIDS in women had been reported to the
Centers for Disease Control (CDC) in sharp contrast to the
approximately 1,100 women reported by the end of 1985.  Approximately
100,000 American women are estimated to be infected with HIV-1.  These
numbers are expected to continue to increase throughout the 1990s.

Major deficiencies remain in understanding the clinical, immunological,
and virological spectrum of HIV disease and AIDS in women.
Gynecological manifestations of HIV infection have not been
sufficiently studied despite early results indicating their importance.
There is also a growing body of evidence that other female genital and
reproductive tract infections, such as vaginal candidiasis, pelvic
inflammatory disease (PID), syphilis, herpes simplex virus-2 (HSV-2),
and other sexually transmitted infections, are more severe and/or more
common in women with HIV-induced immune dysfunction than in comparable
groups of HIV-negative women.  The rate and pattern of decline of CD4+
cells and factors which affect immune function in HIV-infected women
have not been well-characterized.  On the basis of these early reports,
women-specific disease outcomes have been identified suggesting the
need for a large-scale prospective study of HIV infection and disease
in women to address the multiplicity of research questions within a
single research design.  Such information is critically important in
designing and interpreting medical intervention research including
trials of therapeutic interventions and vaccines. These data will be
important in designing programs to improve access to and use of medical
services by HIV-infected women.

The primary purpose of this RFA is to develop a cooperative multi-site
prospective epidemiologic study of the clinical, immunologic, virologic
and behavioral aspects of HIV disease progression in women.  The NIAID
and CDC have jointly developed an organizational working arrangement
for the HERS and for the transition phase incorporating the
NIAID-funded WIHS sites.  This organizational structure of an Executive
Committee and Working Groups is intended to enable the NIAID WIHS sites
expedite implementation of their cooperative agreements, while
protecting the autonomy implicit in an assistance mechanism.  The NIAID
continues to play an active role in facilitating the HERS.

The CDC and the NIAID have initiated the initial phase of this
interagency prospective study of HIV-infected and uninfected women
through the CDC's 1991 program announcement #115 (Federal Register,
vol. 56, no. 65, Thursday, April 4, 1991), the HIV Epidemiology
Research Study (HERS).  Cooperative agreements have been awarded by the
CDC to four clinical sites.  For purposes of clarity in this RFA
AI-92-12, the HERS sites will be referred to as the "CDC HERS sites",
though it should be understood that they are part of the WIHS
initiative.  Accordingly, awardees of this RFA will be referred to as
the "NIAID WIHS sites," and will be named by the WIHS Principal
Investigators themselves after the cooperative agreements are awarded.

A pilot study manual for this phase of the study has been developed by
the CDC, NIAID, the four currently funded clinical sites, and an
interim data center.  Pilot studies of draft data collection
instruments and procedures have been initiated including:  (1) study
subject identification and enrollment; (2) patient sociodemographic and
health history; (3) physical examination; and (4) laboratory specimen
collection and procedures.  The current version of these materials will
be provided to potential applicants upon written request to Dr. Sandra
Melnick, Division of AIDS, NIAID (see INQUIRIES for address and FAX
numbers).  A Request for Proposals (RFP) for a Statistical and Clinical
Coordinating Center (SACCC), which will support WIHS and other NIAID
prospective studies, has recently been announced.  So that applicants
for cooperative agreements under this WIHS RFA are aware of the
services to be provided by the SACCC, each prospective applicant will
also be provided with a copy of the statement of work from the SACCC
RFP.

When new sites are awarded under this RFA, the awardees will review the
study protocols to arrive at data collection procedures and instruments
compatible with those of the HERS sites, and contribute to the
development of new studies and procedures.  The final study design
could be a modular study design that may include both standardized
modules (separate study protocols on a particular topic, consisting of
standardized physical exam procedures and a questionnaire) to be used
at all CDC HERS sites and NIAID WIHS sites, as well as separate modules
for CDC HERS sites that differ from those modules used by the NIAID
WIHS sites.  During the course of the four-year study period, there may
also be modules carried out at a single site. Plans for such
site-specific modules are encouraged in this application (see
Site-Specific Research Studies).

Sample Size Goal

The goal of the entire WIHS research effort is 2,500 HIV-seropositive
women and a comparison group of 775 HIV-seronegative women who engage
in activities that place them at high risk of acquiring HIV.  The
following table shows the sample size goals for the NIAID WIHS sites
and the CDC HERS sites.

