Full Text AI-92-13

WOMEN AND INFANTS TRANSMISSION STUDY (WITS II)

NIH GUIDE, Volume 21, Number 36, October 9, 1992

RFA:  AI-92-13

P.T. 34, AA, II

Keywords: 
  AIDS 
  Infectious Diseases/Agents 
  Epidemiology 
  Diagnosis, Medical 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  October 26, 1992
Application Receipt Date:  January 14, 1993

PURPOSE

The Vaccine Trials and Epidemiology Branch of the Division of AIDS
(DAIDS) of the National Institute of Allergy and Infectious Diseases
(NIAID) announces a Request for Applications (RFA) for funding the
continuation of the Women and Infants Transmission Study (WITS).  The
purpose of this RFA is a competitive renewal of WITS I, a multi-site
epidemiologic cohort study of HIV infected pregnant women and their
offspring.  New sites not participating in WITS I are encouraged to
apply, as are current WITS I sites.  Specific aims are:  (1) to
assess the effects of pregnancy on HIV disease progression, (2)
determine maternal cofactors related to maternal-infant transmission
and timing of transmission, (3) assess early diagnostic techniques to
identify HIV-infected fetuses and infants, (4) evaluate the natural
history of HIV infection among infants during an era of
antiretroviral and other therapeutic modalities, and (5) assess the
feasibility of future vaccine trials in this population.

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 RFA,
Women and Infants Transmission Study (WITS II), 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, laboratories, units of State and
local governments, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Applicants funded under this RFA will be supported through National
Institutes of Health (NIH) Cooperative Agreements (U01).  Cooperative
Agreements are awarded to institutions to encourage
investigator-initiated research in areas of special importance to the
NIH and if substantial programmatic involvement by NIH staff is
anticipated.  The interaction of NIAID staff with the investigators
is expected to assist and facilitate the research.  There is no
intent, real or implied, for staff to direct a research site's
activities or to limit the freedom of investigators.  This RFA
solicitation represents a onetime competition for a four year award
with a specified deadline for receipt of applications.  Program
intents for extensions beyond the initial competitive segments are
uncertain.  If, by the end of the third year of award, NIAID has not
announced an intention to reissue the RFA, awardees who plan to apply
for continuing support should contact NIAID program officials for
advice on how to recompete.

FUNDS AVAILABLE

Approximately $5,000,000 will be available for funding the total
costs for the initial year of awards made pursuant to this RFA.
NIAID anticipates making four to eight 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
availability of funds.  Awards will be made for a 12-month budget
period within a total project period of four years.  Continuation of
funds for each new budget period will be contingent on availability
of funds and will be made on the basis of satisfactory performance in
the areas of recruitment, retention, success in carrying out the WITS
protocols, collaborative efforts with the other WITS sites, and
scientific productivity.  Annual progress reports will be required
and should include a report on scientific, recruitment, and technical
progress.  Funding adjustments may be made related to both study
performance and changing NIH research priorities.  The earliest
anticipated award dates will be July 1993.

Under a separate and distinct initiative, the National Institute of
Child Health and Human Development (NICHD) intends to independently
support one or more clinical sites.  Principal Investigators at those
sites will collaborate with the NIAID sponsored sites in planning and
carrying out the research agenda of WITS II.

RESEARCH OBJECTIVES

Background

The growing magnitude of the HIV epidemic among women of
child-bearing age and their infants is becoming apparent in many
areas of the United States.  The percentages of AIDS cases among
women and children are increasing more rapidly than for any other
risk groups.  In the 1990s, the AIDS epidemic will continue to attack
African American and Hispanic women and children in
disproportionately high numbers.  To date, more than 80 percent of
pediatric AIDS cases have been caused by maternal-infant
transmission.  Moreover, virtually all new cases of pediatric HIV
infection in infants and children will be due to maternal-infant
transmission.

In the face of this growing epidemic among women and their offspring,
there are a number of critical and unanswered questions related to
HIV infection during pregnancy and maternal-infant transmission.
These include the impact of pregnancy on the health of HIV-infected
women, mechanisms and timing of vertical HIV transmission, rates of
maternal-infant transmission (overall and among different
subpopulations of at-risk pregnant women), as well as understanding
cofactors related to HIV transmission.  In addition, major research
issues appropriate therapeutic interventions include:  (1) evaluating
the impact of prenatal and intrapartum, (2) determining as early as
possible which infants are HIV infected, (3) defining risk factors
associated with rapid progression of disease among infants, and (4)
understanding the natural history of pediatric HIV infection.

