HIV PREVENTION TRIAL UNITS

Release Date:  June 18, 1999

RFA:  AI-99-010

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

Letter of Intent Receipt Date:  August 2, 1999
Application Receipt Date:  October 14, 1999

PURPOSE

The Division of AIDS (DAIDS) of the National Institute of Allergy and
Infectious Diseases (NIAID) is soliciting applications for HIV Prevention
Trial Units (HPTUs), which will be integral parts of an HIV Prevention Trials
Network (HPTN) designed to carry out a comprehensive scientific agenda on HIV
prevention strategies.

This initiative is sponsored by the National Institute of Allergy and
Infectious Diseases (NIAID), the National Institute of Child Health and Human
Development (NICHD), the National Institute on Drug Abuse (NIDA), and the
National Institute of Mental Health (NIMH), herein referred to collectively as
NIH.

The HPTN will conduct domestic and international research on promising
biomedical and behavioral strategies for the prevention of HIV transmission
among adult, pediatric and adolescent populations.  Modalities of
interventions may include, but are not limited to:  (1) antiretroviral drugs,
(2) microbicides, (3) behavioral approaches, (4) barrier and other
contraceptive/STD prevention methods, (5) vaccines (in perinatal settings),
(6) chemoprophylaxis, (7) treatment of sexually transmitted diseases, and (8)
combined approaches.

The HPTN will have:

o  The HIV Prevention Leadership Group (PLG). A single leadership group (PLG)
consisting of three components - the Coordinating and Operations Center
(Core), the Central Laboratory (CL), and the Statistical and Data Management
Center (SDMC) - under the leadership of the Principal Investigator (PI) of the
Core.  See RFA # AI-98-015 at grants.nih.gov/grants/guide/rfa-files/RFA-
AI-98-015.html.

o  HIV Prevention Trial Units (HPTUs) being solicited by this RFA.  The HPTUs
will: (1) contribute to the HPTN research agenda, (2) conduct/participate in
Phase I, II, and/or III prevention intervention clinical trials domestically
and/or internationally, and (3) expand for multiple prevention efficacy
trials.

Potential applicants should refer to the following web site for further
information on this initiative: http://www.niaid.nih.gov/daids/vtn-ptn/

In addition to the HPTN, the NIAID is supporting the creation of the HIV
Vaccine Trials Network (HVTN) to perform Phase I, II and expand to Phase III
clinical trials of HIV vaccines (AI-98-014 available at
grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-014.html, released October 23,
1998)  Clinical trials of vaccines focused on questions around maternal-infant
transmission will be conducted within the HPTN and may be in collaboration
with the HVTN and, when desired, the Pediatric AIDS Clinical Trials Network. 
It should be noted that sites funded under the HPTN may also serve as
effective venues for implementation of larger HIV vaccine trials; therefore
linkages between HPTN, HVTN, and 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 Trial Units, is
related to the priority area of HIV infection.  Potential applicants may
obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and non-
profit organizations, public and private institutions (such as universities,
colleges, hospitals, laboratories, state and local governments) and eligible
agencies of the Federal government.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.

An institution may submit more than one HPTU application, and/or a single
application encompassing one or more scientific areas or approaches.  An HPTU
application may be a single site or may include multiple collaborating sites. 
In the case of collaborating sites, one institution will be the grantee and
the other sites will be consortia. In all cases, justification should be
provided in terms of (1) scientific, administrative, and fiscal management;
(2) cost-effectiveness of the structure; and (3) adequacy of provisions for
inter-organization coordination, oversight for the contributing/participating
groups, subcontracts, or organizations.  Documentation should be provided for
any financial relationship between the applicant's organization and other
researchers, organizations, consultants, etc.  See Appendix A for instructions
for Federal Agencies that wish to apply.

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 NIH scientific and programmatic involvement is
anticipated during performance of the activity.  Under the cooperative
agreement, the NIH's purpose 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 anticipated award date is June 2000.

The total project period for applications submitted in response to this RFA
may not exceed five years.  At present, the NIAID is administratively limiting
the duration of U01 cooperative agreements to four years; this administrative
limitation may change in the future.  At this time, the NIAID has not
determined whether and how this solicitation will be continued beyond the
present RFA.