NIAID WIHS sites     CDC HERS sites        Total

1,700 HIV(+) women   800 HIV(+) women      2,500

375 HIV(-)           400 HIV(-)              775
high risk women      high risk women

2,075 women          1,200  women          3,275

RESEARCH OBJECTIVES

The overall objectives of WIHS are to:

o  Determine the spectrum and course of the clinical manifestations of
HIV infection in women, including those affecting the genital tract and
oral cavity.

o  Determine the pattern and rate of decline of CD4+ cells in women and
the relationship of CD4+ changes to other immunologic and virologic
parameter, and to the clinical manifestations of HIV.

o  Investigate factors (e.g., infectious, treatment-related,
nutritional, socioeconomic, drug-use related) that may delay or
accelerate HIV-induced immune dysfunction and specific manifestations
of HIV-associated clinical disease.

o  Study the factors influencing the length of survival and quality of
life of women with HIV infection.

Although the emphasis of this study is not on HIV transmission,
follow-up of the initially seronegative group of women will be
important to:

o  Determine the rate of incident HIV seroconversion and identify the
factors that may increase the risk of incident HIV infection among a
smaller cohort of high-risk women who are HIV-antibody negative at the
time of study enrollment.

o  Access the feasibility of HIV vaccine trial initiation in high-risk
HIV-seronegative women by assessing willingness to participate in
vaccine efficacy trials.

All applicants should provide plans and other evidence describing their
capability to participate in this multicenter collaborative study.  The
Research Plan should be based on the approaches the applicant would
take to participate in the WIHS including recommendations to refine the
draft HERS procedures being provided to applicants.  The Research Plan
should address separately three components of WIHS:

1.  Cohort Studies including

o  Recruitment, Retention, and Service Linkages.

o  Study Visits and Data Collection Including Interviews, Medical
Histories, and Physical Examinations.

o  Laboratory Specimen Collection, Testing, and Storage.

2.  WIHS Organization, Management, and Communications

3.  Site-Specific Research Studies

Each WIHS component is discussed separately in the following
paragraphs.

Cohort studies

o  Recruitment, Retention, and Service Linkages

The applicant should provide a recruitment and retention plan with
information regarding their access to, and ability to enroll and
retain, a minimum of 300 HIV-infected women and 75 HIV-uninfected but
high risk women into a prospective study of HIV-related disease
outcomes.  Adolescents (ages 15 to 18) may be recruited depending on
local Institutional Review Board (IRB) requirements and applicable
State laws. The suggested enrollment ratio of HIV-infected women to
uninfected high risk women is five to one.  Uninfected women should
meet criteria for high-risk of acquiring HIV infection including
current or recent injection drug or crack cocaine use and/or engaging
in high risk sex (e.g., as a commercial sex worker, as a sexual partner
to an injection drug user, and/or engaging in frequent heterosexual
encounters that are not for money).  Applicants should demonstrate
their capability to enroll at least 300 HIV infected women and 75
uninfected high risk women by 18 months.  At least 50 percent of the
HIV infected women should be in later stages of HIV disease.  The
applicant's recruitment and retention plan should address the following
elements:

o   Plans for community outreach, screening for cohort enrollment, HIV
testing and counseling, and informed consent.

o   Evidence of capability to work with women who have substance abuse
problems.

o   Identification of sources of study subjects, e.g., inpatient or
outpatient units providing primary care or substance abuse treatment,
HIV clinics and testing sites, referrals from community-based
physicians or agencies, sexually transmitted disease clinics, and
community-based clinics.

o   Description of procedures for assistance with and referral for
non-protocol-related care.  A strategy for interaction with community
health care providers or agencies to handle referral of HIV-infected
women in this study should be incorporated into the application.  The
cultural, ethnic, and language expertise of the staff to interact with
community-based organizations and with women in their communities, or
alternatively, the ability of the staff to interact with
community-based organizations and with women in a culturally sensitive
manner, should be described.

o   Provision of a detailed and specific plan for retention of study
subjects, including, for example, a patient advocate or study nurse who
provides continuity of care at visits, a small cash award, or
reimbursement/vouchers for transportation expenses, on-site child care
arrangements, culturally sensitive research staff, etc. Collaboration
with community-based organizations is strongly encouraged to facilitate
retention of women, particularly from socioeconomically disadvantaged
backgrounds.

All applicants should describe how clinical care will be provided to
study participants, and describe the amount of primary care, if any,
that will be provided by the research study staff to the study
population.  Clinical care costs directly associated with the WIHS
protocols can be paid for under this award, when these are not covered
by other sources.  Proposed clinical facilities should have
demonstrated experience in providing services to, or effective referral
services for low-income cultural and ethnic minority groups and
chemically dependent women.

