HIV PREVENTION TRIALS NETWORK LEADERSHIP GROUP

Release Date:  October 30, 1998

RFA:  AI-98-015

P.T.

National Institute of Allergy and Infectious Diseases
National Institute of Child Health and Human Development
National Institute on Drug Abuse
National Institute of Mental Health

Pre-Application Conference: November 23, 1998
Letter of Intent Receipt Date: November 30, 1998
Application Receipt Date: February 12, 1999

PURPOSE

The Division of AIDS (DAIDS) of the National Institute of Allergy and
Infectious Diseases (NIAID) requests applications for a Prevention Leadership
Group (PLG) for a proposed HIV Prevention Trials Network (HPTN) to conduct
clinical research on HIV prevention strategies.  This initiative is
cosponsored by the National Institute of Child Health and Human Development
(NICHD), the National Institute on Drug Abuse (NIDA), the National Institute
of Mental Health (NIMH).  The establishment of the HPTN will occur via two
solicitations: this RFA for a PLG and a later RFA for clinical sites that will
serve as HIV Prevention Trials Units (HPTUs).  The purpose of this RFA is to
solicit applications for a single PLG to plan and direct Phase I, II, and III
clinical trials for the prevention of HIV transmission both in the U.S and
internationally within a cooperative network of clinical trial sites (HPTUs).

The primary mission of the HIV Prevention Trials Network will be to conduct
research on promising biomedical and behavioral strategies for the prevention
of HIV transmission among at risk adult and pediatric populations.  The
research will include: (1) evaluation of a broad range of interventions
designed to reduce adult and perinatal transmission of HIV; and (2) basic
laboratory studies which address viral and host factors related to risk of
transmission, mechanisms of transmission and/or modes of action of successful
prevention strategies.  Modalities of intervention may include, but are not
limited to: (1) antiretroviral drugs; (2) microbicides; (3) behavioral
approaches; (4) barrier methods; (5) immunologic strategies; (6)
chemoprophylaxis; (7) treatment of sexually transmitted diseases; and (8)
combined approaches.

In addition to the HPTN, the NIAID is supporting creation of the HIV Vaccine
Trials Network (HVTN) to perform Phase I, II and expand to Phase III clinical
trials of HIV vaccines (see RFA-98-014 HVTN Leadership Group).  However,
clinical trials of vaccines focused on questions around perinatal transmission
will be conducted within the HPTN in collaboration with the HVTN and the
Pediatric AIDS Clinical Trials Networks.  Sites funded under the HPTN may also
serve as effective venues for the eventual implementation of larger HIV
vaccine trials; therefore linkages between HPTN and HVTN, in addition to other
scientific organizations, are strongly encouraged.

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, HIV Prevention Trials Network
Leadership Group, 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 Summary Report: Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC 20402-
9325 (telephone 202/512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations; public and private institutions, such as universities,
colleges, hospitals, laboratories, units of State and local governments; and
eligible agencies of the Federal government.  Foreign organizations may not
submit applications in response to this RFA.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to apply as
Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for these awards will be
the cooperative agreement (U01).  The cooperative agreement is an assistance
mechanism in which substantial scientific and programmatic involvement of the
NIH cosponsoring institutes is anticipated during performance of the activity. 
Under the cooperative agreement, the purpose of the NIH cosponsors is to
support and encourage the recipients' activities by working jointly with the
awardees in a partner role, but not to assume direction, prime responsibility,
or dominance.  Details of the responsibilities, relationships, and governance
of the studies to be funded are described under the section entitled, SPECIAL
REQUIREMENTS, "Terms and Conditions of Award."  The total project period for
each award may not exceed five years.  The anticipated award date is September
1999. The NIAID has not determined whether and how this solicitation will be
continued beyond the present RFA.

FUNDS AVAILABLE

The NIAID, with additional support from NICHD, NIDA, and NIMH, plans to fund
one PLG including the CORE Principal Investigator AND OPERATIONS CENTER,
Central Laboratory (CL), and Statistical and Data Management Center (SDMC). 
Approximately $8,000,000 total costs (direct and indirect) are expected to be
available for the first year of support under this RFA. This will include
approximately $2 million for the CORE (including a discretionary fund not to
exceed $1 million),  $2 million for the CL award and $4 million for the SDMC
award.  The awards for clinical trial sites for the HPTN will be solicited
under a separate RFA.  Approximately $15,000,000 total costs are expected to
be available for the first year of support for clinical trial sites under this
subsequent RFA.  Funding beyond the level awarded in the first year for the
HPTN will be contingent upon the continued availability of funds for this
purpose and the continued progress of the HPTN.

DEFINITIONS

Central Laboratory (CL) - The CL is the central laboratory that enables the
HPTN to implement state-of-the-art assays and technologies that are essential
for the completion of the scientific prevention research agenda, as defined in
the HPTN PLG Application.  In addition to the performance of these assays for
the HPTN, this laboratory may propose to  investigate the feasibility,
validity, and standardization of the assays and techniques that are relevant
to the evaluation of HIV prevention modalities.  The cooperative agreement
award for the CL will be made as part of the HPTN PLG.

Collaborating Institution - A collaborating institution of the HPTN may be
either the CORE, the CL, the SDMC, or a HPTU.

Cooperative Agreement - A cooperative agreement is an assistance mechanism in
which substantial NIH Cosponsoring Institutes' involvement with the recipient
is anticipated during performance of the planned activity.

Coordinating and Operations Center (CORE) - The CORE consists of the PLG
leadership (PI) and Operations Office.  The CORE coordinates all aspects of
the HPTN and has oversight for the CL and SDMC.

CORE Principal Investigator (PI)  - The CORE Principal Investigator is
responsible for the leadership and coordination of all HPTN activities both
scientifically and administratively, and serves as the Principal Investigator
for the CORE Award.  The CORE PI may or may not be associated with a HPTU.

Data and Safety Monitoring Board (DSMB) - The DSMB is an independent group of
experts established by NIAID and charged with the responsibility of monitoring
the progress of trials, the safety of participants, and the efficacy of
treatments being tested.  The DSMB also makes recommendations to NIAID and the
cosponsoring Institutes concerning continuation, termination or modification
of the trials based on observed beneficial or adverse effects of any of the
interventions under study.  This Board is funded separately by NIAID.

Division of AIDS (DAIDS) - The Division within the NIAID that has the primary
responsibility for support of basic and clinical research on HIV/AIDS.

Executive Committee - The Executive Committee, established and chaired by the
PLG PI, represents the main governing body of the HPTN.  This committee will
be responsible for the conduct and overall activities of the HPTN.  (Refer to
"SPECIAL REQUIREMENTS; B. Awardee Rights and Responsibilities" in the RFA.)

HIVNET - The HIV Network for Prevention Trials (HIVNET) is a multisite
clinical trial network supported by the Division of AIDS, which consists of 22
sites in the U.S. and internationally.  The network currently carries out
vaccine and other prevention trials.  The nonvaccine efforts of the HIVNET
will be transitioned into the HIV Prevention Trials Network (HPTN).

HIV Prevention Trials Network (HPTN) - The HPTN is a collaborative network of
institutions comprised of the CORE, CL, HPTUs, and the SDMC.  This group
conducts all phases of clinical trials and laboratory studies.  The HPTN
consists of experienced investigators in multiple disciplines of prevention
(e.g., microbicides, perinatal, pediatric, behavior, infectious diseases,
virology, immunology, epidemiology, obstetrics and gynecology, and
biostatistics).

HIV Prevention Trials Unit (HPTU) - A HPTU is a clinical site that is a member
of the collaborating group of institutions comprising the HPTN.  A HPTU may be
organized as a main clinical site or a main site and several subunits under
the leadership of one Principal Investigator.

Operations Center - The Operations Center is a unit within the CORE that will
take responsibility for coordinating HPTN administrative activities including
technical assistance with research and protocol development, budgetary
activities, preparation of technical reports and AER reporting.  The CORE PI
will serve as PI for the Operations Center, with the award made to the
Operations Center.

Prevention Leadership Group (PLG) - The Prevention Leadership Group consists
of the Principal Investigator for the CORE, the Principal Investigator for the
SMDC, and the Principal Investigator for the LC.  Other members of the PLG
group may be designated by the HPTN in the future.