The scientific and medical complexity of conducting valid
epidemiologic studies of HIV-infected pregnant women and their
offspring, in a way that addresses these research questions, is
considerable.  For example, to address research questions regarding
maternal cofactors related to transmission, a cohort of approximately
1,000 pregnant HIV infected women and their offspring must be
recruited.  In addition, the laboratory techniques involved in HIV
research are complex and rapidly evolving, requiring research efforts
that can flexibly respond to expanding knowledge in this area.

The Women and Infants Transmission Study II will continue and expand
the Women and Infants Transmission Study (WITS I) that began in 1988.
WITS I is co-sponsored by the NIAID and the NICHD.  The current WITS
study is conducted at five sites:  a consortium of hospitals in the
Boston, Worcester, Massachusetts area administered by Brigham and
Women's Hospital in Boston, The Presbyterian Hospital in New York
City, The State University of New York Health Sciences at Brooklyn,
University of Illinois in Chicago, and University of Puerto Rico in
San Juan. Anticipated final accrual for WITS I includes 500 HIV
positive pregnant women, 400 infants born to these women, and 200 HIV
positive nonpregnant women.

WITS II will continue and expand this prospective natural history
cohort study of HIV positive pregnant women and their offspring.  It
will rely heavily on the core protocols already in place for WITS I,
but will also encourage new projects that may shed light on our
understanding of maternal-infant HIV transmission and early diagnosis
of fetal or infant HIV infection.  New applicants should have a copy
of the WITS I protocol summary and objectives of WITS I to aid them
in preparing the RFA application.  This information may be obtained
from Dr. Mary Glenn Fowler, at the address listed under INQUIRIES.

The research efforts of WITS II will complement a number of AIDS
Clinical Trial Group (ACTG) perinatal and pediatric clinical trials
currently underway or being planned.  WITS II will also complement
the Women's Interagency HIV Study funded by the NIAID and the Centers
for Disease Control, which is evaluating the natural history of
disease progression among HIV infected women.

WITS II will have three major foci:

o  Continued evaluation of maternal cofactors related to
maternal-infant HIV transmission including timing of transmission.

o  Assessment of promising early diagnostic techniques to rapidly
identify HIV-infected infants.

o  Determination of the natural history of HIV infection among
infants and children in an era of antiretroviral, prophylactic, and
immunotherapy. Identification of infants at risk for rapid HIV
disease progression will be an important element of this research.
This component will be accomplished through follow up of infants
currently enrolled in WITS I as well as infants born to pregnant HIV
positive women enrolled in WITS II.

Specific objective of WITS II are:

o  Determine maternal cofactors related to maternal-infant
transmission, including assessment of mechanisms and timing of
transmission.

o  Determine the impact of pregnancy on the natural history of HIV
infection among women through the post partum period, including
immunologic and virologic changes in pregnant HIV positive women.

o  Evaluate early diagnostic tests to determine infant HIV infection
status as rapidly as possible.

o  Determine the natural history of HIV infection among congenitally
exposed infants and children in light of antiretroviral,
prophylactic, and immune-based therapy.

o  Assess the feasibility of future vaccine trials in a cohort of HIV
infected pregnant women by evaluating their attitudes and potential
willingness to take part in future clinical vaccine trials for
themselves or their infants.

To achieve the objectives of WITS II, the NIAID seeks applicants to
help develop and carry out this continuing epidemiologic natural
history study of pregnant HIV women and their children.  New
prospective sites as well as current WITS I sites are encouraged to
apply.  The template for this study will be the research protocols
designed for WITS I, which includes a schedule of research visits
with designated evaluations and data collection instruments (medical
history questionnaires, physical exam forms, laboratory specimen
collection procedures).  In addition, specific new research studies
are also encouraged that may provide critical information directed
toward the primary research aims of WITS II.  Applicants who are not
current WITS sites may contact Dr. Mary Glenn Fowler (301/496-6177)
to obtain a summary of the research protocol and objectives of WITS
I.