Applicants are encouraged to form linkages with other AIDS-related
studies and services.  Applications should include letters of agreement
in the application that should be co-signed by the Principal
Investigator of the applicant institution and each cooperating site.
All letters should be explicit as to the intended purpose and role of
the collaborating site or organization.  See Appendices 5-13 for
listings of contacts for AIDS-related services and studies, including:

Contact List                                        Appendix

AIDS Clinical Trial Units (ACTUs),
which comprise the AIDS Clinical Trials Group (ACTG)       5

Community Programs for Clinical Research on AIDS (CPCRA)   6

General Clinical Research Centers (GCRCs)                  7

Research Centers at Minority Institutions (RCMIs)          8

Centers for AIDS Research (CFAR)                           9

National Institute on Drug Abuse (NIDA)
  Cooperative Agreement Awardees                          10

American Foundation for AIDS Research (AmFAR)
  Community-based Clinical Trials Network                 11

AIDS Vaccine Evaluation Units (AVEUs) which comprise
  the AIDS Vaccine Evaluation Group (AVEG)                12

Health Resource and Services Administration (HRSA)
  Ryan White CARE Act Titles I & II Grantees              13

Applicants should describe plans for establishing, within two months of
award, a Community Advisory Board (CAB).  The purpose of the CAB is to
foster interaction between the WIHS staff and HIV-infected women in the
community, health care and other service providers, and other related
community-based groups.  (If an appropriate CAB is already in place, it
is not necessary to establish a separated CAB for this project).
Applications should describe the role and relationship of the CAB to
the applicant institution. Applications should also specify the
composition of the CAB, functions it will perform for the WIHS, and a
proposed meeting schedule.  Inclusion on the CAB of women, particularly
those representing minority populations, to reflect the demographics of
HIV-infected women in the catchment area may ensure representation of
concerns of community members and patient advocates.

o  Study Visits and Data Collection including Interviews, Medical
Histories, and Physical Examinations

The applicant should submit a plan for initial and follow-up study
visits.  As stated above, the enrollment goal is at least 300
HIV-infected women and 75 uninfected women in the first 18 months of
the study.  The applicant should assume that the final WIHS procedures
and data collection forms will be completed by the WIHS Executive
Committee and Working Groups (see "2.  WIHS Organization, Management,
and Communication" below) within the first nine months after award of
the WIHS cooperative agreements.

The applicant's plan should be based on (1) the six WIHS objectives
stated above and the associated suggested areas for study-wide data
collection stated in Appendix 2 to this RFA and (2) a review the HERS
study visit procedures and data collection instruments.  The
applicant's plan should address each of the six objectives and should
include the applicant's recommendations for refinement of these HERS
procedures and data collection instruments.

Based on the HERS pilot study materials and possible refinements, a
typical initial study visit could entail: (1) an interview;  (2) a
physical examination; (3) laboratory specimen collection;  and (4)
medical record extraction.  The applicant should address their plans
for conducting these initial visits as efficiently as possible.

The applicants should base their plans for follow-up visits on the
following considerations:  (1) follow-up visits should be conducted
every six months for all study participants;  and (2) additional
contacts (which may be short visits or phone calls) should be made to
collect data on major clinical events between the regular 6-month
visits for women who (a) have fewer than 350 CD4+ cells/ul at their
last 6-month visit, (b) have AIDS-related clinical conditions, and/or
(c) are pregnant.  The applicant should discuss potential approaches to
obtaining data between the regular six month visits.

In preparing their plans and budgets for study visits, the applicants
should consider possible attrition rates, reasons for attrition, and
the implications for the study and study budgets.

The applicant should assume that no study visits will be conducted
during the final six months of the four year award period; that six
month period will be devoted to ensuring that all study data have been
completed, validated, and submitted to the SACCC.

o  Laboratory Specimen Collection, Testing, and Storage

Applicants should submit a plan and budget for the collection and
processing of WIHS study specimens.  Certain specimens may be analyzed
at the clinical research site and funded through this cooperative
agreement.  Other specimens may be obtained and shipped to central
laboratories to establish consistency across sites.  Applicants should
review the draft HERS Laboratory Procedures and Data Collection
Instruments and two appendices to this RFA: Appendix 3 for suggested
components of the Laboratory Protocol and Appendix 4 for local and
central processing of specimens (Appendix 4 is a summary of information
from Appendix 3).  Awardee laboratories will be required to participate
in a quality assurance (QA) program.