Prevention Science Research Committee (PSRC) - The Division of AIDS has an
internal scientific review committee which is responsible for the programmatic
review of protocols developed by Clinical Trial Networks sponsored by DAIDS
within the Vaccine and Prevention Research Program.  NICHD, NIDA, AND NIMH
REPRESENTATIVES will serve on the PSRC that reviews of HPTN protocols.  The
review will include careful assessment of the scientific objectives, safety,
and design of research protocols proposed by investigators within the HPTN and
HVTN.

Statistical and Data Management Center (SDMC) - The SDMC is the component of
the HPTN that is responsible to the PLG leadership for the statistical aspects
of study design and analysis and management of the HPTN database.

Subunit - A subunit is an institution supported under the fiscal and
managerial umbrella of a HPTU.  Subunits may be established to support the
scientific agenda and/or accrual goals.  All subunits are subject to the same
policies and procedures mandated by Federal regulations, DAIDS and NIAID
policies, and the bylaws of the HPTN.

Vaccine and Prevention Research Program (VPRP) - The VPRP is a program within
the DAIDS that is responsible for the scientific, administrative, and
operational management of clinical vaccine and prevention research funded by
the Division.

SOLICITATION PROCESS

Each proposed PLG will submit a group package consisting of up to three
individual applications which address the three components of the PLG: (1) A
CORE OPERATIONS CENTER (CORE) under the PRINCIPAL INVESTIGATOR (PI) who heads
the PLG team, (2) A CENTRAL LABORATORY (CL) and (3) A STATISTICAL AND DATA
MANAGEMENT CENTER (SDMC).  A group may choose to combine two components, such
as the CORE and SDMC components and apply as a COORDINATING CENTER.  Either
two or three separate awards will be made in support of these three major
components of the PLG.

When applying for PLG components (Central Laboratory or Statistical and Data
Management Center), each applicant must identify the PLG CORE with whom they
propose to work and must coordinate the preparation of their application with
all other components of the PLG.  Unaffiliated applications will not be
accepted.

The application for the PI who heads the PLG team and Operations Center's
(CORE) should address the RESEARCH SCOPE AND GOALS and responsibilities
identified in Terms and Conditions of Award below.  The HPTU application
process will occur approximately 4-6 months after the PLG application process. 
At the time of the HPTU submission, it is unlikely that the PLG will have been
awarded.  Therefore, potential HPTU applicants are encouraged to communicate
with PLG applicants and to attend the PLG Pre-Application Meeting (see
APPLICATION PROCEDURE below).

The responsibilities for the Central Laboratory and for the Statistical and
Data Management Center are described in Terms and Conditions of Award below. 
These responsibilities should be addressed in the relevant applications.

RESEARCH OBJECTIVES

A.  BACKGROUND

The HIV epidemic continues to grow worldwide despite major advances in
understanding the pathogenesis of HIV infection and in our ability to treat
the disease.  HIV disease is now the leading cause of death among young men
and women in the United States (U.S.) and worldwide.  The World Health
Organization estimates that by the year 2000, approximately 40,000,000 adults
and children worldwide will have been infected with HIV, by sexual
transmission, mother to infant transmission around the time of birth or
through breast feeding, or by injection drug use.  This translates into 16,000
new HIV infections worldwide each day mostly among young adults and with 1,600
new infant infections daily.

Control of the epidemic requires improved methods and strategies for
preventing HIV infection.  In pursuit of this goal, the Vaccine and Prevention
Research Program (VPRP), DAIDS, NIAID, and the other co-sponsoring Institutes
fosters basic and applied research leading to the development of safe and
effective HIV prevention modalities.  Through the HIV Network for Prevention
Trials (HIVNET) begun in 1993, NIAID and the other co-sponsoring Institutes
have supported domestic and international studies to evaluate prevention trial
preparedness and the safety and efficacy of promising interventions to prevent
sexual and perinatal transmission using HIV seroincidence as the primary trial
endpoint.  The interventions evaluated encompassed topical microbicides,
sexually transmitted disease (STD) treatment, prophylaxis to prevent mother to
child transmission, and behavioral risk reduction strategies.  HIVNET studies
are carried out in close coordination and collaboration with other agencies
that are involved in prevention research.

B.  RESEARCH GOALS AND SCOPE

The goal of this RFA is to establish a PLG that will design, direct, and
manage a comprehensive program of clinical research on HIV prevention both in
the U.S. and internationally through the HPTN.  The CORE Principal
Investigator (PI) will have the necessary expertise and experience to lead
other investigators in the development of the overall scientific agenda which
will guide the HPTN in the development of effective HIV prevention modalities. 
As part of the application, the CORE PI should identify the highest priority
research questions in HIV prevention research, and develop a comprehensive HIV
prevention agenda to be carried out within the HPTN.  Relevant research to be
considered by the PLG includes, but is not limited to, the following areas:

o  Identifying strategies for the prevention of adult and perinatal HIV
infections with emphasis on interventions with high efficacy, low cost, low
potential toxicity, and the potential for worldwide use.  Examples might
include:
- microbicides for prevention of sexual or perinatal HIV transmission
- preventive treatment of sexually transmitted diseases
- chemoprophylaxis for prevention of adult or perinatal transmission
- interventions to prevent transmission via breast milk including active and
passive immunotherapy and antiretrovirals
- immunoprophylaxis agents
- barrier methods
- vaccines to prevent perinatal transmission
- combinations of the above
behavioral interventions (assessed independently and in conjunction with or
combination with biomedical strategies)

o  Conducting cooperative, multi-site trials, domestically and
internationally, to evaluate:
- safety, pharmacokinetics, tolerance and activity of promising new agents for
use in preventing HIV transmission;
- surrogate markers to assess the antiviral activity of microbicides, anti-
retroviral therapeutics and or immunoprophylaxis agents as prophylactic agents
against high risk exposure; and
- efficacy of promising new agents either alone or in combination for the
prevention of adult and perinatal infections (except evaluations of vaccine
efficacy in uninfected adults).

o  Supporting  basic laboratory and epidemiologic studies nested within these
clinical trials  that address questions such as the infectious unit of
transmission, the basic biology and virology of mucosal transmission, the role
of various cellular coreceptors in transmission, the role of host
immunogenetics on risk of transmission, the effect of viral load and viral
characteristics in various body compartments, such as the genital tract, on
risk of transmission, and mechanisms of breast feeding transmission.

o  Monitoring HIV incidence within the cohorts studied by the HPTN and
characterization of the  prevalent HIV subtypes transmitted to these
populations.

o  Supporting community outreach and educational efforts in preparation for
HIV prevention trials including studies of factors affecting acceptability and
adherence to prevention modalities or sociocultural factors related to
implementation of successful prevention strategies.

o  Integrating prevention research efforts with HIV vaccine clinical studies
in adults (in the HTVN) as well as collaborating in the planning for and
implementing of large scale HIV vaccine trials in the U.S. and
internationally.

o  Integrating behavioral research in HPTN protocols including acceptability
of interventions by age, gender, cultural groups; methods to promote adherence
to prevention interventions; community-based interventions to change norms
about HIV/STD transmission and maintenance of lower risk behaviors, and other
methodologic behavioral research in support of HPTN studies.

In addition, the HPTN PLG leadership MUST describe how they plan to transition
the current HIVNET research activities to the proposed prevention research
within the HPTN.  This provisional transition plan should address plans for
ongoing clinical trials at the time of the transition, plans for phase in and
phase out of sites, and plans for data and laboratory management during the
transition.  A detailed transition plan will be developed in conjunction with
the HIVNET after the award of the HPTN PLG.

SPECIAL REQUIREMENTS

TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the award
statement and provided to each Principal Investigator as well as the
institutional officials at the time of award.  These terms are in addition to,
not in lieu of, otherwise applicable Office of Management and Budget (OMB)
administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part
74 and 92, and other HHS, PHS, and NIH Grants Administration policy
statements.

The administrative and funding instrument used for this program is the
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during the
performance of the activity. Under the cooperative agreement, the NIH purpose
is to support and/or stimulate the recipient's activity by involvement in and
otherwise working jointly with the award recipient in a partner role, but it
is not to assume direction, prime responsibility, or a dominant role in the
activity.  Consistent with the cooperative agreement concept, the dominant
role and prime responsibility for the planned activity resides with the
awardees for the HPTN.  Specific tasks and activities in carrying out the
activity will be shared among the awardees, NIH staff and DAIDS contractors.

The cooperative agreement funding mechanism will require collaboration among:
the NIAID, NICHD, NIDA, and NIMH representatives; the CORE PI; the Principal
Investigator of the CL; and the Principal Investigator of the SDMC.  The DAIDS
will assist in coordinating the activities of the HPTN as defined below and
will facilitate the exchange of information.