The applicants for this RFA should provide information that
demonstrates scientific, technical, and operational capabilities to
plan, implement, and participate effectively in a multi-site
collaborative interdisciplinary research study.  These capabilities
will enable the applicant to respond to the urgent need to determine
factors related to maternal-infant transmission; identify early
diagnostic techniques to determine HIV status of infants; evaluate
the natural history of HIV infection among infants and children; and
assess feasibility of carrying out future vaccine trials.  The
application should demonstrate, at a minimum, the following
capabilities:

o  Recruit and retain at least 30 and ideally over 50 HIV pregnant
women and their children to fulfill the objectives of the WITS II
study (See Specific Instructions, Section 1, Accrual and Retention
Plan).  Women should be recruited as early in pregnancy as possible.
Demonstrated linkages with a Community Advisory Board will be
required and linkages with other community based groups are strongly
encouraged. (See Specific Instructions, Section 1, Linkages)

o  Carry out cohort studies of HIV infected pregnant women to
evaluate factors related to maternal-infant transmission; determine
mechanisms and timing of transmission; and assess early diagnostic
studies to determine HIV status of infants born to HIV positive
women.  This effort will involve refinement and continuation of the
current WITS I core protocols.

o  Implement follow up studies for the cohort of infants born to HIV
positive women who are enrolled in WITS I and WITS II.  Such studies
would include assessment of survival, morbidity, growth and
development, and quality of life for these children.  Depending on
the final selection of WITS II sites, successful new sites may
subcontract with some current WITS I sites, if these sites do not
recompete or secure a new award, to follow up infants currently
enrolled in WITS I.  Modification and refinement of existing WITS I
protocols will be the template for this follow up.

o  Propose budgets, based on per patient capitation costs, to carry
out the WITS protocols.

o  Carry out virologic, immunologic, and other laboratory studies
relevant to the WITS protocols either on site or through linkages
with an ACTU laboratory.  Laboratory evaluations carried out on site
must meet NIAID quality assurance requirements.

o  Coordinate and oversee specimen collection for the timely
processing, storage, and retrieval of laboratory specimens as needed
for WITS II studies.  This would include the ability to transfer
certain specimens to a central repository and transfer of other
specimens to designated labs for early diagnostic and other specific
laboratory studies.

Structural Arrangements of the WITS II Cooperative Agreement

WITS Steering Committee and Meetings

The WITS II Steering Committee (WSC) will develop general WITS
policies concerning subcommittee or working group structure and
membership, publications, access to data, interim data monitoring,
agendas for working group meetings, and developing and/or refining
WITS protocols.  Membership in the WSC will consist of one Principal
Investigator from each WITS study site; the Principal Investigator of
the Statistical and Clinical Coordinating Center (SACCC), which is
responsible for central data management of the WITS study; and a
program coordinator from the NIAID and the NICHD.  The WSC will be
chaired by an awardee Principal Investigator.  The Chief of the
Perinatal Transmission and Pediatric Section of the Vaccine Trials
and Epidemiology Branch of the NIAID will serve as the NIAID program
coordinator and the Special Assistant for Obstetrics in the
Pediatric, Adolescent, and Maternal AIDS Branch, NICHD will serve as
the NICHD program coordinator.  The Program Coordinators together
will have one vote on the WSC.  The program coordinators and SACCC
will assist in coordinating four WSC meetings per year in the
Bethesda, Maryland area to discuss and define research activities
with an agenda based on input from all WSC members.  At the WSC
meetings members will be responsible for suggesting and defining new
inter-institutional studies as offered by the applicants consistent
with Specific Instructions - Section 2 of the RFA, thus having been
peer-reviewed and evaluated.  The WSC will have a Publications
Subcommittee and Working Groups set up as part of the infrastructure.
Interim conference calls and/or meetings will be utilized by working
groups and subcommittees.

Data Access, and Publication

In addition to the standard reporting requirements currently in
existence for awardees of NIH research cooperative agreements, the
following apply:

It is the primary responsibility of the WITS Principal Investigators
to clearly state the objectives and approaches of WITS II, to plan
and conduct the research stipulated in WITS II, and to ensure that
the results obtained are analyzed and published in a timely manner.
The data obtained will be the property of the awardees.  The NIAID
and NICHD program coordinators will have access to the data generated
under these cooperative agreements and may periodically review the
progress by interim analyses.  Information obtained from the data may
be used by NIH program coordinators for the preparation of internal
reports on WITS activities.