Funds are not available in this RFA for new laboratory equipment or for
the expansion of facilities.  Applicants are encouraged to make
arrangements with other institutions if necessary to have adequate
laboratory capabilities.  The laboratory studies plan should provide
documentation of the following:  (1) prior experience with each
proposed laboratory procedure; (2) facilities available for performance
of laboratory procedures; (3) current quality assurance programs; (4)
experience with multi-institutional prospective studies; and (5)
facilities and processes for the storage and shipment of study
specimens.

The applicant's budget should be based on the information in RFA
Appendices 3 and 4 and in the HERS draft procedures and data collection
instruments.  The applicant should address possible changes or
improvements in the laboratory efforts that could be incorporated into
WIHS with the approval of the WIHS Executive Committee.

Site-specific research studies

Access to significant numbers of clinical specimens from
well-characterized study subjects will be a important resource for the
support of research studies of HIV and AIDS-related issues.  Applicants
should propose site-specific research studies that will investigate
issues associated with one or more of the major objectives of WIHS
(stated above) and the associated suggested areas for study-wide data
collection presented in Appendix 2 of this RFA.  These proposed
research studies should take advantage of samples and data generated
under the WIHS protocols.  Research that does not require the use of
WIHS samples, WIHS data, or WIHS study subjects will not be supported
by this RFA; applicants for such research are encouraged to seek
funding through other funding sources and mechanisms.

SPECIAL REQUIREMENTS

Terms and conditions

Special Requirements Under the Cooperative Agreement

Successful applicant(s) funded under this RFA will be supported through
Cooperative Agreements.  Within a cooperative agreement, a partnership
relationship exists between the recipient of the award and the NIAID.
Each party to this partnership within the WIHS will have rights and
responsibilities as well as a defined working relationship.

Awardee Rights and Responsibilities

The WIHS Principal Investigators will be responsible for directing the
research efforts of the WIHS, as well as the conduct of the studies
performed at their respective clinical sites.  As a group (the
Executive Committee), WIHS investigators will identify scientific
objectives and research hypotheses, arrive at mutually-agreed upon data
collection instruments and physical exam protocols, and verify that the
data collection instruments will meet the objectives and produce high
quality data. Investigators will implement the protocols and the data
collection instruments, and be responsible for ensuring patient
accrual.  WIHS investigators will hold leadership positions in the
Executive Committee, on the Working Groups, and ad hoc committees,
thereby providing the direction for the study. These responsibilities
will also include overseeing study design, data analyses, and
presentation of results according to Executive Committee policies.
WIHS site performance during each budget period will determine the
subsequent budget awards.

Applicant institutions are reminded that adequate protection for human
subjects in research is an essential requirement for the NIH.  Awardee
institutions, each subordinate entity to the Awardee, and each
performance site, whether institutions or independent investigators,
should agree that the rights and welfare of human subjects involved in
research under this cooperative agreement shall be protected in
accordance with 45 CFR 46.  As a condition of award, not as a condition
of application, applicants and affiliated performance sites are
required to designate an Institutional Review Board (IRB) and possess
an applicable assurance of compliance which has been approved by the
Office for Protection from Research Risks (OPRR) of the NIH. Applicants
will be notified if additional information is required on this matter.

NIAID Rights and Responsibilities

The NIAID staff will assist the WIHS Principal Investigators through a
Program Official who will be designated by the Chief of the Vaccine
Trials and Epidemiology Branch of NIAID's Division of AIDS.  The NIAID
Program Official will have overall responsibility to assure the
scientific and technical integrity of the project on behalf of the
Institute.  It is again emphasized that the role of NIAID will be to
act as a facilitator and not to direct the activities of the WIHS
investigators.  It is anticipated that decisions aimed towards
achieving the research objectives of the WIHS project will be made by
the Executive Committee.

NIAID staff will assist the WIHS awardees by

o  Providing scientific and technical assistance in the development of
research plans, data collection methods, analyses and reporting.

o  Providing technical support in areas including statistical and data
collection, analysis, and publication through the SACCC.

o  Providing logistical and other support services for meetings of the
Executive Committee and Working Groups.

o  Preventing duplication of efforts among WIHS sites, other WIHS
grantees, and other related NIAID projects by overseeing efforts of all
the sites, and other NIAID projects.

o  Coordinating research reagents and technologies used by WIHS sites
to achieve standardization.

The NIAID will establish an arbitration process to resolve any
difference of opinion between the awardee and the NIAID with regard to
programmatic decisions on scientific-technical matters.  An arbitration
panel, composed of one WIHS awardee designee, one NIAID designee, and
a third designee with expertise in the relevant area and chosen by the
other two, will be formed to review any scientific or programmatic
issue that is significantly restricting progress.  While the decisions
of the Arbitration Panel are binding, these special arbitration
procedures will in no way affect the awardee's right 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.