FUNDS AVAILABLE

Approximately $15 million total costs will be available for the first year of
support.  NIH anticipates 10 to 15 awards.  The usual PHS policies governing
grants administration and management will apply.  Although this program is
provided for in the financial plans of the NIH, awards pursuant to this RFA
are contingent upon the availability of funds for this purpose, and the
receipt of a sufficient number of applications of high scientific merit. 
Funding beyond the first and subsequent four years of the grant will be
contingent upon satisfactory progress during the preceding years and
availability of funds for this purpose.

DEFINITIONS

Central Laboratory (CL).  The CL will implement state-of-the-art assays and
technologies that are essential for the completion of the prevention research
agenda, as defined in the HPTN PLG Application.  In addition to the
performance of these assays for the HPTN, this laboratory may investigate the
feasibility, validity, and standardization of the assays and techniques.  The
cooperative agreement award for the CL will be made as part of the HPTN PLG
and will provide support for protocol-related studies only.

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.

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 large clinical trials, the safety of participants, and the
efficacy of treatments being tested.  The DSMB also makes recommendations to
NIAID concerning continuation, termination or modification of these trials
based on observed beneficial or adverse effects of the interventions under
study.  This board panel is funded and managed separately by NIAID.

Division of AIDS (DAIDS).  The extramural Division that has the primary
responsibility within the NIAID for the design, implementation and oversight
of basic and clinical research programs on HIV/AIDS.

Executive Committee.  The Executive Committee, established and chaired by the
PI of the PLG, represents the main governing body of the HPTN.  This committee
will be responsible for the conduct and overall activities of the HPTN.

HIV Network for Prevention Trials/HIV Network for Efficacy Trials (HIVNET). 
Multi-institutional clinical infrastructure currently responsible for the
conduct of Phase I-III clinical trials of non-vaccine prevention modalities
and Phase II/III vaccine clinical trials.  This contract program is scheduled
to terminate in Fiscal Year 2000 and will be extended to provide for a
transition of ongoing trials to the HPTN.

HIV Prevention Trials Network (HPTN).  The HPTN will be a collaborative
network of institutions comprised of the CORE, CL, HPTUs, and the SDMC,
designed to carry out a comprehensive scientific agenda of HIV prevention
research.  The network will conduct domestic and international clinical and
related laboratory research towards this objective.  The mission will be to
identify, prioritize, and conduct research on promising prevention
intervention concepts for the prevention of HIV disease worldwide.

HIV Prevention Trial Units (HPTUs).  The HPTUs will: (1) contribute to the
HPTN research agenda, (2) conduct and participate in Phase I, II, and/or III
prevention intervention clinical trials domestically and/or internationally,
and (3) expand for multiple prevention efficacy trials.

HIV Vaccine Trials Network (HVTN) - The HVTN will be a collaborative network
of institutions comprised of the CORE, CL, HVTUs, and the SDMC, designed to
carry out a comprehensive scientific agenda on HIV vaccines.  The network will
conduct domestic and international clinical and related laboratory research
towards this objective.  The mission will be to identify, prioritize, and
conduct research on promising vaccine concepts for the prevention of HIV
disease worldwide.

HIV Vaccine Trials Unit (HVTU) - An HVTU is a clinical site that is a member
of the collaborating group of institutions comprising the HVTN.  An HVTU may
be organized as a main clinical site or a main site and several subunits under
the leadership of a Principal Investigator, or Co-Principal Investigators.

Prevention Leadership Group (PLG).  The Prevention Leadership Group consists
of the Principal Investigator for the CORE, the Principal Investigator for the
SDMC and the Principal Investigator for the CL; these three will be the core
of the Executive Committee.  The Executive Committee will lead the HPTN. 
Members of the Executive Committee will be designated by HPTN policies and
procedures.

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 by subcontract within an HPTU. 
Subunits may be established to contribute to the scientific agenda and/or
clinical trial accrual goals.

Vaccine Leadership Group (VLG) - The Vaccine Leadership Group consists of the
Principal Investigator for the CORE, the Principal Investigator for the SDMC
and the Principal Investigator for the CL; these three will be the core of the
Executive Committee.  The Executive Committee will lead the HVTN.  Members of
the Executive Committee will be designated by HVTN policies and procedures

Vaccine and Prevention Research Program (VPRP) - The VPRP is a unit within
DAIDS that is responsible for the design, implementation, and oversight of HIV
vaccine and prevention research programs funded by the Division.