WITS II publication policies will closely follow those established
for WITS I, with the Principal Investigators taking the lead role in
presentation and publication of scientific data generated by the WITS
study.  Specific publication policies will cover combined data from
WITS I and WITS II, and will ensure that both WITS I and WITS II
investigators contributions as well as those of the NIH program
coordinators and the SACCC are appropriately acknowledged in terms of
authorship and publications.  All published (abstracts, peer reviewed
manuscripts, reviews) and oral presentations of work supported in
part or in total by the cooperative agreement must be acknowledged in
the presentation and will include the mechanism, cooperative
agreement number and Institute; for example, "This work was supported
in part by the cooperative agreement number AI-92-13, NIAID."

WITS awardee institutions will generate data that will be submitted
to the SACCC.  The total database for the WITS core protocols will
include data from all funded sites.  The use and publication of the
data will be governed by policies established by the WITS
investigators through the WSC.  Final approval of publications will
be by the WSC.  Working groups and subcommittees such as a
publication subcommittee, will be established by the WSC to
coordinate efforts including, but not limited to, definition of
research questions of interest, analysis of data, and publication of
findings.

The WSC will determine at the completion of WITS II whether or not to
make the data from WITS II available to the public.  These data could
be made available through the National Technical Information Service.
Data requestors would be asked to explicitly acknowledge the WITS
research project and specific Principal Investigators or their
designees in any publication or presentation involving the WITS data.

Defined Working Relationship Within a Cooperative Agreement

Assistance via a Cooperative Agreement differs from the traditional
research grant in that in addition to the normal programmatic and
administrative stewardship responsibilities, the component awarding
the Cooperative Agreement anticipates substantial programmatic
involvement during performance of the project.  Within a cooperative
agreement, a partnership relationship exists between the recipient of
the award and NIAID.  Each party to this partnership within WITS II
will have rights and responsibilities as well as a defined working
relationship.  To be responsive to this cooperative agreement, an
applicant must indicate willingness to work collaboratively with
other WITS II investigators, with the assistance of the NIAID and
NICHD program coordinators, in carrying out the WITS II research
agenda.

Awardee rights and responsibilities

WITS II investigators will be responsible for overall conduct of the
study including design of new studies, patient accrual and retention,
production of high-quality data, and the analysis and publication of
the research findings.  WITS II investigators with the assistance of
NIAID and NICHD program coordinators will establish and serve on the
WSC and all working groups.

NIH rights and responsibilities

The NIAID and NICHD program coordinators, Chief of Vaccine Trials and
Epidemiology Branch of NIAID and the Chief of the Pediatric,
Adolescent and Medicine AIDS Branch, will assist the WITS II
Principal Investigators.  In addition, these coordinators, when
appropriate, may designate other NIH staff to offer specific
expertise on subjects determined by the WSC.  It is again emphasized
that the role of NIH will be to facilitate and not to direct the
activity of the WITS II investigators.

To ensure that the scientific research in WITS II is of the highest
caliber and is directed appropriately to meet the objectives of WITS
II, the NIH program coordinators may convene an external advisory
scientific panel to review the WITS II protocol within the first year
of the study.

SPECIAL REQUIREMENTS

Specific Instructions - Section 1

As part of items 1-4 of the research plan of PHS Form 398, applicants
for the RFA awards should demonstrate the following minimum
requirements

Proficiency in conduct of epidemiologic research or clinical trials
(5 page limit recommended)

The applicant should describe the extent and scope of previous
experience in carrying out epidemiologic or clinical trial studies;
complications for women, infants and children and participation or
capability to participate in multi-site clinical studies.  The
following should be done to permit an evaluation of performance:

o  Describe the epidemiologic research or clinical trials experience
of key personnel in terms of kinds of studies and numbers and
description of patients.

o  For current WITS sites, describe the total accruals to date, from
the beginning of the study to the present, missed visits and
retention data.  In addition, applications from current WITS I sites
should include information on data forms completion rates, data entry
turn around time, and information on proportion of required
repository specimen volumes that were actually collected, summarized
across all patients by visit.  For new sites, describe the
anticipated potential accrual per year of pregnant HIV infected
women.

o  Describe the level of scientific contribution in such studies
(i.e., protocol design, cooperative efforts in carrying out the WITS
protocols, oversight, handling of laboratory specimens, data
management, publication contributions).

o  Describe the capability and willingness to administer a
subcontract to follow up infants and children from the WITS I cohort
who might be enrolled at a WITS I site that did not successfully
recompete for WITS II.  Assume semi-annual visits including physical
and neuropsychological evaluations, and immunologic and virologic
laboratory studies.