I.  Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research
objectives, approaches, and details for the project within the guidelines of
the RFA, performing the scientific activity.  Awardees have primary
responsibility as described below.

A.  Prevention Leadership Group Responsibilities

1.  Research Agenda -- The Principal Investigator (CORE PI), in collaboration
with other HPTN investigators constituting the key scientific and managerial
leadership (Executive Committee), will be responsible for developing,
implementing, monitoring, and updating the HPTN scientific prevention research
agenda.  The PLG will assume responsibility for further developing the
scientific and managerial guidelines of the HPTN, in consultation with the
Executive Committee (see below), through the development of the HPTN bylaws
and governance.  These research goals will be reviewed on a mutually agreed
upon schedule with the Associate Director for VPRP, DAIDS or designee.

2.  Transition Plan -- The PLG, in conjunction with the leadership of the
current HIVNET, will develop a detailed transition plan that adequately
addresses the transition from the current HIVNET prevention research
activities to the proposed HPTN.  This plan will delineate the transition of
ongoing clinical trials, propose procedures, timeline and planning for the
phase in and phase out of clinical sites, statistical center and central
laboratory contracts.  The Plan will be completed and implemented with
sufficient time to ensure timely completion of all ongoing studies.

3.  Bylaws/Operating Procedures -- The PI of the PLG CORE will be responsible
for ensuring that well-documented policies, procedures, and bylaws are
developed, implemented, and when necessary updated to guide all aspects of the
cooperative HPTN activities.

4.  Executive Committee -- An Executive Committee will be established as the
main governing body of the HPTN.  The membership must include: the DAIDS
Associate Director for VPRP, or designee, as a voting member representing the
NIH Coordinating Committee (See Section II, 1) and representatives of the
other co-sponsoring Institutes (NICHD, NIDA, NIMH) as non-voting ad-hoc
members.

5.  Administrative Support -- The Operations Office, within the CORE, will be
responsible for coordinating, administering, and supporting all research
activities at the direction of the CORE PI or designee.  These activities
include, but are not limited to: (i) protocol development, distribution, and
site training; (ii) administrative support for the CORE PI; (iii) the
scientific leadership of the HPTN and all committees; (iv) assembly, review,
and submission of regulatory documents to designated DAIDS staff for the
registration of sites to conduct clinical trials; (v) maintenance of group
administrative records and archives; (vi) coordination of efforts with DAIDS
and cosponsoring Institutes regarding two annual group meetings one of which
will be held in the Washington D.C. metropolitan area; and (vii) preparation
of administrative and scientific reports (in conjunction with the group's
SDMC.)

6.  Protocol Development -- The HPTN CORE will initiate development of each
protocol only when there is sufficient commitment among the Principal
Investigators and other scientific leaders within the group to proceed
expeditiously to write the protocol, complete accrual, and analyze and publish
the study results.  NIH medical staff will serve as medical officers in the
development and implementation phases of the protocol.  Early notification
that the HPTN is considering a trial must be provided to the DAIDS to allow
for comment on scientific rationale, feasibility, costs, and compatibility
with overall NIAID, NICHD, NIDA, AND NIMH research priorities and activities. 
The HPTN must have clear procedures for designating members of protocol teams,
selecting sites for limited-site trials, and providing protocol-specific
training.  The HPTN must develop a mechanism to monitor progress, from study
initiation through publication, and provide status reports to the DAIDS, on
each study, in a format and on a schedule mutually agreed upon.

7.  Broad Community Participation -- In formulating and implementing the
research plan, provision should be made for broad community participation at
both domestic and international sites.  This plan should include consideration
that the process of building a research relationship with a community takes
time and commitment.  There should be opportunities for education and training
for researchers and community members.  Researchers might work with
communities more effectively if they had knowledge of ethics, cultural
competency, and participatory research techniques.  Community members could be
more effective with knowledge of research processes.  The following specific
issues need to be considered:  (i) the need to develop model programs that not
only include health research goals but also community capacity-building goals
for conducting specific research activities; (ii) community training to
improve understanding of research; (iii) support for the development of local
organizations; and (iv) community mobilization skills.

8.  Study Oversight Responsibility - The HPTN leadership must establish
procedures to: (i) assure adequate protection of the rights and safety of
subjects involved in its clinical investigations; (ii) guarantee the quality
and integrity of resulting data; and (iii) maintain accurate and timely
information on the progress of each study.  This oversight must include
compliance with all Federal regulations and NIH policies and procedures as
outlined in the "Serious Adverse Experience Reporting Manual for the Vaccine
and Prevention Research Program," which is available from Dr. MaryAnn Luzar
(see Inquiries).

9.  Federally and Internationally Mandated Regulatory and Ethical Requirements
-- The HPTN must be in compliance with all Federal regulations and NIH
policies applying to the conduct of research involving human subjects.  These
include, but are not limited to, Title 21 CFR 50, 56, 312, and Title 45 CFR
46.  The HPTN must assure that: (i) each institution conducting HPTN trials
has a current, approved Assurance Number on file with the NIH Office for
Protection from Research Risks (OPRR); (ii) each protocol and informed consent
is approved by the responsible Institutional Review Board (IRB) prior to
subject entry; (iii) each investigator has supplied a completed (including
curriculum vitae) FDA 1572 to DAIDS for each protocol conducted at each site;
and (iv) each subject (or legal representative) gives written informed consent
prior to entry on study.  For trials conducted in foreign countries, the HPTN
must assure compliance with the host country regulations for human subjects
and AIDS research and must assure that the trials are conducted according to
the International Ethical Guidelines for Biomedical Research Involving Human
Subjects (CIOMS).

10. Reporting Requirements - The HPTN will submit to the DAIDS requisite
information in order to meet administrative, oversight, and regulatory needs.

a.  Administrative - To facilitate DAIDS compliance with reporting
obligations, the CORE PI, working through the Operations Office and SDMC, will
submit various administrative information to DAIDS.  Types of information will
include address lists of investigators and other key contacts, protocol
abstracts, tracking data, participating sites, accrual and demographic data,
and publication information.  Some information such as protocol
enrollment/accrual status may be required weekly, some less often.  Submission
by electronic means, wherever possible, is preferred.

b.  Performance  - The HPTN Executive Committee will establish procedures for
regularly evaluating performance of the HPTUs, Operations Office, CL, and the
SDMC.  Procedures will include a process recommending reduction, expansion, or
removal of HPTUs and subunits based on scientific contributions/protocol
participation; observance of protocol requirements; data management/quality;
and subject accrual and retention.  This mechanism will include a procedure
for recommending to DAIDS an adjustment of institutional funds based on the
level of contribution and performance.

c.  Annual Report - The CORE PI will submit to DAIDS an annual progress report
summarizing the data on protocol performance by the HPTN as a whole and by
each participating clinical unit.  These reports will include at a minimum:
(i) subject accrual and retention rates; (ii) subject demographics; (iii)
timeliness and completeness of all data, including adverse events; (iv)
timeliness of IRB approvals of new protocol versions; (v) completeness and
quality of laboratory data; and (vi) scientific contributions, including
publications.  These data should be compiled across all studies and by
protocol, as appropriate.

d.  Regulatory - Reporting requirements will be in agreement with Federal
regulations and NIAID procedures for clinical trials.  Prior to the date
specified, the CORE PI will submit to the DAIDS data summary reports that are
required of Investigational New Drug (IND) sponsors by the Food and Drug
Administration (FDA).  The HPTN will submit to DAIDS a narrative summary of
the data contained in these reports and future plans for each study one month
in advance of each IND report's due date.  A system for providing such
information in a timely manner must be implemented by the HPTN.

11. Publication of Data Results - Prompt and timely presentation and
publication in the scientific literature of major findings is essential. 
Publications or oral presentations of work performed under this cooperative
agreement will require acknowledgment of NIAID, NICHD, NIDA, AND NIMH support. 
Prior to the submission of manuscripts for publication, the HPTN will provide
a copy to DAIDS.  Although the awardee will retain custody and primary rights
to the data consistent with current HHS, PHS and NIH policies, DAIDS will have
access to all data generated under this cooperative agreement and may
periodically review it.

12. Collaborative Responsibilities - The PLG is expected to develop scientific
collaborations that can expand the scope of the HPTN.  The PLG should develop
a process that would make data and biological specimens available to the
general scientific community to further investigations in HIV prevention
research, including the objective review of such requests.