RESEARCH OBJECTIVES

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, by the transfusion of HIV infected blood or blood
products, 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 identification of improved affordable 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 foster 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, NIH has supported
domestic and international studies to evaluate prevention trial preparedness
and the safety and efficacy of promising interventions to prevent sexual,
parenteral, and perinatal transmission using HIV seroincidence as the primary
trial endpoint.  The interventions evaluated encompass topical microbicides,
sexually transmitted disease (STD) treatment, prophylaxis to prevent mother-
to-child transmission, and behavioral risk reduction strategies.  HIVNET
studies have been carried out in close coordination and collaboration with
other agencies that are involved in prevention research.

The HPTN will be a coordinated group of clinical and laboratory researchers
that will have the capability and capacity to carry out a comprehensive HIV
prevention research agenda focused on the clinical evaluation of promising HIV
prevention interventions, and addressing key scientific questions related to
prevention research and development.  The HPTN will transition ongoing studies
from the HIVNET and initiate new studies according to the network's scientific
agenda and priorities.

In addition to the HPTN, the NIAID is supporting the creation of the HIV
Vaccine Trials Network (HVTN) to perform Phase I, II and expand to Phase III
clinical trials of HIV vaccines (RFA-98-014 available at
grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-014.html, released October 23,
1998.)  Clinical trials of vaccines focused on questions around maternal-
infant transmission will be conducted within the HPTN and may be in
collaboration with the HVTN and, when desired, the Pediatric AIDS Clinical
Trials Network.  It should be noted that sites funded under the HPTN may also
serve as effective venues for implementation of larger HIV vaccine trials;
therefore linkages between HPTN, HVTN, and other scientific organizations, are
strongly encouraged.

SCOPE

The objective of this RFA is to solicit clinical field sites (HPTUs) that will
implement the scientific agenda of the HPTN and contribute to updating and
expanding that agenda as necessary.  As such, responses to this RFA are
required, at a minimum, to address three major areas:  (1) scientific ability
to contribute to the HPTN research agenda, (2) capability and clinical
expertise of a site to conduct Phase I, II, and/or III prevention intervention
clinical trials domestically and/or internationally, and (3) ability to expand
for multiple prevention efficacy trials.

1.  Ability to contribute to HPTN research agenda.  Applicants should describe
their expertise, experience, and capacity to conduct prevention research in
the U.S. and/or a foreign country for specific technical areas  (e.g.,
microbicides, perinatal interventions, behavioral interventions, hormonal
contraceptive use, and HIV, etc.) as it relates to the HPTN scientific agenda. 
Applicants should describe their ability to lead, contribute to, and
prioritize prevention research activities, including their scientific
contributions to the design and conduct of HIV prevention trials, such as
addressing basic research questions utilizing prevention trial specimens.

2.  HPTU capabilities.  The ability to implement and manage prevention
research in the U.S. and/or a foreign country should be described as outlined
in the PLG scientific agenda (see APPLICATION PROCEDURES for information
regarding how to receive copies of available PLG scientific agendas). 
Expertise of key staff should be described.  Applications should describe the
applicant's clinical research organization and include plans, information and
documentation that describe the capability to accomplish the work
successfully.  Requirements of sites are outlined in Awardee Rights and
Responsibilities in TERMS and CONDITIONS OF AWARD, below.

3.  Plans for expansion for multiple efficacy trials.  Applications should
contain a plan for expansion for additional populations for prevention trials,
as outlined in the PLG scientific agenda.  The plan must specify the
additional resources, including facilities and personnel, required to expand
recruitment, enrollment, short-term and long-term follow-up, consistent with
the requirements of the HPTN research agenda.

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 HPTUs.  Specific tasks and activities in carrying out the
activity will be shared among the awardees, NIH staff and its contractors.

A.  Awardee Rights and Responsibilities

Awardees will have the primary responsibility for conducting the research
within the guidelines of the RFA, and agree to the participation of NIH staff
in those aspects of scientific and technical management of the project
described in these terms and conditions. The organization or individual
awarded cooperative agreement by NIH that is responsible and accountable for
the use of the funds provided and for the performance of the grant-supported
project or activities.  The grantee is the entire legal entity even if a
particular component is designated in the award document. The grantee is
legally responsible and accountable to NIH for the performance and financial
aspects o of the grant-supported project. Specifically, awardees have primary
responsibilities as described below.