Organizational Structure for Conduct of Epidemiologic or Clinical
Trials (6-page limit recommended)

The applicant should detail the essential features present at their
site for the performance of multi-site clinical studies, including
qualifications of key personnel and facilities. The narrative must
specifically address the following:

o  Personnel - describe in detail, the qualifications of other staff
(other than those key personnel already mentioned above in 1a), who
would help conduct the study, as well as personnel for delivery of
ancillary services.  Culturally sensitive individuals reflective of
local demographics should be represented among key staff as well as
personnel for ancillary services.

o  Facilities - describe facilities and resources available for
conducting the clinical studies and ancillary services (e.g.,
obstetrical, perinatal, and pediatric care facilities, outreach and
social services, child care, transportation).

Accrual and Retention Plan (6-page limit recommended, plus supporting
letters)

Applicants should document the capability to access a population of
HIV pregnant women and their offspring.  The applicant should
document their potential ability to recruit a minimum of at least 30
and ideally 50 or more pregnant HIV infected women in the first year,
a number that will help define the size of the first year budget.
Especially useful is an assessment of local data derived from HIV
prevalence newborn screening surveys.  The application should
describe:

o  The primary source(s) of WITS study subjects.

o  The demographic features of the HIV-positive pregnant women in the
catchment area including HIV seroprevalence data, race/ethnicity, and
risk transmission categories.

o  A plan for outreach to pregnant HIV women, including strategies
for interaction with community health care providers or agencies that
are likely to lead to referral of HIV-infected pregnant women into
the WITS study.   The number, background, and experience of staff who
are culturally sensitive to the needs of these women should be
described and provisions made for training to increase the
sensitivity of WITS staff.

o  Policies and procedures for accessing referral patients, such as
communication, provision of ancillary services, outreach and
non-study related care, follow-up by research staff or primary care
providers, and amount of primary care provided by the research study
staff to the populations, should be mentioned.  Letters of agreement
to document, describe, and support interactions with specific
referral sites must be provided.  All applicants should present a
plan to provide or refer WITS enrollees for comprehensive clinical
care including substance abuse treatment when appropriate.

Linkages (5-page limit recommended, plus supporting letters)

The following support linkages are either REQUIRED as specified or
strongly ENCOURAGED when not specified:

o  Community Advisory Board (REQUIRED).  A Community Advisory Board
(CAB) associated with each site should be established within two
months of award.  The purpose of the CAB is to foster interaction
between the WITS personnel and HIV infected individuals in the
community, community health providers, community leaders, and
advocacy groups.  (If an appropriate CAB is already in place, it is
not necessary to establish a separated CAB for the WITS).  Applicants
may contact the WITS NIAID Program Coordinator, Dr. Mary Glenn
Fowler, 301-496-6177, to clarify any questions regarding the CAB.

o  AIDS Clinical Trials Unit (ACTU):  An establishment of linkage
with a ACTU funded by the NIAID or the NICHD, if one is located
within the same geographic area, is encouraged, and a letter of
agreement describing the relationship should be included. (See
Appendix 1 for listing).

o  Clinical Programs for Clinical Research on AIDS (CPCRA):  An
establishment of linkage with a CPCRA site if one is located within
the same geographic area is encouraged, and a letter of agreement
describing the relationship should be included.  (See Appendix 2 for
listing).

o  General Clinical Research Center (GCRC):  Applicants from
institutions that have a GCRC funded by the NIH National Center for
Research Resources are encouraged to identify the GCRC as a resource
for conducting the proposed research.  A letter of agreement from
either the GCRC Program Director or the Principal Investigator should
be included with the application.  (See Appendix 3 for listing).

o  Research Centers at Minority Institutions (RCMI):  An
establishment of linkage with an RCMI- funded or cofunded by the
NIAID, if one is located within the same geographic area, is
encouraged, and a letter of agreement describing the relationship
should be included.  (see Appendix 4 for listing)

o  Centers for AIDS Research (CFAR):  An establishment of linkage
with a CFAR funded by the NIAID, if one is located within the same
geographic area, is encouraged and a letter of agreement describing
the relationship should be included.  (See Appendix 5 for listing)

o  National Institute on Drug Abuse (NIDA) Treatment and Research
Centers:  An establishment of linkage with a NIDA project, if one is
located within the geographic area, is encouraged, and a letter of
agreement describing the relationship should be included.  (See
Appendix 6 for listing)

