HIV VACCINE CLINICAL TRIAL UNITS

Release Date:  June 18, 1999

RFA:  AI-99-009

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  August 18, 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 Vaccine Trial Clinical Units
(HVTUs) which are integral parts of an HIV Vaccine Trials Network (HVTN) designed
to carry out a comprehensive scientific agenda on HIV vaccines.

The HIV Vaccine Trials Network (HVTN) will be a cooperative network of NIAID
awardees that will implement a comprehensive agenda of clinical research on HIV
vaccines in the U.S. and abroad. The HVTN will have:

o  A single Vaccine Leadership Group (VLG) 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.  Applications for the VLG have been
solicited under RFA AI-98-014 available at
grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-014.html

o  The HIV Vaccine Trial Clinical Units (HVTUs) being solicited by this RFA. The
HVTUs will (1) contribute to the HVTN research agenda, (2) participate in
domestic and international Phase I and II clinical trials of candidate HIV
vaccines, and (3) participate in domestic and international Phase III efficacy
trials of HIV vaccines.

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 HVTN, the NIAID is supporting the creation of the HIV Prevention
Trials Network (HPTN), to perform Phase I, II and III trials of other prevention
strategies to prevent HIV-1 transmission, domestically and internationally (RFA
AI-98-015 available at
grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-015.html was released October 30,
1998)  Clinical trials of vaccines focused on questions around maternal-infant
transmission will be conducted within the HPTN in collaboration with the HVTN
and, when desirable, the Pediatric AIDS Clinical Trials Network.  Sites funded
under the HPTN may 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 Vaccine 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 HVTU application, and/or a single
application encompassing one or more scientific area's or approaches.  An HVTU
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 NIAID scientific and programmatic involvement is
anticipated during performance of the activity.  Under the cooperative agreement,
the NIAID'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 $13 million total costs (direct and indirect) will be available for
the first year of support.  NIAID estimates that 8 to 10 awards will be made. 
The usual PHS policies governing grants administration and management will apply. 
Although this program is provided for in the financial plans of the NIAID, 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,
the numbers of participants needed for the research agenda, and availability of
funds for this purpose.

DEFINITIONS

AIDS Vaccine Evaluation Group (AVEG) - Multi-institutional clinical
infrastructure currently responsible for the conduct of Phase I/II HIV vaccines. 
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 HVTN.

Central Laboratory (CL) - the HVTN component that will implement state-of-the-art
assays and technologies that are essential for the completion of the vaccine
research agenda.  In addition to the performance of these assays for the HVTN,
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 HVTN VLG and will provide support for protocol related
studies only.

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

Data and Safety Monitoring Board (DSMB) - 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 - Established and chaired by the PI of the VLG, this is the
main governing body of the HVTN responsible for the conduct and overall
activities of the HVTN.  Membership of the Executive Committee will be determined
by HVTN policies and procedures.

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

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 single clinical site or a main site and several satellites
(subunits) under the leadership of a Principal Investigator.

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

Subunit - A subunit is an institution supported by subcontract under the
cooperative agreement award to a HVTU.  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.

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 development of safe and effective HIV vaccines for worldwide use is one of
the highest priorities to the NIAID.

As the pandemic of the Acquired Immunodeficiency Syndrome (AIDS) continues to
grow, the importance of developing safe and effective vaccines and other
prevention modalities to prevent infection with the Human Immunodeficiency Virus
(HIV) and the development of AIDS assumes increasing importance.  In pursuit of
this goal, the Vaccine and Prevention Research Program (VPRP), DAIDS, NIAID,
supports a comprehensive program of basic and applied research directed toward
the development of safe and effective AIDS vaccines and other prevention
interventions.

NIAID-funded HIV vaccine research groups (primarily the AVEG -AIDS Vaccine
Evaluation Group) have thus far evaluated the safety and immunogenicity of twenty
candidate AIDS vaccines in Phase I trials in over 1750 volunteers who are at low
risk of exposure to and infection with HIV-1.  Several additional new candidate
vaccines will enter Phase I testing in the next five years.  One Phase II trial
has been completed with nearly 300 volunteers enrolled from heterogeneous
populations, including those at high risk of exposure to HIV.  The study was
comprised of two HIV-1 gp120 subunit vaccines and evaluated their safety and
immunogenicity.  The impact of trial participation on high-risk activity in
populations at risk for acquiring HIV-1 infection was also evaluated.  A second
Phase II trial, evaluating the safety and immunogenicity of live recombinant
canarypox-HIV constructs (ALVAC vCP205 - Pasteur Merieux Connaught) administered
with or without HIV-1 SF2 recombinant gp120 (Chiron Vaccines), is in the follow-
up phase with 435 enrolled volunteers.