1.  The awardee agrees to accept and abide by the Bylaws of the awarded HPTN,
the research priorities of the HPTN scientific agenda, and accept the
performance standards established by the HPTN.

2.  The awardee will follow the International Conference on Harmonization's
(ICH) Guideline for Good Clinical Practice. In addition, each HPTU will have
experienced physician/doctoral level investigators associated with the project
who have demonstrated expertise in multi-center prevention clinical trials. 
Plans for adequate staffing should be included, such as the required nursing,
pharmacy,  data management and outreach personnel needed to recruit and screen
potential participants, implement clinical research protocols, perform
protocol required assessments, dispense investigational agents (if applicable)
and appropriately document clinical data, to meet all data reporting
requirements of the HPTN and DAIDS.  Plans will also include the necessary
coordination and support of research activities, including medical/clinical
procedures and/or social services, quality assurance, laboratory procedures,
and secretarial and administrative support.  Applicants proposing sub-sites to
a main site, or a consortia of sites, should provide plans for a co-
investigator(s) at an appropriate level of effort who shall provide scientific
leadership and shall be responsible for development and implementation of
mechanisms to ensure local government (if international) and community
preparedness for and involvement in clinical trials research plans and
activities in concert with the Principal Investigator of the main unit of the
HPTU.

3.  The awardee will develop and implement strategies for recruitment,
retention and long-term follow up of study participants appropriate to conduct
Phase I, II, and/or III clinical trials, both domestically and in foreign
countries in the specified technical areas.  The awardee will make every
effort to recruit volunteers for domestic or international trials who are
representative of the populations within their geographical region, paying
particular attention to gender and members of minority groups (e.g., in the
U.S. should include African-Americans, Latinos/Latinas, Asians and Pacific
Islanders, and Native Americans).

4.  The awardee will provide long-term follow-up for volunteers who become
infected with HIV after trial enrollment.  The awardee will refer an infected
volunteer to a qualified physician or clinic for medical care after HIV
infection is determined.  In addition, HPTN clinical sites will submit
information on the availability and locality of clinical trials with
potentially beneficial treatments for HIV-1 infection and disease to the
infected volunteers.

5.  Quality Assurance: Investigational Drug Management.  The awardee
performing clinical studies sponsored by the NIH must comply with all Federal
regulations for investigational agents, and with DAIDS Standard Operating
Procedures.  Before clinical studies are initiated, the awardee must submit
and receive approval from DAIDS of a site registration plan, a pharmacy plan,
and the individual protocols.

6.  Quality Assurance: Internal Data Quality Control.  The awardee must
establish an internal quality assurance, and quality management plan to assess
the quality of the research record, and operating procedures.  These plans are
subject to approval by the HPTN leadership and DAIDS, and apply to both the
main unit and any affiliated sites.

7.  Quality Assurance: External Data Quality Control.  The awardee shall
cooperate with the DAIDS Clinical Site Monitoring contractor, and other
federally supported site monitoring staff who will inspect records to assure
compliance with all federal regulations and IHC's GCP guidelines, and NIH
policies on patient safety, data completeness and accuracy, and quality
control.

8.  Quality Assurance: Local Laboratories.  The awardee shall follow the
standards set forth by the HPTN for certification and specifications.

9.  Participation of New Investigators, Women and Minorities.  The awardee
will establish procedures, and opportunities to ensure the participation of
new investigators, especially women, and racial/ethnic minorities, in all
aspects of the research effort.

10.  Community Advisory Boards (CABs). The awardee is required to establish a
CAB to ensure community input into the research process and to foster a
partnership between researchers and the community, particularly the population
served by the individual unit and/or research study.

11.  Federally Mandated Regulatory Requirements.  The awardee must comply 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 awardee must be able to demonstrate
that: (i) each institution conducting trials has a current, approved Project
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 their legal representative) gives written informed consent prior to entry
on study.  In addition, DAIDS has established policies and procedures
delineated in the "Serious Adverse Experience Reporting Manual for the Vaccine
and Prevention Research Program" A copy of this document can be requested by
contacting Dr. MaryAnne Luzar, listed under Inquiries.  The awardee must
comply with all SAE reporting requirements.