Cooperative Agreements are subject to the administrative requirements
outlined in OMB circulars.  All pertinent HHS, PHS, and NIH grant
regulations, policies and procedures, with particular emphasis on PHS
regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Parts 74
and 92, are applicable.  These special terms and conditions pertaining
to the scope and nature of the interaction between NIAID and the
investigators will be incorporated in the Notice of Grant Award.
However, these terms will be in addition to, not in lieu of, the
customary programmatic and financial negotiations which occur in the
administration of cooperative agreements.

WIHS Organization, Management, and Communication

The planned organizational structure for WIHS and the current
organizational structure for HERS are presented in Appendix 1 to this
RFA.  In that appendix, the roles of the Executive Committees and
Working Groups for both WIHS and HERS are outlined.

Executive Committee.  To ensure that the WIHS addresses questions of
the highest scientific priority and to provide leadership and direction
for the study, WIHS Principal Investigators, and the NIAID WIHS Program
Official will be members of the Executive Committee with voting
privileges. The Principal Investigator from the SACCC and one program
official from each Federal agency contributing funds to the project
will participate as ex officio members of the Executive Committee.
This organizational structure of an Executive Committee and Working
Groups is intended to enable the NIAID WIHS sites to expedite
implementation of their cooperative agreements while protecting the
autonomy implicit in an assistance mechanism.

The Executive Committee will develop general WIHS policies concerning:
subcommittee or Working Group structure and membership; publications;
access to data; interim data monitoring; agendas for group meetings;
protocol and questionnaire development; evaluation of WIHS performance;
and schedule and content of WIHS meetings.  Most importantly, the
Executive Committee will be charged with the establishment of overall
scientific priorities.

Working Groups.  Within this cooperative framework, clinical staff may
participate in study-wide Working Groups and contribute to the broader
study goals outside of the sphere of their own clinical center.  These
Working Groups will have responsibility for the development of a
research agenda for specific topic areas, for developing and modifying
modules (specific clinical physical examination and laboratory specimen
collection procedures) to address that agenda, assess the progress in
specific topic areas, and publish the results of collaborative study
findings.  These activities will be conducted according to procedures
and standards developed and/or overseen by the Executive Committee.
While the CDC HERS sites and NIAID WIHS sites will each have their own
Executive Committee, it is the intention of NIAID and CDC Program
Officials to encourage the merger of the two Executive Committees, or
develop other collaborative arrangements, as soon as is practical and
desirable.

Applicants should review the material in Appendix 1 with particular
reference to the Working Groups which have been established for the
HERS study.  Given the objectives and scope of WIHS, applicants are
requested to recommend Working Groups for WIHS, to state why these
specific Working Groups will be needed, and to identify which proposed
staff would be recommended as members of each Working Group.

Applicants are also asked to recommend an approach which could be taken
during the first nine months after the award of WIHS to use the
Executive Committee and Working Groups structure to develop final data
collection procedures and instruments.

Study-wide data management issues

Data Management and Study Coordination

The WIHS will be assisted by the SACCC, contracted by the NIAID, to
provide extensive technical and logistical support.  This contract
will:  1) provide statistical expertise and data analysis, in
conjunction with the Executive Committee; 2) establish and administer
an effective and responsive data management system; and 3) assist with
the design and implementation of educational and training activities
involving data quality assurance, including clinical training for the
staff performing physical examinations at the WIHS clinical sites.
Each applicant will be sent a copy of the work statement from the
Request for Proposals (RFP) for the SACCC so that the applicant can be
aware of the full range of services to be provided by the SACCC.

Applicants may plan for either:

o   On-site data entry, using a data entry module that will be
developed by the SACCC.  Computer tapes or diskettes containing files
of the data entered on site will be sent to the SACCC.

       OR

o    Central data entry by photocopying and retaining copies of
completed data collection instruments on site, and sending the
originals to the SACCC for data entry.

Inconsistencies discovered by the SACCC and reported to the sites will
be the responsibility of the sites to resolve regardless of whether
they elect on-site or central data entry.  Selection of either option
does not preclude the participation of the site investigators in any of
the above activities, including statistical analyses of their own data.