13. National Meetings - It is anticipated that at least 2 national
meetings/year will be required.  The PLG is expected to hold at least one
national meeting per year in the Washington, metropolitan area.  They may
chose to meet jointly with other HIV prevention research groups, or groups
engaged in clinical trials of HIV vaccines.  Portions of these meeting are
open to the public.  Responsibility for logistical support and scientific
content will reside with the PLG.

14. Conflict of Interest - The PLG will assure the development and
implementation of a Conflict of Interest Policy (COI), acceptable to the
NIAID, addressing any conflicts of interest that may occur through financial
interest or other associations between members of the HPTN and the private
sector.

15. Discretionary Fund  - The Operations Office will maintain and manage a
Discretionary Fund.  These funds will be expended only upon approval by the
Executive Committee.  The Executive Committee will develop criteria and review
procedures for allocating discretionary funds, based on scientific and
administrative needs and priorities of the group.  Appropriate uses may
include innovative pilot studies; supplementing budgets of collaborating
institutions which are undertaking resource intensive studies; facilitating
the initiation of large efficacy studies; accommodating non-routine protocol
mandated requirements on an as needed basis; and supporting additional
clinical or laboratory sites needed by the group.

16. Linkages with HVTN - The HVTN application will be solicited
contemporaneously with the HPTN.  The HPTN may be a unique scientific resource
and offer a desirable capacity for conducting population-based studies.  The
HPTN may collaborate in large-scale evaluation of HIV vaccines.  The HVTN
leadership (VLG), in concert with the leadership of the HPTN (PLG) will
develop and maintain collaborative linkages relevant to planning of large-
scale vaccine trials.  These linkages will allow for ongoing exchange of
information and planning to allow for rapid inclusion of HPTN (and other)
sites in large-scale HIV vaccine trials, should the need arise.  The VLG may
propose a number of different mechanism and approaches to meet this need. 
These mechanisms may include ongoing activities such as having joint
membership in leadership groups or identifying specific individuals
responsible for assuring information sharing.  There may also be specific
activities such as joint protocol development or common scientific meetings. 
These linkage plans will be evaluated on their likelihood of maintaining close
and productive collaboration between the two Networks.

17. Other Collaborations - The PLG should propose plans to interact with other
NIH-sponsored AIDS clinical research groups, including mechanisms to integrate
and complement the scientific agendas of the cosponsoring NIH institutes to
address specific HIV problems.

B. Central Laboratory Responsibilities

1.  Conduct of Laboratory Assays and Research -- The CL will be responsible
for the following: (I) performing timely laboratory studies as needed for
specific clinical trials; (ii) providing laboratory-based scientific
leadership and consultation for the HPTN and collaborating institutions and
organizations; and (iii) collaborating at all stages of protocol development
concerning laboratory testing and implementation.

2.  Organization/Management of the Central Laboratory -- The PLG will contain
a single CL with responsibility for providing appropriate and coordinated
laboratory support for HPTN investigations.  It is anticipated that the CL
will not possess the technical capability/capacity to perform all the required
laboratory assays in house.  The CL may organize, through a series of
subcontracts, a network of laboratories (subsites) with various virologic and
immunologic expertises to address the laboratory needs inherent in the
prevention research agenda.  These laboratories should demonstrate both
scientific excellence in clinical-based assays and interest in participating
in the research agenda defined by the HPTN.  The scope of the laboratory
research should include virologic and immunologic assays, as well as assay and
reagent development, relevant to HIV prevention studies.

3.  Coordination with the Statistical and Data Management Center -- The CL
will be responsible for coordinating with the SDMC to assure transfer of
quality laboratory data for preparing analyses of study findings and for use
in preparation of annual and interim reports to the NIAID, FDA, and the DSMB. 
The CL will assure that a common laboratory data management system is utilized
for specimen tracking and data transmission.

4.  Quality Assurance of Laboratory Performance -- The CL will be responsible
for conducting/ overseeing quality assurance of laboratory assays performed at
HPTN clinical and laboratory sites in order to improve the planning, design,
conduct, and interpretation of HPTN trials.  This will include written QA
monitoring reports to the Associate Director, VPRP or designee.  The CL will
also be responsible for training of field site laboratories for performing all
assays and quality control procedures specified by study protocols and for
periodic site visits to monitor site lab performance.

C.  Statistical and Data Management Center Responsibilities

1.  Study Design, Conduct, Analysis and Publications -- The statistical staff
will be responsible for the following:  (I) providing statistical scientific
leadership for the HPTN and collaborating institutions and organizations; (ii)
collaborating at all stages of protocol development and implementation; (iii)
performing timely interim analyses of safety results for review by protocol
teams and safety and efficacy results for the NIAID Prevention DSMB; (iv)
performing final analyses for publication, participating in the writing of
scientific papers and publishing study results in conjunction with other
protocol team members; (v) producing study monitoring reports (such as accrual
and AERs), deliverable to the CORE PI and the Associate Director, VPRP or
designee; (vi) conducting secondary analyses of HPTN data to improve the
planning, design, conduct and interpretation of HPTN trials; and (vii)
preparing summary tables and data analyses for use in annual and interim
submissions to the NIAID, FDA, and the DSMB.

2.  Data Management -- The data management staff will: (I) provide central
registration and randomization of subjects on all studies; (ii) develop case
report forms; (iii) develop standardized criteria for verification of clinical
endpoints; (iv) design and implement a system to provide for the efficient,
secure, and confidential transfer of study results from clinical sites to a
central database, using either a centralized or distributed data entry
approach; (v) in conjunction with the Laboratory Data Management System
contractor and the NIAID AIDS Specimen Repository, facilitate the tracking and
identification of laboratory specimens and the merger of laboratory test
results with subject clinical data; (vi) provide for centralized storage,
security, processing, and retrieval of study results; (vii) provide limited
online access for HPTUs to their own blinded data in the central database;
(viii) prepare selected public access databases for DAIDS, as provided for in
the approved plan for providing public access in a reasonable time after the
primary analysis and publications (see 1. above); (ix) provide for an
electronic mail system, capable of exchanging messages through the Internet,
to facilitate communication among HPTUs, other HPTN components, and the NIH
sponsoring institutes; (x) provide data management training of the clinical
unit staff and DAIDS Clinical Site Monitoring contractor in the areas of form
completion and use of the e-mail system and clinical methodology; (xi) develop
reports detailing site performance in data management, deliverable to the CORE
PI and the Associate Director, VPRP (the data management staff must function
in accordance with policies and bylaws of the HPTN); and (xii) provide
recruitment and retention and other relevant summary data to the sites and
protocol teams as designated by the PLG.

3.  Collaborations -- Develop processes for facilitating and monitoring HPTN
Executive Committee-approved collaborations with investigators external to the
HPTN.  Such plans should be included in the SDMC application and address: (I)
the capacity to assist external collaborators with the design of their
studies; (ii) the monitoring plans for overseeing the status and availability
of HPTN biological specimens in the NIAID AIDS Specimen Repository; and (iii)
the plans for monitoring the progress of external collaborations, and
reporting such progress to the HPTN Executive Committee.  When collaborating
with other HIV prevention or vaccine clinical study groups, procedures of
conduct will be determined by the Associate Director for VPRP, DAIDS and the
leadership of each participating group.  Generally, the procedures of the lead
sponsor will be followed.

4.  Statistical Methodology -- Develop innovative HIV prevention clinical
trial designs and analysis methodologies consistent with and in support of the
PLG research agenda.

5.  SAE Reporting -- The SDMC will receive and record serious adverse event
experiences reports from the HPTN and collaborating institutions and report
these events to DAIDS.

D.  HPTU Clinical Sites

While the HPTU Clinical Sits will be solicited under a separate RFA, the PLG
applicants should be aware that HPTU responsibilities will include:

1.  Protocol implementation including volunteer enrollment, clinical
procedures, and follow up;
2.  Laboratory support for certain assays, particularly standard clinical
laboratory assays (e.g. CBC) for patient assessment;
3.  Individual quality assurance plans for Investigational Drug Management and
internal data generation; and
Community Advisory Board plans.
5. Contribute to the design and updating of the HPTN research agenda through
participation on committees and working groups of the Network.