12.  For trials conducted in foreign countries, the awardee 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 Council for International Organizations of Medical Sciences (CIOMS).

13.  Reporting Requirements.  The HPTN Executive Committee will establish
policies for reporting requirements of the sites.  Reports may include
volunteer recruitment and retention rates, volunteer demographics, timeliness
and completeness of all data, including adverse events, completeness and
quality of laboratory data, etc.  The awardee must follow all reporting
policies set forth by the HPTN.

14.  Publication of Data.  The awardee must comply with the rules and
regulations set forth by the HVTN leadership, DAIDS, and manufacturers,
regarding presentation and publication in the scientific literature of major
findings.  Publications or oral presentations of work performed under this
cooperative agreement will require acknowledgment of NIAID/NIH support.  Prior
to the submission of manuscripts for publication, a copy must be provided to
DAIDS.  The awardee retains the rights to the data consistent with current
HHS, PHS, and NIH policies; however, DAIDS will have access to all data
generated under this cooperative agreement and may periodically review it.

B.  NIH Responsibilities

The NIH will have substantial scientific and 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.  Although communication primarily will be with the Executive
Committee of the HPTN, substantial communication is anticipated with all
members of the HPTN.  The following are specific responsibilities of NIH staff
in terms of interventional clinical research, and the NIAID's  role as a drug
sponsor as defined in 21 CFR Part 312.  This project is a part of NIH's
overall program of prevention research.

1.  NIH Coordinating Committee.  The Associate Director for VPRP, DAIDS,
NIAID, will establish an NIH Coordinating Committee for the HPTN.  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, or designee,
will serve as chair of this committee.

2.  Scientific Role in Sponsored Clinical Research.  The Associate Director
for VPRP, or designee will work closely with other members of the HPTN
Executive Committee to assure that the research efforts are consistent with
the NIH agenda for HIV clinical research.  DAIDS will serve as a
liaison/facilitator between pharmaceutical companies, the FDA, and HPTN
investigators.  NIH staff of sponsoring NIH components 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.

3.  Role in Protocol Development.  In order for a clinical study to be
initiated, the final protocol must be approved by the Associate Director,
VPRP.  The Prevention Sciences Review Committee (PSRC) PSRC is a DAIDS
committee created to provide scientific support and assistance during protocol
development, and overall evaluation of research plans; in the context of
relevance to NIAID HIV/AIDS research and on the basis of sound methodology,
reasonable feasibility and safe, ethical standards) will evaluate the initial
trial concept as well as a near final protocol relative to:  (i) the NIH
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.  If
significant safety or regulatory concerns exist and the protocol is
disapproved, NIH will not provide investigational products or permit
expenditure of NIH funds for the proposed investigation.

4.  Involvement in Investigational New Drug Applications.  DAIDS or other
involved NIH organizations will have the option to file an IND on
investigational agents evaluated in HPTN studies.  Appropriate DAIDS staff
will advise the HPTU investigators on specific regulatory requirements for IND
sponsorship.  In situations where DAIDS is the IND sponsor, DAIDS will also
assemble, review, and submit the required regulatory documents to the FDA.  A
DAIDS pharmacist will participate on the protocol team, consult on the
pharmaceutical aspects of protocol development, and will interact with
pharmaceutical companies to ensure product availability.

5.  Clinical Trials Agreements (CTA).  Pharmaceutical collaborators providing
investigational agents to DAIDS will negotiate a CTA with DAIDS describing
respective responsibilities and rights.  The agreement will include, but is
not limited to, IND sponsorship, safety and data monitoring, publications, and
access to data.  Generally, terms in the CTA covering data access and sharing
will conform to policies developed jointly by the HPTN and DAIDS. 
Pharmaceutical collaborators generally request that patentable inventions
discovered in the studies be brought to their attention, and subsequently the
company will have right of first refusal, provided that the collaborator has
rights to the background patent.  The intellectual property administrator for
each primary trial site must provide a Letter of Understanding to DAIDS
acknowledging these rights.

6.  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 domestic and international collaborators or for vaccine
studies being conducted in domestic and 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 organization or
company, monitoring activities will be the responsibility of their medical
representatives.

7.  Role in Protocol Closure.  The Associate Director, VPRP, or designee, and
designees from co-sponsoring institutes, 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 HPTN Leadership.  NIH
co-sponsoring institutes, upon reviewing the recommendations from the DSMB
and/or reviewing other relevant information, 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.