At a minimum, applicants should have equipment available for
computer-to- computer electronic mail communications and report
generation.  This equipment should be dedicated for WIHS-related
operations, and should include:

o  IBM compatible 386/33 microcomputer.
o  Monochrome or color VGA display.
o  Minimum of 40 megabyte hard disk, 2 megabyte memory, (dual 3.5" and
5" drives are recommended).
o  Hayes compatible 9600 baud modem.
o  Hewlett-Packard IIIP or comparable laser printer.
o  WordPerfect word processing software, version 5.1.
o  ProComm Plus or compatible communications software.

Reporting Requirements, Access to Data, and Publication of Research
Findings

In addition to the reporting requirements currently in existence for
awardees of traditional NIH research project grants, the following
apply:

o  Site-Specific Data

WIHS awardee institutions will generate data that will be submitted to
the SACCC as explained above.  In most cases, these institutional data
will represent a subset of the total database for a given protocol.
These data may have limited value or may have substantial independent
scientific value for specific research questions.  The WIHS Executive
Committee may establish policies encouraging or limiting publication of
such site-specific institutional data as appropriate for a given
circumstance.  These institutional data will remain the property of the
awardee.

o  Study-Wide Data

The total database for the WIHS core protocol will come from all funded
sites, including the HERS sites.  While physically located at the
SACCC, the use and publication of the data will be governed by policies
established by the Executive Committee.  Working groups will be
established to define research questions of interest, coordinate data
analyses, and determine publication policies and dissemination of
findings.

NIAID Program staff, in collaboration with the EC, (or Program staff
from other Federal funding agencies) may have access to data generated
under this cooperative agreement.  Information obtained from the data
may be used by NIAID for the preparation of internal reports on WIHS
activities.  However, the awardees will retain rights to the data.
Publication policies will be established by the Executive Committee.
Publication of major findings is the responsibility of the Executive
Committee in accordance with these policies.  Publication or oral
presentation of work performed under this agreement will require
appropriate acknowledgement of NIAID support.

Specific instructions

This section supplements the instructions for preparing a grant
application, form PHS 398 (rev. 9/91).  Additional information is
provided on the organization of the application to accommodate a
multi-component studies.  The cooperative agreement application should
be assembled and paginated as one complete application.

Research Plans

Separate research plans are required for each of the three WIHS
components:  (1) Cohort Studies; (2) WIHS Organization, Management, and
Communications; and (3) Site-Specific Research Studies.

o  Component 1 - Cohort Studies.  As part of items 1-4 of the Research
Plan section of the PHS 398 form, applicants should present their plans
for the required cohort studies including: (a) recruitment, retention,
and service linkages; (b) study visits and data collection; and (c)
laboratory specimen collection, testing, and storage (see pages 14-18
of the RFA).  This section may not exceed 20 pages in length.  A
separate PHS 398 page 2, titled "Component 1 - Cohort Studies", should
precede this section.

o  Component 2 - WIHS Organization, Management, and Communications.  In
place of items 1-4 of the Research Plan section of the PHS form 398,
applicants should present their plans for participation in central WIHS
activities (see RFA pages 21-22.  This section may not exceed five
pages in length.  A separate PHS 398 page 2, titled "Component 2 - WIHS
Organization, Management, and Communications" should precede this
section.

o  Site-Specific Research Studies.  For each proposed research study,
the applicant should complete the Research Plan section of the PHS 398
(see RFA page 18).  Items 1-4 of the Research Plan should be limited to
10 pages with emphasis on "1.  Specific Aims" and  "4.  Research Design
and Methods" since much of the background and significance will be
discussed in the cohort studies section of the application.  A separate
PHS 398 page 2, with the title of each proposed research study, should
precede each proposed study.

Budgets

An overall composite budget for all components of WIHS must be
submitted by the applicant on pages 4 and 5 of the PHS 398 form.  The
composite budget must be the sum of separate itemized budgets for each
component of WIHS; the itemized budgets for each component should
immediately follow the composite budget.  A separate itemized budget
(PHS 398 form pages 4 and 5, renumber appropriately) must be completed
for the following components of WIHS:

o  Cohort Studies.  The budget for the cohort studies should be based
on (a) the applicants proposed number of study subjects including
estimated retention rates; (b) the visits, exams, and laboratory
studies presented in the draft HERS protocols; (c) supplies to carry
out the study activities; and (d) computer equipment.

NOTE:  Budget justification should include a breakdown of laboratory
costs (i.e., cost per test).  On-site laboratory costs charged to this
grant must be the actual cost of the test.  Applicants must include
cost of shipping those tests that will be processed at a central
laboratory (see Appendix 4).