II.  NIAID, NICHD, NIDA, AND NIMH Responsibilities

The NIAID and cosponsors will have substantial scientific/programmatic
involvement during the conduct of this activity, through technical assistance,
advice, and coordination.  The role of the NIH staff, as described throughout
these terms of cooperation, is to assist and facilitate, not to direct the
research activities.  Communication and interaction will occur primarily with
the CORE PI and the scientific leadership of the HPTN.  NIH staff will also
interact directly with the Principal Investigators of any collaborating
institutions and the SDMC as needed.  Following are specific responsibilities
of NIH staff in terms of investigational drug research and the Division's role
as a drug sponsor as defined in 21 CFR Part 312.  This project is a part of
NIAID's and the other co-sponsoring institutes' larger program of prevention
research.

1.  NIH Coordinating Committee.  The Associate Director for VPRP, DAIDS,
NIAID, will establish an NIH Coordinating Committee for this program.  Members
will be selected from each of the sponsoring NIH components.  The role of the
committee will be to ensure that the awardees receive consistent advice and
optimal assistance from the NIH.  The VPRP Associate Director will serve as
chair of this committee.

2.  Scientific Role Sponsored Clinical Research --  The Associate Director for
VPRP, or designee will work closely with other members of the Executive
Committee to assure that the research efforts are consistent with the NIAID
agenda for HIV clinical research and complement those of other NIAID, NICHD,
NIDA, AND NICHD programs.  The DAIDS will serve as a liaison/facilitator
between pharmaceutical companies, the FDA, and HPN investigators.  DAIDS,
NICHD, NIDA, AND NIMH staff will serve as a resource, and will disseminate
information regarding promising new agents, prevention strategies, or
developments.  DAIDS will also independently support a Data and Safety
Monitoring Board (DSMB) that will oversee prevention trials.

2.  NIH Role in Protocol Development -- In order for a clinical study to be
initiated, the protocol must be approved by the Associate Director, VPRP. 
Once notified that a study is under consideration, the Prevention Sciences
Research Committee (PSRC) will evaluate the proposal relative to: (I) the
NIAID and other co-sponsoring Institutes' research agenda and other NIH
clinical studies; (ii) subject safety; (iii) compliance with Federal
regulations; (iv) study oversight and monitoring; (v) feasibility of timely
completion; and (vi) when appropriate, plans for interim monitoring and
analysis.  The Associate Director, VPRP or designee will return comments and
recommendations to the group within 30 days after review.  If a protocol is
disapproved, DAIDS will not provide investigational products or permit
expenditure of NIH funds for the proposed investigation.

In addition, DAIDS pharmacists will participate on HPTN protocol teams,
consulting on available dosage forms and placebos.  They also will interact
with pharmaceutical companies to ensure adequate and timely supply of
products.

3.  DAIDS Involvement in Investigational New Drug Applications -- The DAIDS
will have the option to file an IND on investigational agents evaluated in
HPTN studies.  Appropriate DAIDS staff will advise the investigators on behalf
of HIH on the specific regulatory requirements for IND sponsorship.  In
situations where DAIDS is the IND sponsor, they will also assemble, review,
and submit the required regulatory documents to the FDA.

4.  Clinical Trials Agreements (CTA) -- When a pharmaceutical collaborator
provides an investigational agent to DAIDS, a CTA will be negotiated
describing respective responsibilities and rights.  The agreement will
include, but is not limited to, IND sponsorship, safety and data monitoring,
and access to data.  The PLG Core PI generally will be consulted on the terms
prior to the execution of the CTA.  Pharmaceutical collaborators generally
request that patentable inventions discovered in the studies be brought to
their attention, and the company has rights of first refusal provided that the
collaborator has rights to the background patent.  In general, terms in the
CTA covering data access and sharing will conform to policies developed
jointly by the PLG and DAIDS.

5.  DAIDS Role during Study Conduct -- DAIDS will provide Regulatory Training
at the annual meeting held in Washington, D.C.  DAIDS will also provide
ongoing and start-up training to international collaborators or for vaccine
studies being conducted in international settings.  A DAIDS Medical Officer
will monitor the safety and efficacy of the intervention(s) for ongoing
studies, and will be provided with interim and final reports.  For protocols
in which DAIDS is the IND sponsor, DAIDS will assign medical monitors.  When a
protocol is sponsored by a collaborating institution or research group,
monitoring activities will be conducted by their medical representatives.

6.  DAIDS Role in Protocol Closure -- The Associate Director for VPRP, or
designee will monitor the progress of the studies by reviewing reports
submitted to DAIDS by the Data Safety and Monitoring Board, and through
regular meetings with the PLG Leadership.  NIAID, upon reviewing the
recommendations from the DSMB and in consultation with NICHD, NIDA, and NIMH,
may find it necessary to terminate an ongoing study for the any of the
following reasons:  (I) risk to subject safety; (ii) the scientific question
is no longer relevant or the objectives will not be answered; (iii) slow
accrual; or (iv) the objectives of the study have been met.

7.  Access to Data -- The Associate Director for VPRP, or designee, will have
access to all data generated under this cooperative agreement, and may review
the data as recorded on the case report forms or in the central database. 
Data must be available for external checking against the original source
documentation as required by federal regulation and DAIDS as the IND sponsor. 
The awardees will retain the primary rights to the data consistent with HHS,
PHS, and NIH policies, but are encouraged to provide public access to selected
data sets generated with the use of public funds within a reasonable time
after the primary analysis and publication.

8.  Site Monitoring -- The DAIDS has an external Clinical Site Monitoring
Contract to evaluate good clinical research practice, regulatory compliance,
accurate protocol implementation, internal quality assurance, and test agent
accountability.  The monitoring contractor will visit performance sites
periodically to review selected protocols, provide training on general
protocol conduct, review internal QA/QC plans, audit pharmacies, and document
error resolution.

9.  Review of Performance -- The performance of all group components will be
reviewed at least annually by the Associate Director for VPRP, using the
comprehensive annual progress report, clinical site evaluations developed by
the Executive Committee, and site monitoring reports provided to DAIDS by its
contractor.  DAIDS staff will assist the PLG in developing evaluation
instruments.  Substandard data, insufficient subject accrual or retention,
inadequate progress in fulfilling the research agenda, non-compliance with
federal regulations or these Terms of Award may result in a reduction in
budget, withholding of support or termination of award.

10. SAE Reporting -- In order to provide for consistent reporting of serious
adverse experiences across clinical trials groups, DAIDS has established
policies and procedures delineated in the "Serious AE Reporting Manual."

11. DAIDS Review of Quality Control and Study Monitoring Procedures - DAIDS
staff in coordination with the site monitoring contract will periodically
conduct a review of the HPTN sites for the reliability of and compliance with
clinical and regulatory systems, and will advise on the same.

III. Collaborative Responsibilities

1.  Group Governance -- The PLG will establish an Executive Committee as the
central decision making body for the Group.  The Executive Committee will
include the DAIDS Associate Director for VPRP, or designee, as a voting
member.  NICHD, NIDA, and NIMH will each be represented by a non-voting ad hoc
member.  A Chairperson, other than the DAIDS staff, will be elected by the
Group membership as defined in the HPTN Bylaws.

IV. Arbitration

Any disagreement that may arise on scientific or programmatic matters (within
the scope of the award) between award recipients and the NIAID may be brought
to arbitration.  An arbitration panel will be composed of three members: one
selected by the Executive Committee (with the NIAID member not voting) or by
the individual awardee in the event of an individual disagreement, a second
member selected by the NIAID, and the third member with expertise in the
relevant area, selected by the first two members 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 adversary
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 A-102 and A-110.  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 Part 74, are
applicable.  These special terms and conditions pertaining to the scope and
nature of the interaction between the NIH 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 that occur in the administration of cooperative agreements.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear,
compelling rationale, and justification are provided that inclusion is
inappropriate with respect to the health of the subjects of the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research", published in the Federal Register of March 28, 1994 (FR 59 14508-
14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18,
1994, which is available at
http//grants.nih.gov/grants/guide/notice-files/not94-105.html. 
Investigators may obtain copies from these sources or from the program staff
listed under INQUIRIES.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.  All investigators proposing research involving
human subjects should read the "NIH Policy and Guidelines on the Inclusion of
Children as Participants in Research Involving Human Subjects" that was
published in the NIH Guide for Grants and Contracts, March 6, 1998, and is
available at the following URL address:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

For the purpose of this RFA adults are defined as persons 16 years of age and
older.  The NIH has other programs for HIV clinical research in children under
16 years of age.