8.  Access to Data.  The Associate Director, VPRP, or designee, and designee's
from co-sponsoring institutes, 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.  Secondary data analysis may be undertaken by the NIH with the
concurrence of the grantee.

9.  Site Monitoring.  DAIDS has an external Clinical Site Monitoring Contract
to evaluate GCP, regulatory compliance, accurate protocol implementation,
internal quality assurance, and test agent accountability.  The monitoring
contractor will visit the site periodically to review selected protocols,
provide training on general protocol conduct, review internal (Quality
Assurance/Quality Control) QA/QC plans, audit pharmacies, and document error
resolution.

10.  Review of Performance.  The performance of all sites will be reviewed at
least annually by the Associate Director, VPRP, other VPRP staff, the co-
sponsoring institutes, and the HPTN Executive Committee using a comprehensive
annual progress report, clinical site evaluations developed by the HPTN
Executive Committee, and site monitoring reports provided by the DAIDS
contractor.  DAIDS and co-sponsoring Institute staff will assist the HPTN 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.

C.  Collaborative Responsibilities

1.  Group Governance - The PLG will establish an Executive Committee as the
central decision-making body for the HPTN and will include the PIs of the
three PLG components:  the Core, Statistical and Data Management Center,
Central Laboratory, as well as representative HPTU PIs.  The PI of the core
will serve as the chairperson.  The Committee also will include the Associate
Director, VPRP, or designee, as a voting member, and representatives of co-
sponsoring Institutes included as non-voting ad hoc members.  Additional
membership and any change in the chairperson will be accomplished as defined
in the HPTN Bylaws.

2.  Performance.  The leadership of the HPTN will establish procedures for
evaluating the performance of all awardees.  This mechanism will include a
procedure for making a recommendation to DAIDS regarding adjustment of
institutional funds based on level of contribution and performance.

3.  National Meetings.  The awardee's Principal Investigator will attend two
2-day national meetings/year.  The HPTN is expected to hold at least one of
the two national meetings in the Washington, D.C. metropolitan area.

D.  Arbitration

Any disagreement that may arise on scientific or programmatic matters (within
the scope of the award) between award recipients and the NIH 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 NIH, and a 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 adverse
action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and
HHS regulations at 45 CFR Part 16.

Cooperative agreements are subject to the administrative requirements outlined
in OMB circulars 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 NIAID and the investigators will be
incorporated in the Notice of Grant Award.  However, these terms will be in
addition to, not in lieu of, the customary programmatic and financial
negotiations 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:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and 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 August 18, 1999, a letter of
intent that includes a descriptive title of the overall proposed research, the
name, address, telephone number, and email address of the Principal
Investigator, and the number and title of this RFA.  Please note that 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 NIAID 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

Each competing HPTU will submit an application that addresses the RESEARCH
OBJECTIVES AND SCOPE, and Awardee Rights and Responsibilities (in Terms and
Conditions of Award) stated above.  Applicants should be aware that the PLG
will not have been awarded at the time applications are due in response to
this HPTU RFA.  It is also possible that the highest scoring PLG may be
modified as a result of the peer review process prior to award.  It is the
intent of NIAID to aid applicants responding to this RFA by making available
the research agendas of those applicants who responded to the PLG RFA, when
permission of the applicants has been granted.  Requests for the available
research agenda(s) must be made in writing to Dr. Rodney Hoff at the address
that appears under the INQUIRIES section.  Upon receipt of a written request,
the research agenda(s) will be mailed (either hard copy, or electronically if
possible).  In addition, HPTU applicants may have the opportunity to submit a
brief addendum to their application prior to review for the purpose of
clarifying or addressing issues raised by the NIAID after review of the PLG
research agenda.  Further guidance from NIAID on prevention needs, can be
found in the HPLG RFA.

Applications must be submitted on the standard research grant application form
PHS 398 (rev. 4/98).  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 20892-7910 telephone (301)
710-0267, Email:  grantsinfo@nih.gov.  Applications are also available on the
internet at https://grants.nih.gov/grants/forms.htm

Each application requesting support as an HPTU is subject to  the following
page limitations:

o  25 pages for the Research Plan for a single clinical site application as
specified in the Form PHS 398.

o  5 additional pages for each additional clinical site

The RFA title (HIV Prevention Trial Units) and number (AI-99-010) must be
typed on line 2 of the face page of the application, and the YES box must be
marked. The RFA label and line 2 of the application should both indicate the
RFA number.  The RFA label must be affixed to the bottom of the face page. 
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.