NOTE:  Although applicants are encouraged to recommend refinements in
the HERS protocols, the budget should be based on the current HERS
design.

o  WIHS Organization, Management, and Communications.  The budget for
this component should address personnel involved in carrying out study
activities, and travel/meeting information should be based on the
assumptions presented on pages 26 and 27 of the RFA.  Travel costs for
meetings other than those related to the conduct of the WIHS will not
be covered by this award.

o  Site-Specific Research Studies.  A separate budget must be prepared
for each proposed research study, using pages 4 and 5 of the PHS 398
kit (renumbered appropriately).

For budget purposes, applicants should assume the following:

Executive Committee.  While the actual number and scheduling of the
Executive Committee will be determined by the Principal Investigators,
for budgetary purposes, assume there will be two one-day meetings per
year of the Executive Committee during the first nine months of WIHS to
develop, review, and make final WIHS policies and procedures prior to,
or during the initial phase of, enrollment of the study subjects.
Assume that there will be a third one-day meeting of the Executive
Committee at the end of the first year of WIHS.   Assume that three of
the meetings will be held in Bethesda, MD and two will be held in
Atlanta, GA.  Assume that participants from each awardee will include
the Principal Investigator and one other senior staff member.

For the second through fourth years of WIHS study, assume there will be
three one-day Executive Committee meetings per year.  Assume that two
of the meetings will be held in Bethesda, MD and one in Atlanta, GA.

These meetings are intended to provide a forum for the Executive
Committee(s) and working groups (see below) to review research
findings, define research activities, and discuss and resolve issues.
Meetings will include the Principal Investigator and one other senior
staff member from each funded site.

Assume that the Executive Committee will also hold conference calls
twice monthly for the duration of the project.

Working Groups.  While the actual number and content of the Working
Groups will be decided by the Executive Committee, assume there will be
seven Working Groups.   Assume that each awardee will have one staff
member from his/her clinical sites on each Working Group.

During the first nine months of the WIHS awards, assume that each
Working Group will meet two times for two-day meetings; one meeting to
be held in Bethesda, MD and one meeting to be held in Atlanta, GA.
Although the purposes of these meetings will be specifically determined
by the Executive Committee,  the general goal will be to provide a
forum to review and discuss refinements and changes to the protocols
for approval by the Executive Committee.  Assume an additional two-day
meeting will take place at the end of the first year of the WIHS in
Bethesda, MD.

During the second through fourth years of the WIHS study, assume there
will be three two-day meetings annually of each Working Group.  In
addition, assume all working groups will hold conference calls twice
monthly.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and women
in study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to apply
to adult males and females.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population-based studies a clear compelling rationale should be
provided.

The composition of the proposed study population should be described in
terms of racial/ethnic group.  In addition, racial/ethnic issues should
be addressed developing a research design and sample sizes appropriate
for the scientific objectives of the study.  This information should be
included in the form PHS 398 in Sections 1-4 of the Research Plan AND
summarized in Section 5, Human Subjects.  Applicants are urged to
assess carefully the feasibility of including the broadest possible
representation of minority groups.  However, NIH recognizes that it may
not be feasible or appropriate in all research projects to include
representation of the full array of United States racial/ethnic
minority populations (i.e., Asian and Pacific Islanders, African
Americans/Blacks, Hispanics/Latinos, and Native Americans, which
includes American Indians and Alaskan Natives).  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include tissues from racial/ethnic
minorities when it is important to apply the results of the study
broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned without further review or
consideration by the NIH.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
minorities in a study design is inadequate to answer the scientific
question(s) addressed AND the justification for the selected study
population is inadequate, it will be considered a scientific weakness
or deficiency in the study design and will be reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding elements will not award grants or
cooperative agreements that do not comply with these policies.

NOTE:   This study fully meets the requirements for inclusion of women
because it is exclusively comprised of female subjects.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 11, 1993, a
letter of intent that includes a descriptive title of the proposed
research and the name, address, and telephone number of the Principal
Investigator; the identities of other key personnel and participating
institutions; and the number and title of the RFA in response to which
the application may be submitted.  The letter of intent is requested in
order to provide an indication of the number and scope of applications
to be reviewed.  The letter of intent does not commit the sender to
submit an application, nor is it a requirement for submission of an
application.

The letter of intent is to be sent to:

Dr. Sandra L. Melnick
Vaccine Trials and Epidemiology Branch
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building Room 2A28
6003 Executive Boulevard
Bethesda, MD  20892

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these cooperative agreements.  These forms are
available from the Office of Grants Inquiries, Division of Research
Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, Maryland, 20892, telephone 301/496-7441.