LETTER OF INTENT

Prospective applicants are asked to submit, by November 30, 1998, a letter of
intent that includes a descriptive title of the overall proposed research; the
name, address and telephone number of the Principal Investigator; and the
number and title of this RFA.  Although the letter of intent is not required,
is not binding, does not commit the sender to submit an application, and does
not enter into the review of subsequent applications, the information that it
contains allows NIH staff to estimate the potential review workload and to
avoid conflict of interest in the review.  The letter of intent is to be sent
to Dr. Dianne Tingley at the address listed under INQUIRIES.

APPLICATION PROCEDURES

The individual applications that together make up the PLG package must be
submitted on the standard research grant application PHS form 398 (rev. 5/95). 
Application kits are available at most institutional offices of sponsored
research and may be obtained from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda MD 20892-7710, telephone (301) 710-0267, E-mail:
[email protected].

The RFA label available in the PHS 398 application kit must be affixed to the
bottom of the face page of the application.  Failure to use this label could
result in delayed processing of the application such that it may not reach the
review committee in time for review.  In addition, the RFA title ("HPTN
LEADERSHIP CORE" and/or "HPTN CENTRAL LABORATORY" and/or "HPTN STATISTICAL AND
DATA MANAGEMENT CENTER") and number (AI-98-015) must be typed on line 2 of the
face page of the application and the YES box must be marked.

Submit a signed, typewritten original of each application, including the
Checklist, and three signed exact photocopies.  Each group application for the
CORE, CL, and SDMC (or CORE/Coordinating Center and CL) must be submitted in
one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application package
and all five copies of appendices must also be sent to:

Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C07, MSC 7610
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-2550
FAX:  (301) 402-2638
Email:  [email protected]

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

The deadline for the receipt of applications is February 12, 1999. 
Applications received after this date will be considered non-responsive to
this RFA and will be returned without review.

SPECIAL INSTRUCTIONS FOR THE PREPARATION OF COOPERATIVE AGREEMENT APPLICATIONS

I. Identification of Potential Applicants and Formation of the PLG

It is the responsibility of potential applicants for the CORE award, CL award,
and SDMC award as components of the PLG to identify themselves to each other
and to establish affiliations.

II.  Pre-Application meeting - November 23, 1998

A preapplication meeting will be held at the Marriott Hotel at Dulles Airport
in Herndon, VA on November 23, 1998.  The purpose of this meeting is to
provide potential applicants with: (1) additional information about the
structures and functions of DAIDS clinical research programs; (2) the
opportunity to ask questions and obtain clarifications; and (3) the
opportunity to establish affiliations.  All applicants who are seriously
considering a response to this RFA are strongly encouraged to attend this
preapplication meeting.  Investigators who are considering applying to become
a site in the HVTN are also encouraged to attend this meeting.  For further
information, contact Dr. Margaret Johnston at the address listed under
INQUIRIES.

Questions and snwers resulting from this meeting will be available, for
individuals who are unable to attend, at the following website:
http://www.niaid.nih.gov/research/DAIDS.htm

III.  Application Preparation

All applications must be submitted on the form PHS 398 (rev. 5/95).  All
component applications for each PLG must be submitted in one package.  The
structure of the PLG requires close integration among the components, under
the leadership of the PI of the CORE.  Thus, applicants for each PLG are
strongly encouraged to interact and collaborate during the preparation of
their applications.  Successful applications for HPTN components (CORE, CL,
and SDMC) will be awarded as separate cooperative agreements to the sponsoring
institutions and will include the Terms and Conditions of Award specified in
this RFA.

Each individual application must contain a detailed budget for the first 12-
month period and a budget for the entire proposed project period for direct
costs.

On page 11 of the PHS 398 application brochure, in the section entitled
PERSONNEL, it is imperative that all applicants list ALL individuals and their
institutions participating in the scientific execution of the project in the
specified format, including those with no requested salary support.  All
applicants must ensure that the list is complete using as many continuation
pages as necessary.

Biographical sketches and other Support pages should be placed at the end of
each individual application with the Principal Investigator first, followed by
other key personnel in alphabetical order; biographical sketches are limited
to two pages each.

A key feature of this RFA is that it requires a CORE application to be
submitted by a CORE PI/Principal Investigator of the HPTN CORE.  The Central
Laboratory and Statistical and Data Management Center application must be
submitted separately, and must also identify the CORE with which each will
affiliate.  The use of tables (e.g., accrual and protocol type), diagrams, and
organization and flow charts is strongly encouraged throughout the preparation
of all applications.

Under a separate RFA, all HPTUs seeking membership in a collaborative group
must submit a separate application and identify the CORE with which they are
planning to affiliate.

In summary, applications in response to this RFA must include, but are not
limited to, the minimum requirements:

A.  HIV Prevention Coordinating and Operations Center (CORE) Application

The CORE application is not subject to the page limitations as stated in the
form PHS 398.  However, the entire Research Plan must be limited to 150 pages. 
When preparing your application, use the topics listed below as a guide for
writing the research plan in lieu of items a-d listed on pages 16-17 of the
PHS 398 application kit.  Also look at the Awardee Rights and Responsibilities
(Terms and Conditions of Award) in this RFA.  The "Gender and Minority
Inclusion for Research Involving Human Subjects", "Participation of Children",
and "Human Subjects" must be included in the Research Plan.  The PI of the
Core should take responsibility in the CORE application for ensuring that the
overall representation of study population, HPTN-wide, will be appropriately
inclusive of under-represented populations.

Research Plan and Scientific Agenda - The application should present the
proposed research agenda and should discuss the PI's plan, process, and
timeline to implement this agenda.  The research agenda must clearly identify
the priority areas in depth.  The application should also identify and name
the scientific and managerial leadership required for the PLG and the HPTN to
effectively and efficiently carry out its research plan.  The applicant must
demonstrate, in the preparation of the research plan, scientific and
administrative linkages with the CL and SDMC components.

For committees (e.g., Executive Committee) - Include an outline of proposed
expertise and plans for determining membership (including, where available,
gender and minority status for individuals who choose to be self-identified)
and responsibilities of this committee.

Operations and Management - The application should provide well-documented,
clearly defined policies, and operating procedures (e.g., protocol
development, review, initiation, training, conduct and closure, data
collection, and publication, etc.).  An outline or specific examples of
policies, procedures and bylaws should included in the application (e.g.,
delineating the requirements and expectations of collaborating institutions,
membership criteria and process for new site consideration by the HPTN,
standards of performance, and procedures for removing institutions due to poor
performance).  The CORE application should also include the principles and
procedures that will guide the transition (transition plan) from the current
AVEG and HIVNET to the proposed PLG and HPVN.  An outline and timeline for
development and implementation of a Conflict of Interest Policy and
development of the guidelines for scientific collaborations (including making
samples and datasets available) should be included.

In addition to a discussion of the support needed for the Operations Office,
each CORE application should include a plan and a budget, developed by the
CORE PI, for administrative/managerial support.  The CORE, CL, and SDMC
components must show evidence of ongoing cooperation in the preparation of
their applications.

Operations Office Procedures - The application must describe the steps that
the CORE PI will take to ensure internal and external management between the
Operations Office, CL, SDMC, HPTUs, and collaborating institutions (e.g.
DAIDS, NICHD, NIDA, and NIMH).

Community Participation - The application must describe the mechanisms and
procedures that will be put in place for monitoring community participation
and accrual efforts at the individual HPTUs.  The application must also
describe the steps taken to establish ongoing involvement in community
outreach, including ability to establish and maintain an active community
advisory board.

Discretionary Funding - The CORE PI may also request a discretionary budget in
this application that will be used to: fund innovative pilot studies,
supplement the budgets of collaborating institutions undertaking resource
intensive studies, facilitate the initiation of large efficacy studies,
accommodate non-routine protocol mandated requirements on an as needed basis,
and support any additional clinical or laboratory sites needed by the group. 
The Discretionary Funds may not exceed $1,500,000 total costs per year.  The
application must describe how the funds will be used (including examples of
studies), what review procedures will guide the Executive Committee for
distributing the funds, and what criteria will be used for distribution of
funds.

Budget - As a part of the proposed detailed overall first year budget and
summary budgets for future years, the applicant should demonstrate evidence
that the budget requests for the CL and SDMC are consistent with the work
scope of the scientific agenda.  A composite budget should be included,
followed by individual budgets.  At a minimum the budget request should
include four categories: (i) Operations Center; (ii) administrative support
for the PLG Leader, scientific committees and annual meetings; (iii) projected
transitioning costs for ongoing clinical trials; and (iv) discretionary funds
not to exceed $1.5 million of the total cost budget request.