Submit a signed, typewritten original of the application, including the
checklist, and three signed exact photocopies (without appendices) 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 five copies of any 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

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 October 14, 1999. 
Applications received after this date will be considered non-responsive to
this RFA and will be returned without review.

In summary, applications in response to this RFA must include, but are not
limited to, responses to the details set forth in the SCOPE section. 
Specifically:

1.  Ability to contribute to HPTN research agenda.  Applicants should describe
their expertise, experience, and capacity to conduct prevention research in
the U.S. and/or a foreign country for specific technical areas  (e.g.,
microbicides, perinatal interventions, behavioral interventions, hormonal
contraceptive use, and HIV, etc.) as it relates to the HPTN scientific agenda. 
Applicants should describe their ability to lead, contribute to, and
prioritize prevention research activities, including their scientific
contributions to the design and conduct of HIV prevention trials, such as
addressing basic research questions utilizing prevention trial specimens.

2. HPTU capabilities.  The ability to implement and manage prevention research
in the U.S. and/or a foreign country should be described as outlined in the
PLG scientific agenda (see APPLICATION PROCEDURES for information regarding
how to receive copies of available PLG scientific agendas).  Expertise of key
staff should be described.  Applications should describe the applicant's
clinical research organization and include plans, information and
documentation that describe the capability to accomplish the work
successfully.  Requirements of sites are outlined in Awardee Rights and
Responsibilities in TERMS and CONDITIONS OF AWARD, below.

3. Plans for expansion for multiple efficacy trials.  Applications should
contain a plan for expansion for additional populations for prevention trials,
as outlined in the PLG scientific agenda.  The plan must specify the
additional resources, including facilities and personnel, required to expand
recruitment, enrollment, short-term and long-term follow-up, consistent with
the requirements of the HPTN research agenda.

BUDGET INSTRUCTIONS

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.  Note that for HIVNET sites conducting prevention intervention clinical
trials, the HPTN leadership group will develop a plan for transition of these
studies to the HPTN.  For this application, include in the budget the costs
for completion of these current studies, and any new studies that may be
implemented under the HPTN.  If applicable, budgets should address
participation in any ongoing HIVNET studies, and any new studies that may be
implemented under the HPTN.  Budgets should address at a minimum the
following:

o  Scientific, medical, technical, recruiting/outreach and support staff

o  Local laboratory costs consistent with performance of the clinical
laboratory tests required in typical Phase I-III prevention intervention
clinical  trials.  The applicant should also include laboratory costs for
screening potential volunteers.

o  Travel, communications, general recruiting and outreach costs (including
volunteer reimbursement costs)

o  Support of a Community Advisory Board, including travel of CAB members to
HVTN meetings

o  Costs for the Principal Investigator to attend two 2-day meetings annually

o  Necessary equipment and supplies

PERSONNEL

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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for responsiveness by NIAID 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 will focus on the scientific merit
of each applicant's proposed contributions to the cooperative group consistent
with the HPTN's scientific agenda.  The second level of review will be
provided by the National Advisory Allergy and Infectious Diseases Council
(NAAIDC).

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 these 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

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?

-  Quality of the scientific contribution to the HPTN research agenda
-  Quality of the operational contribution to the HPTN research agenda
-  Evidence that the scientific contribution reflects a broad understanding of
HIV prevention research within the changing context of the HIV/AIDS epidemic
and of the implications/consequences of prevention research worldwide

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?