o  American Foundation for AIDS Research Community-based Clinical
Trials (CBCT) Network:  An establishment of linkage with a CBCT, if
one is located within the geographic region, is encouraged, and a
letter of agreement describing the relationship should be included.
(See Appendix 7 for listing)

o  AIDS Vaccine Evaluation Group (AVEG, NIAID):  An establishment of
linkage with an AVEG funded by NIAID, if one is located within the
same geographic area, is encouraged and a letter of agreement
describing the relationship should be included.  (See Appendix 8 for
listing)

o  Health Resources Services Administration (HRSA) AIDS Demonstration
Project:  An establishment of linkage with a HRSA AIDS Demonstration
Project, if one is located within the same geographic area, is
encouraged, and a letter of agreement describing the relationship
should be included.  (See Appendix 9 for listing)

Applicants are encouraged to form other linkages, including, but not
limited to, community-based organizations that serve populations at
increased risk for HIV infection, designated State/County/Public
Health AIDS Centers, and community-based AIDS clinics.  A letter of
agreement for each linkage should be included with the application.

All letters of agreement should be explicit about the intended
purpose and role of the collaborating site or organization,
referencing prior successful collaborations.

Laboratory Capabilities (5-page limit recommended)

Applicants should demonstrate a capability to collect and process
blood and cervical specimens for laboratory analyses including, but
not limited to, immunology, virology assays and cultures, cervical
cultures, serology, chemistry, and hematology studies.  This
capability could be either in the applicants' own laboratories, by a
ACTG-certified laboratory, or other laboratories likely to be deemed
suitable by peer reviewers and by NIAID staff.  Funds will not be
provided to support equipment, personnel, or facilities for the
establishment of new laboratories, although funds may be requested
for supplementary equipment at existing laboratories.  Detailed
justification is required.  Awardee laboratories will be required to
participate in a quality assurance (QA) program supported by the
NIAID.

A key part of the WITS protocols includes collection, transfer, and
storage of designated laboratory specimens (urine and blood samples)
at a central NIAID-supported specimen repository.The purpose is to
permit future nested studies in which technologies, sample sizes, or
hypotheses are not currently known or available.  Applicants should
indicate in their application (1) their agreement to transfer
designated specimens; (2) describe their abilities to collect, store,
and transfer required quantities of designated specimens to a central
repository; and (3) their experience in similar activities.

Data Coordination (5-page limit recommended)

The WITS will be assisted by a Statistical and Clinical Coordinating
Center (SACCC), contracted by the NIAID to provide extensive
technical and logistical support for data analyses.  This contract
will:  (1) provide statistical leadership; (2) establish and
administer an effective and responsive data management system; (3)
design and implement educational/training assistance to WITS
investigators and quality assurance with respect to WITS data; and
(4) facilitate communications, meetings, conference calls,
publications, and study-related coordination between the clinical
sites and the government.

Applicants should present capabilities to do either (a) on-site data
entry using SACCC-produced data entry modules or (b) photocopying and
sending data collection instruments and sending them to the SACCC for
data entry.  If specific required hardware/software equipment for
data entry is not available at an applicant site doing on-site data
entry, it may be proposed in the budget.  However, applicants are
strongly encouraged to use existing facilities and data entry
equipment already available to them at their site.  For on-site data
entry, computer tapes or diskettes that contain files of the site
data will be sent to the SACCC.  Inconsistencies found by the SACCC
and reported to the sites will be the responsibility of the sites to
resolve, irrespective of whether sites enter their own data or send
hard copies to SACCC for data entry.  The SACCC staff will support
the WITS investigators in their analyses of the findings from WITS
II.  Each applicant will be sent a copy of the Request for Proposals
for the SACCC so that the applicant can be aware of the full range of
services to be provided by the SACCC.

Specific Instructions - Section 2 - Development Research Component
(Optional)

The essential research for WITS II will be based on refinement of the
WITS I protocols.  However, WITS II also wishes to encourage a
limited number of new research protocols to address the objectives of
WITS II in light of the most current scientific knowledge available.
Interested investigators may briefly describe (3-6 single spaced
pages) specific research projects that they would propose to be added
to WITS II that address specific research objectives of WITS II.
Research areas of particular interest to the NIAID include evaluation
of maternal-infant pairs with respect to genotypic sequencing, host
effects related to transmission, placental and other studies which
may shed light on timing and mechanisms of transmission, TB related
studies, new diagnostic studies that might identify HIV infected
infants in the newborn period or prenatally; and HIV vaccine
feasibility studies.  Applicants responding to this optional section
should also complete a separate budget for this section using pages 3
and 4 of the budget section of PHS 398 application form (rev.9/91).
Although the scientific merit of applications in this section will be
peer reviewed and evaluated, this review will not be used in the
overall scoring of the application.