Linkages - CORE applicants should include in their application their current
linkages and or specific plans for linkages with other relevant HIV research
related efforts.  The following support linkages are either REQUIRED as
specified or strongly ENCOURAGED when not specified:

a. Community Advisory Boards [REQUIRED]: U.S and international
b. HIV Vaccine Trials Network Leadership [ENCOURAGED]
c. Acute Infection and Early Disease Research Network [ENCOURAGED]
d. Pediatric ACTG [ENCOURAGED]
e. CFAR [ENCOURAGED]
f. OTHER PHS GROUPS [ENCOURAGED]-DMID, NIDA, NICHD, NIMH, CDC, etc
g. INTERNATIONAL RESEARCH GROUPS [ENCOURAGED] - UNAIDS/WHO, IAVI, etc

B.  Central Laboratory Application

The CL application is not subject to the page limitations as stated in the
form PHS 398.  However, the Research Plan must be limited to 75 pages. 
Appendices may be used for SOPs and other detailed information, with the
understanding that these may not be made available to all reviewers.  When
preparing your application, use the topics listed below and items under
(Special Requirements, Terms and Conditions of Award) Central Laboratory
Responsibilities  as a guide for writing the research plan in lieu of items a-
d listed on pages 16-17 of the PHS 398 application brochure.  However, the
"Gender and Minority Inclusion for Research Involving Human Subjects",
"Participation of Children", and (e) "Human Subjects" must be included in the
Research Plan.  The workscope and activities proposed by the CL must be
consistent with the research agenda proposed by the CORE.  The CL application
should clearly describe the role, experience and expertise in the
development/execution of laboratory work in the context of the scientific
research agenda.  The CL budget must show linkage to the research priorities
in the CORE application.

Principal Investigator and Coordinating and Operations Center (CORE) Affiliate
-The PI for the CL will indicate in the CL application the CORE with which
they plan to affiliate.  The CORE affiliate must be stated both in a cover
letter and in the application.  The applications should be included in the
same package with the affiliated CORE and SDMC.

Laboratory Expertise - The application must provide documentation of plans and
standard operating procedures for carrying out laboratory studies in the area
of virology, pharmacology and immunology that would be necessary for
anticipated clinical trials in the HPTN.  This would include procedures for
supplying scientific, administrative and regulatory reports to the Executive
Committee and DAIDS.

Organizational Structure/Management Plan - The CL application must include an
organizational chart, procedures for communicating with the Operations Office
and other collaborating institutions, and availability of experienced
laboratory staff including areas of laboratory based scientific expertise. 
The management plan must address areas of responsibility of key personnel. 
The justification for staffing levels for each category of staff should relate
to projected workload in terms of study size, study phase, number, and
complexity of protocols.  If the CL is organized as a network, justification
for each of the subsites, as it relates to the scientific research agenda, and
including a budget justification, needs to be included.  Additionally, a
detailed management plan to assure the coordinated functioning of the CL
network should be included.  A plan for transition from current sites should
be included, if appropriate.

Central Laboratory Capabilities - Each application for a CL must provide
evidence of laboratory research and assay capabilities by describing SOPs that
address:  (a) plans for laboratory administration; (b) procedures for
collection and testing of laboratory specimens including quality control
procedures; (c) plans for coordinating with the HPTN statistical center
developing/maintaining laboratory tracking systems, centralized storage and
retrieval of specimens; (d) interface with HPTN statistical center for
tracking laboratory specimens and merger of laboratory data with clinical
data;  and (e) plans for training clinical site laboratory personnel to carry
out some laboratory testing as defined in specific protocols.  The application
should describe, in detail, the laboratory requirements and expectations to be
imposed on the HPTUs and other collaborators.

C.  Statistical and Data Management Center Application

The SDMC application is not subject to the page limitations as stated in the
form PHS 398.  However, the Research Plan must be limited to 100 pages. 
Appendices may be used for SOPs and other detailed information, with the
understanding that these may not be made available to all reviewers.  When
preparing your application, use the topics listed below and items under SDMC
Responsibilities (Special Requirements, Terms and Conditions of Award) as a
guide for writing the research plan in lieu of items a-d listed on pages 16-17
of the PHS 398 application brochure.  However, the "Gender and Minority
Inclusion for Research Involving Human Subjects", "Participation of Children",
and (e) "Human Subjects" must be included in the Research Plan.  The SDMC
should address in its application how it will ensure that the conditions of
the new Guidelines for Gender and Minority Representation and Inclusion of
children, when appropriate, are met with regard to clinical trials design
(e.g., stratifications, sample sizes, levels of statistical significance
required according to what is previously known about gender/ethnicity/age
effects), and how it will conduct appropriate analyses of any data collected.

The workscope and activities proposed by the SDMC must be consistent with the
research agenda proposed by the CORE.  The SDMC budget must be consistent with
the research agenda and priorities in the CORE application.

Principal Investigator and Coordinating and Operations Center (CORE) Affiliate
-The Principal Investigator for the SDMC application must indicate affiliation
with only one HPTN CORE application, and the CORE affiliate must be stated in
both a cover letter and in the application.  The applications should be
included in the same package with the affiliated CORE and CL.

Statistical Expertise - The application must provide documentation of plans
and standard operating procedures for the timely interim analyses of safety
and efficacy, final analyses for publication, and procedures for supplying
scientific, administrative and regulatory reports to the Executive Committee
and DAIDS.  Samples of protocols should be provided in the appendices to
demonstrate experimental design, methods of analysis, and sample size
calculations.  If the SOPs and protocols are not available, this information
should be described in detail in the text of the application.

Organizational Structure/Management Plan - The application must include an
organizational chart, procedures for communicating with the Operations Office
and other collaborating institutions, availability of experienced
biostatisticians and other key statistical scientific leadership.  The
management plan must address areas of responsibility of key personnel.  The
justification for staffing levels for each category of staff should relate to
projected workload in terms of study size, study phase, number, and complexity
of protocols.  The application should also include plans for developing the
processes related to collaborations with investigators external to the HPTN
and plans for providing public access to selected datasets in a timely
fashion.

Data Management Capabilities - Each application for a SDMC must provide
evidence of data management capabilities by describing SOPs that address:  (a)
plans for database design and administration; (b) procedures for data
collection, management, analysis and quality control; (c) plans for
developing/maintaining subject randomization systems, centralized storage and
retrieval of data; (d) interface with HPTN Central Lab and HPTN site
laboratory personnel for tracking laboratory specimens and merger of
laboratory data with clinical data; (e) plans for training site personnel and
DAIDS Clinical Site Monitoring contractor; and (f) plans for providing an
electronic mail system.  In addition, the application should describe, in
detail, plans for transition, if necessary.  The application should also
describe, in detail, any hardware and software requirements and expectations
to be imposed on the HPTUs and other collaborators.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for responsiveness by the NIH staff.  Incomplete
and/or non-responsive applications will be returned to the applicant without
further consideration or review.  Applications that are complete and
responsive to the RFA will be evaluated for scientific and technical merit by
an appropriate peer review group convened by the NIAID in accordance with the
review criteria stated below.  The review of the HPTN CORE, CL, and SC
applications will focus on each applicant's ability to contribute to the HPTN
scientific agenda, as well as the ability to provide leadership and expertise
in the conduct of prevention clinical trials.

The second level of review will be provided by the Advisory Councils of the
NIAID, NICHD, NIDA, and NIMH.

General Review Criteria

The criteria to be used in the evaluation of grant applications are listed
below.  Criteria specific to this RFA are included with the general criteria.

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

Specific Review Criteria

Coordinating and Operations Center (CORE) Application

1. Significance.  Does this study address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?
--Adequacy of the proposed plans to address the prevention research questions
of the NIH cosponsoring Institutes' HIV/AIDS Research Agenda.  Adequacy of the
proposed ranking of the research priorities and justifications.
-- Evidence that the research agenda reflects a broad understanding of HIV
prevention research within the changing context of the worldwide HIV/AIDS
epidemic and of the implications/ consequences of this research.

2. Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?
-- Strength and adequacy of the plans for transition of the research agenda
from the current prevention activities of the HIVNET to the HPTN research
agenda, including transition plans for ongoing clinical trials and transition
of sites of the HIVNET which may or may not be successful in their
applications as a HPTU statistical, laboratory or clinical site.  These
transition plans should provide strategies to ensure for a smooth transition
of data management, laboratory and clinical efforts from current HIVNET
prevention activities to the proposed HPTN research activities.
-- Strength and adequacy of the plans for overall HPTN management and
operations, including the plans and mechanisms for effective communication
among group membership and committees.
-- Adequacy of proposed bylaws; procedures for protocol development; and
procedures for delegation of responsibilities; plans for performance
evaluation; plans to improve performance; and procedures to eliminate
inadequate performers.  Adequacy of plans for managing discretionary funds.
-- Adequacy of plans for establishing, monitoring and enforcing a Conflict of
Interest policy.
-- Adequacy of plans for effective communication and collaboration between the
HPTN and the HVTN in planning and implementation of phase II/III vaccine
trials.
-- Adequacy of proposed plan to accomplish mutual, ongoing collaborations
between the Operations Office, the CL, and the SDMC.  Adequacy of proposed
coordination of the CORE application and budget with the CL and SDMC
applications and budgets in meeting the research agenda priorities of the
HPTN.
-- Adequacy of plans to: (i) assure appropriate protection of the rights and
safety of subjects involved in its clinical investigations; (ii) guarantee the
quality and integrity of resulting data; and (iii) maintain accurate and
timely information on the progress of each study.  This oversight must include
compliance with all Federal regulations and NIH policies and procedures.
-- Strength and adequacy of plans for community outreach and education, as
well as inclusion of community representation in HPTN research and
organizational activities.
-- Adequacy and feasibility of plans to foster participation of new
investigators, especially women and racial/ethnic minorities, in activities at
all levels of the HPTN.
-- Demonstration of current and proposed linkages with other relevant HIV
prevention research groups.

3. Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?
-- Evidence that the research agenda addresses innovative approaches to the
development and clinical evaluation of HIV prevention strategies, and the
ability to respond to changing scientific priorities.

4. Investigator.  Are the investigators appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers?
-- Adequacy of the qualifications, research experience, and time commitment of
the CORE PI.
-- Adequacy of the qualifications and research experience of the proposed
scientific leadership, including previous experience with design,
administration, management, and coordination of multi-center clinical trials.
-- Adequacy of the available or proposed resources and personnel for
administering the HPTN.  Adequacy of Operations Office capabilities in
research administration, protocol development, and management of regulatory
documents.

5. Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

HIV Prevention Trials Central Laboratory (CL) Application

1. Significance.  Does this study address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?
-- Strength of the proposed scientific contributions of the CL to the HPTN
scientific agenda.  Adequacy of the plans for achieving the proposed CL
scientific contributions.

2. Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?
-- Adequacy of the plans for collecting, transporting and testing of specimens
and promptly transmitting reliable laboratory data; and in developing and
implementing an internal program for data quality assurance, security and
confidentiality.
-- Adequacy of plans of the CL to assure that virology, immunology, and
pharmacology laboratories supported through the HPTN adhere to guidelines set
forth by the scientific leadership of the HPTN.
-- Adequacy of plans for management and coordination of HPTN laboratory
activities, including communication and cooperation with other HPTN
components.

3. Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?
-- Quality of the plan to develop and implement new assay technologies.

4. Investigator.  Are the investigators appropriately trained and well suited
to carry  out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers?
-- Adequacy of the qualifications and availability of key personnel to achieve
the stated goals of the CL.
-- Adequacy of information provided concerning the ability of the applicants
to carry out core virologic, pharmacologic and immunologic studies which would
be needed within the conduct of the HPTN clinical trials.  Strength of
evidence that the applicants will be able to deal with the volume and types of
laboratory assays required to carry out the research agenda of the HPTN. 
[Reviewers will consider the prior HIV/AIDS laboratory research experience,
including coordination of laboratory testing in multi-center trial networks
experience.]
--  Strength of the applicant's prior experience in, collecting, transporting
and testing of specimens and promptly transmitting reliable laboratory data;
and in developing and implementing an internal program for data quality
assurance, security and confidentiality.

5. Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?
-- Adequacy of available facilities and resources to conduct the proposed
work.  Adequacy of proposed plans to provide or to obtain core laboratory
services as required in the CORE application as needed to carry out the HPTN
research agenda.

Statistical and Data Management Center Application

1. Significance.  Does this study address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?
-- Strength of the proposed scientific contributions of the SDMC to the HPTN
scientific agenda.

2. Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?
--Adequacy of the proposed linkage between the work scope of the SDMC and the
research agenda priorities proposed in the CORE application.  The adequacy of
the proposed organizational structure of the SDMC to carry out the proposed
responsibilities and the adequacy of SDMC budget consist with the priorities
presented in the CORE application.
-- Adequacy of plans for database design, security, confidentiality and
administration, and adequacy of proposed procedures and policies for data
collection, analysis and quality control; quality of sample protocols.
-- Adequacy of plans, including sample protocols, for developing and
maintaining systems for: patient registration/ randomization; receiving,
recording and reporting of adverse events from the HPTN and collaborating
institutions; providing timely interim analyses of safety and efficacy, and
final analyses for publication; and supplying scientific, administrative, and
regulatory reports to DAIDS.
-- Adequacy of the plan for interfacing and collaborating with the HPTN
Central Laboratory and site laboratory data management systems for tracking
laboratory specimens.  Adequacy of the plan for the merger of laboratory data
with the clinical database.
-- Adequacy of plans for establishing an electronic mail system, capable of
exchanging messages through the Internet, for all collaborating HPTN
institutions and DAIDS.
-- Adequacy of procedures for interacting with the CORE Operations Office, and
other clinical trials groups, as needed.
-- Adequacy of the plan for training clinical (HPTU) site staff and the DAIDS
Clinical Site Monitoring contractor in: forms completion and data management;
the use of the e-mail system; and in clinical trials methodology.
-- Adequacy of plans to ensure the inclusion of women, children, minorities
and community representatives in all aspect of the proposed research and Group
activities.

3. Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?
-- Strength of experience in development of innovative trial designs and
analyses.
-- Quality of the plan to evaluate and implement new technologies and data
collection procedures.

4. Investigator.  Are the investigators appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers?
-- Strength of the qualifications, research experience and availability of the
proposed program director as well as other biostatisticians and data systems
personnel to provide statistical scientific leadership for the design and
analysis of multi-center clinical trials.

5. Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

Review Criteria for Protection of Human Subjects and for Gender and Minority
and for Children Representation

The following section expands upon review criteria for the Protection of Human
Subjects and for Gender and Minority and for Children Representation.  This
section applies to all applications responding to this RFA.

1.  Adequacy of the proposed means for protecting against adverse effects of
the research upon humans, animals or the environment, where such are involved.

2.  In clinical studies, if there is inadequate representation of any gender
and/or racial/ethnic minorities and/or children in a study design AND this
affects the potential to answer the scientific question(s) addressed, such
inadequacy will be considered deficient in the study design.  The deficiency
will be reflected in the priority score, unless a convincing justification is
provided by the investigator to explain the inadequate representation.

AWARD CRITERIA

The predominant criteria for funding priorities will be the scientific and
technical merit of applications in response to this RFA.  Consideration will
be given to the following factors in the final selection of applications to be
funded: (1) inclusion of populations currently under-represented in clinical
trials in the described research agenda; (2) cost-effectiveness of proposed
studies; and (3) the ability of the HPTN to cover all points of the scientific
agenda.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope of this
RFA are strongly encouraged.

Direct inquiries to regarding programmatic issues to:

Rod Hoff, Sc.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A12, MSC 7620,
Bethesda, MD  20892-7620 (for express/ courier use 20852)
Telephone:  (301) 496-6177
FAX:  (301) 402 3684
Email: [email protected]

Direct inquiries regarding regulatory affairs and oversight information to:

MaryAnn Luzar, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2B10
Bethesda, MD  20892-7620
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 435-3737
FAX:  (301)  480-5703
Email:  [email protected]

Direct inquiries regarding review issues and special instructions for
application preparation; address the letter of intent to; and mail two copies
of the application and all five sets of appendices to:

Dianne Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C07
Bethesda, MD  20892-7610
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 496-2550
FAX:  (301) 402-2638
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Jane W. Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B25 - MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 402-6824
FAX:  (301) 480-3780
Email:  [email protected]

Schedule

Pre-Application Meeting:        November 23, 1998
Letter of Intent Receipt Date:  November 30, 1998
Application Receipt Date:       February 12, 1999
Scientific Review Date:         June 1999
Advisory Council Date:          September 1999
Earliest Award Date:            September 1999

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic Assistance Nos.
93.855 and 93.856.  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 and 45 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or Health
Systems review.

The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or, in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood
development services are provided to children.  This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.

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