The RFA label available in the PHS 398 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,
WOMEN'S INTERAGENCY HIV STUDY, RFA AI-92-12 should be typed on line 2a
of the face page of the application form and the "YES" box should be
marked.

Submit a signed, typewritten original of the application, including the
checklist, and three signed, identical single-sided photocopies, in one
package, to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
5333 Westbard Avenue
Bethesda, MD  20892**

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

Dr. Dianne Tingley
Division of AIDS
Division of Extramural Activities
National Institutes of Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD  20892

Applications must be received by both the Division of Research Grants
(DRG) and Dr. Tingley by February 18, 1993. Applications received after
February 18, 1993 will be returned to the applicant without review.
The DRG will not accept any application in response to this
announcement that is virtually identical to one currently pending
initial review, unless the applicant withdraws the pending application.
The DRG will not accept any application that is essentially the same as
one already reviewed.  This does not preclude, however, the submission
of substantial revisions of previously reviewed applications which are
suitably tailored to the guidelines and requirements expressed in this
RFA.

Applications that are not received as a single package from the
principal investigator will be judged non-responsive and will be
returned to the applicant.  Applications must also conform to the
instructions contained in PHS 398 (rev. 9/91), with the exceptions that
the research plan and page length limitations for the usual grant
applications are modified as stated in the RFA.

Applications that do not follow the prescribed font sizes outlined in
form 398 will be judged non-responsive and will be returned to the
applicant.  Applicants should use standard, easily readable
printer/typewriter fonts; it is not in the self-interest of an
applicant to submit an application that is hard to read or that exceeds
the above page length limitations.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed DRG for completeness and by
NIAID review staff for responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is complete, but is judged not responsive to the RFA, it
will be returned to the applicant without further consideration, though
the applicant may then submit a revision, within page length
limitations of PHS 398 (rev. 9/91), for review as unsolicited,
investigator-initiated research at the next DRG review cycle.  A triage
may be performed by a peer review group to determine relative
competitiveness of applications responding to this RFA.  The NIH will
withdraw from further competition those applications judged to be
non-competitive for award and notify the applicant Principal
Investigator and institutional official.  Those applications judged to
be competitive for award will be evaluated in accordance with the
criteria stated below for scientific/technical merit by an appropriate
peer review group convened by the NIAID.  The second level of review
will be provided by the National Advisory Allergy and Infectious
Disease Council in June 1993.  The earliest possible award date is July
1993. The following criteria will be considered in the review of the
applications:

o  Demonstration of the applicant's willingness and capability to
participate in this multicenter study.

o  Adequacy of applicant's plan for achieving the recruitment and
retention goals.

o  Adequacy of the plans for linkages with and utilization of other
AIDS-related studies and services, including the requisite plans for
establishing or utilizing a Community Advisory Board.

o  Adequacy of applicant's plan for refining and implementing HERS
study visit procedures and data collection forms.

o  Adequacy of applicant's plan for collecting and distributing or
analyzing laboratory specimens.

o  Adequacy of applicant's plan for participation in central WIHS
activities (Executive Committee and Working Groups).

o  Adequacy of applicant's plan for any site-specific studies.
Applicant must demonstrate that each proposed site-specific research
study will use WIHS study participants, specimens, or data, alone or in
some combination.

o  The professional qualifications and the scientific experience of the
Principal Investigator and key personnel responsible for various
aspects of the clinical and research investigations proposed.

o  Adequacy of the administrative and organizational structure that
facilitates attainment of the objectives of the program, including
arrangements for internal quality control, allocation of funds,
day-to-day management, internal communications, and cooperation among
the investigators, contractual agreements, and replacement of the
Principal Investigator on an interim or permanent basis.

INQUIRIES

Direct inquiries pertaining to programmatic issues and for copies of
HERS materials and the statement of work from the SACCC RFP, and the
Appendices of the RFA to:

Dr. Sandra Melnick
Vaccine Trials and Epidemiology Branch
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2A28
6003 Executive Boulevard
Bethesda, MD  20892
FAX:  (301) 402-1506

Direct inquiries pertaining to fiscal and policy matters to

Ms. Jane Unsworth
Chief, AIDS Grants Management Section/GMB/DEA
National Institutes of Allergy and Infectious Diseases
Solar Building, Room 4B25
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Direct inquiries pertaining to the review process and review
requirements to

Dr. Dianne Tingley
Division of AIDS
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818
FAX:  (301) 402-2638

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.856, Microbiology and Infectious Disease Research and No. 93.855
Immunology, Allergic and Immunologic Diseases 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, 45 CFR Part 74, and 45 CFR Part 92.  This
program is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.