Specific Instructions for Preparing an Application Budget

This section supplements the instructions for preparing a grant
application form PHS 398 (rev. 9/91).  Applicant budgets should
follow the instructions contained in the PHS 398 (rev. 9/91) to
complete the budget pages for Sections 1 and for Section 2
separately.  In addition, for Section 1, applicants should include as
additional budgetary attachments, worksheets showing the breakdown of
separate budgets for the following components of the study:

o  A core budget that includes (1) personnel costs for the Principal
Investigator and other key personnel (study coordinator, research
assistant,); (2) travel for meetings to include four meetings of the
study Principal Investigators to be held in the Bethesda, Maryland
area, one national meeting, and one international meeting; (3)
supplies--laboratory, data management, and other supplies needed to
carry out the study; (4) community based efforts for recruitment of
pregnant HIV infected women.  Budgets should indicate funds allocated
for support of community based personnel who would help with
recruitment and retention, counselling and other logistic support.

o  Annual costs for recruitment and evaluation of pregnant women at a
site, based on total estimated accrual per year, number of visits per
year, clinical assessments, and laboratory costs per visit (See
Appendix 10 for specific information regarding number of visits,
costs anticipated for lab tests, and costs for shipping three urines
and two pap smears per patient per year).  Costs for ancillary
services such as transportation, child care, and incentive costs
related to patient visits should also be itemized in the budget
worksheet.

o  Annual costs for evaluations of the offspring born to the HIV
infected women enrolled in WITS II, based on total estimated accrual
per year, number of visits per year, staff, clinical and
neuropsychologic evaluations, and laboratory costs per visit.  (See
Appendix 11 for specifics on number of visits, and estimated costs
for laboratory tests).  Costs for ancillary services such as
transportation, child care,and incentive costs related to patient
visits should also be itemized in the budget worksheet.

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 are 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 must 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 both genders and all ages.  Because this RFA addresses
research on the effects of HIV infection among women and their
infants, many of whom are from minority race/ethnicity groups, it is
anticipated that women and minorities will be adequately represented
in applications for this RFA.

Because the research in this RFA is directed at the effects of HIV
infection on women and their infants, the noninclusion of adult males
in submitted proposals is justified.  The composition of the proposed
study population must be described in terms of racial/ethnic groups.
In addition, racial/ethnic issues must be addressed in developing a
research design and sample size appropriate for the scientific
objectives of the study.  This information must be included in the
application Under SPECIAL INSTRUCTIONS, STUDY POPULATIONS.
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 U.S.
racial/ethnic minority populations (i.e., Native American Indians or
Native Alaskans, Asian/Pacific Islanders, African-American,
Hispanics/Latinos).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as 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 PHS/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 may be exempted from
these usual PHS/NIH policies.  However, every effort would be made to
include human tissues from women and 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
as determined by NIAID program coordinator, the application will be
returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
minorities in the proposed study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population(s) is inadequate, it will be considered a
scientific weakness or deficiency in the study design and 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 components will not award
grants or cooperative agreement that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 26, 1992, 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 to provide an indication of the number and scope of
applications to be reviewed.  The letter of intent is not binding,
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:

Mary Glenn Fowler, M.D., M.P.H.
Vaccine Trials and Epidemiology Branch
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A24
Bethesda, MD  20892
(for express mail or courier, use Rockville, MD 20852)

APPLICATION PROCEDURES

The research grant application form PHS 398 (revised 9/91) is to be
used in applying for these cooperative agreements.  These forms are
available from most institutional offices of sponsored research; the
Office of Grants Inquiries, Division of Research Grants, National
Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD
20892, telephone 301/496-7441; and from the NIH program coordinator
named below.

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 AND INFANTS TRANSMISSION STUDY", RFA
AI-92-13 must be typed on line 2a 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, exact, single-sided photocopies, in
one package, to:

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

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

Dr. Dianne Tingley
AIDS Scientific Review Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C16
Bethesda, MD  20892

If sending the application by overnight mail or courier service use
"Rockville, Maryland 20852".