-  Availability of relevant populations for HIV prevention interventions
studies
-  Strength and adequacy of plans and mechanisms for recruitment and retention
of clinical trial participants from relevant populations, particularly
minority populations for U.S. sites and subsites (if applicable)
-  Strength and adequacy of the site's and subsites' (if applicable)
management and communication plan, particularly for subsites/sites outside the
U.S.
-  Appropriateness of arrangement and clearances with local and national
authorities
-  Adequacy of plans for implementing multiple efficacy trials including
ability to expand
-  Adequacy of the plans for CAB and community involvement at the site and
subsites (if applicable)
-  Adequacy and feasibility of plans to foster participation of new
investigators, especially women and racial/ethnic minorities

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

- Evidence that the proposed scientific contribution to the HPTN incorporates
innovative approaches to the development and clinical evaluation of prevention
interventions
- Evidence that the proposed plans for recruiting and retaining target
populations employ innovative methods, especially in studies recruiting
populations at higher risk for acquisition of HIV
- Evidence that the proposed plans for implementing multiple efficacy trials
employ innovative approaches for expanding recruitment and ensuring adequate
retention
- Evidence that the proposed plans for community education regarding HIV
preventive interventions trials incorporates effective strategies

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 professional qualifications, research experience, and time
commitment of the PI and key personnel, and previous experience with
participation in a multi-center clinical trials network

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?

-  Evidence of the necessary expertise, experience and capacity of the site
and subsites (if applicable) to carry out the aims of the HPTN research agenda
-  Strength and adequacy of the plan to ensure a synergistic environment for
institutions that submit more than one site application

Additional Specific Review Criteria

The following section expands upon review criteria for the Protection of Human
Subjects and for Gender and Minority and 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, 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 applicant to contribute to the scientific
agenda.

SCHEDULE

Letter of Intent Receipt Date:  August 18, 1999
Application Receipt Date:       October 14, 1999
Scientific Review Date:         January 2000
Advisory Council Date:          April 2000
Earliest Award Date:            June 1, 2000

INQUIRIES

Inquiries concerning this RFA are strongly encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Rodney Hoff, Sc.D., MPH
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A12
Bethesda, MD  20892-7620
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 496-6177
FAX:  (301) 402-3684
Email:  rh25v@nih.gov

Direct inquiries regarding regulatory affairs and oversight information to:

MaryAnne 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:  ml29g@nih.gov

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:  dt15g@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jane Unsworth
Grants Management Branch
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B25
Bethesda, MD  20892-7610
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 402-6824
FAX:  (301) 480-3780
Email:  ju3a@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog 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 52 and 45 CFR Part 74.  This program is not subject
to the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

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

APPENDIX A

Federal institutions are, in general, eligible to receive NIH grants,
including research project grants and training grants. Federal institutions
must also meet the eligibility requirements of the grant program from which
support is sought.  PHS organizational segments, other than PHS hospitals, may
receive NIH grant support under exceptional circumstances only.  Such
circumstances may include situations where a project cannot be supported
within the mission of the applicant PHS agency or organizational segment, the
activity cannot be performed elsewhere, its non-pursuit would have an adverse
or potentially important impact on the NIH mission, and a grant is determined
to be the appropriate means of carrying out the activity.  However, NIH may
not award a grant to an NIH component.

Although the performance site may be at a level lower than the agency or
department level of the Federal institution, when an award is made to an
eligible Federal institution, the Federal agency or department will be the
designated grantee and must assume responsibility for the project.  A Federal
institution must also ensure that its own authorizing legislation will allow
it to receive NIH grants and to be able to comply with the award terms and
conditions.

A document certifying both the assumption of responsibility and authority to
receive a grant must accompany each new and competing continuation
application.  The certification must be signed by the head of the responsible
Federal department or independent agency or a designee who reports directly to
the department or agency head.  (In the case of the Department of Defense, the
Departments of the Army, Navy, and Air Force shall be considered the Federal
department; and their Secretaries, the responsible Department head.)  This
certification is in addition to any certifications that are made by the
authorized institutional official's signature on the face page of the
application.  The certification requirement does not apply to Department of
Veterans Affairs' Medical Centers (VAMC), Bureau of Prisons' (Department of
Justice) hospitals, PHS hospitals (including Indian Health Service hospitals),
or other PHS organizational segments.

Investigators with joint appointments at the Department of Veterans Affairs
(VA) and an affiliated university must have a memorandum of understanding
(MOU) that specifies the title of the PI's appointment, the responsibilities
(at both the university and the VA) of the proposed PI, and the percentage of
effort available for research.  The MOU must be signed by the appropriate
officials of the grantee organization and the VAMC and must be updated at
least annually.  Under this model, there is no involvement of a VA-affiliated
non-profit research corporation (VANPC).  The joint VA/university appointment
of the investigator constitutes 100 percent of his or her total professional
responsibilities.

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