Applications must be received by both DRG and Dr. Tingley by January
14, 1993.  Applications received after January 14, 1993 will be
returned to the applicant without review.  If the application
submitted in response to this RFA is substantially similar to a grant
application already submitted to the NIH for review, but has not yet
been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of
identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
that is essentially identical to one that has already been 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.

Applications that are not received as a single package from the
Principal Investigator and that do not conform to the instructions
contained in PHS 398 (rev. 9/91) and the specific instructions
including the page guidelines to not exceed 32 pages for section 1 of
this RFA will be judged non-responsive and will be returned to the
applicant.

Upon receipt, applications will be reviewed by DRG staff for
completeness and NIAID staff for responsiveness.  Incomplete
applications will be returned to the applicant without further
consideration.  If the application is not responsive to the RFA,
NIAID staff will contact the applicant to determine whether to return
the application to the applicant or submit it for review in
competition with unsolicited applications at the next review cycle.

Applications may be triaged by a NIAID peer review group to determine
their relative competitiveness.  The NIAID will withdraw from further
competition those applications judged to be non-competitive for award
and will notify the Principal Investigator and institutional
official.  Those applications judged to be competitive will be
evaluated in accordance with the criteria stated below for
scientific/technical merit by an appropriate peer review group
convened by the AIDS Review Section, DEA, NIAID.  The second level of
review will be provided by the National Advisory Allergy and
Infectious Diseases Council in June 1993.  The earliest possible
award date is July 1993.

Applications will be evaluated for scientific merit including the
originality, feasibility, and technical excellence of the research
projects.

REVIEW CONSIDERATIONS

This application must be directed at and address the research
objectives identified in this RFA; that portion of the application
corresponding to this research plan should follow in form the
specific instructions given in this RFA.  The primary factors that
will be considered in the review of the application will be
demonstrated ability or potential to recruit adequate numbers of HIV
pregnant women into the study; capability to carry out the clinical
and laboratory studies of WITS II including commitment to a
multi-site research collaborative effort; and cost efficiency in
carrying out the research protocols.  The following specific factors
will be considered in the review of the application:

Section 1

o  Prior success or demonstrated potential of the applicant to
recruit adequate numbers of HIV pregnant women for the study.  (To be
competitive an applicant site should demonstrate the capability to
recruit and retain at least 30 and ideally over 50 HIV pregnant women
annually.)

o  Capability to carry out the clinical, and laboratory studies of
WITS II, including adequacy of available physical facilities to
accommodate conduct of physical examination, phlebotomy,
interviewing, counselling, neurodevelopmental testing of infants and
children, handling of laboratory specimens, and data management.

o  Potential for original research bearing on the research objectives
of WITS II.

o  The professional qualifications and the scientific expertise of
the Principal Investigator and key personnel in research areas
emphasized by the study.  This includes experience in multi-site
collaborative efforts and adequacy of proposed staffing levels to
meet the research objectives of the RFA.

o  The establishment and adequacy of community support linkages.

o  Evidence of institutional commitment to the study as demonstrated
by administrative experience and capabilities and listing of
resources that will be dedicated to the study.

o  Efficiency in terms of costing, and utilization of available
resources.

Section 2

Scientific merit of the proposed optional research study.

AWARD CRITERIA

Awards will be made on the basis of high scientific and technical
merit, adequacy of funds and program relevance.  However, after
applications have been approved by the National Advisory Allergy and
Infectious Diseases Council, NIAID staff reserve the right to give
consideration to the following factors in the final selection of
applications to be funded:  WITS II sites reflect the
racial/ethnicity and socioeconomic characteristics of the nation-wide
HIV epidemic among women and infants and reflect the HIV-AIDS
incidence/geographic distribution of the epidemic among U.S. women
and their infants.

INQUIRIES

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

Mary Glenn Fowler, M.D., M.P.H.
Vaccine Trials and Epidemiology Branch
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A24
Bethesda, MD  20892
Telephone:  (301) 496-6177
FAX:  (301) 402-1506 or (301) 480-5703

Direct inquiries concerning fiscal and policy issues to:

Jane Unsworth
Chief, AIDS Grants Management Section
Grants Management Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B25
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Direct inquiries concerning the review process and review
requirements to:

Dr. Dianne Tingley
AIDS Scientific Review Branch
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C16
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 Nos. 93.856 and 93.855.  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 Public Health Service Act 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.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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