NIAID-sponsored trials of HIV vaccine candidates have demonstrated the safety of
candidates tested thus far, including recombinant envelope proteins (e.g., gp120,
gp160, and gp41); a variety of pox virus recombinants, alone and in combination
with recombinant envelope proteins, and a DNA vaccine product containing gag/pol
structural proteins.  A number of these candidate vaccines have elicited binding
antibodies and neutralizing antibodies to homologous virus.  These studies have
also demonstrated the ability of certain vaccine products, (e.g., pox virus/HIV
recombinants) to elicit cellular immunity as demonstrated by lymphoproliferation,
antibody-dependent cellular cytotoxicity (ADCC) and cytotoxic T lymphocytes (CTL)
against selected HIV epitopes.  Studies have also demonstrated that certain
adjuvants are useful for inducing increased levels of antibody response.

NIAID is now establishing the HVTN, a group of clinical and laboratory
researchers that will have the capability and capacity to carry out a
comprehensive HIV vaccine research agenda focused on the clinical evaluation of
promising HIV vaccine candidates, and addressing key scientific questions related
to vaccine research and development.  Through this process the HVTN will
transition ongoing studies from the AVEG and HIVNET and initiate new studies
according to the network's scientific agenda and priorities.

The HVTN needs capacity and capability to conduct Phase I and Phase II (safety
and immunogenicity) trials of candidate HIV vaccines, domestically and in foreign
countries.  Utilization of data and biological specimens from these studies to
expand basic knowledge on human immunology, viral pathogenesis, and vaccine
design/development are highly encouraged.  The HVTN must also be prepared to
rapidly implement Phase II/III or III (efficacy) studies, domestically and
internationally, should one or more vaccine candidates merit such testing.

In addition to the HVTN, the NIAID is supporting the creation of the HIV
Prevention Trials Network (HPTN), to perform Phase I, II and III trials of other
prevention strategies to prevent HIV-1 transmission, domestically and
internationally (RFA AI-98-015 available at
http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-98-015.html was released October
30, 1998)  Clinical trials of vaccines focused on questions around maternal-
infant transmission will be conducted within the HPTN in collaboration with the
HVTN and, when desirable, the Pediatric AIDS Clinical Trials Network.  Sites
funded under the HPTN may 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.

SCOPE

The objective of this RFA is to solicit applications from clinical sites (HVTUs)
that will implement the scientific agenda of the HVTN and contribute to updating
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 HVTN research agenda, (2) capability and clinical expertise of a site to
conduct Phase I and II clinical trials of candidate HIV vaccines, domestically
and/or internationally, and (3) ability to expand to recruit participants for
large, multi-center efficacy trials of one or more HIV vaccine candidates.

1.Contribute to the HVTN research agenda.  Applicants should describe their
expertise, experience and capacity to conduct vaccine research in the U.S. and
foreign countries, as it relates to the HVTN scientific agenda.  Applicants
should demonstrate their ability to lead, contribute to, and prioritize vaccine
clinical research, including their scientific contributions to the design and
conduct of HIV vaccine or related trials and the conduct of laboratory research
ancillary to HIV vaccine trials, such as the development or applications of new
assays, or addressing basic research questions utilizing vaccine trial specimens.

2.  Phase I and II Vaccine Trials.  The capability and experience to implement
and manage a Phase I and/or II vaccine clinical trial based in the U.S. and/or
a foreign country as it relates to the HVTN scientific agenda should be
described.  Applicants should assume that they will be participating in four to
six domestic phase I trials and one phase II domestic trial at any time, and/or
in one phase 1 or phase II trial at international sites, at any time Requirements
for HVTUs are presented in A.  Awardee Rights and Responsibilities in TERMS AND
CONDITIONS OF AWARD below.

3.  Efficacy trials.  Applications should describe a plan for transition from
Phase I and II vaccine study activity to vaccine efficacy trial recruitment,
enrollment, immunization, and short-term and long-term follow-up, consistent with
the requirements of the HVTN 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 HVTUs. 
Specific tasks and activities in carrying out the activity will be shared among
the awardees, DAIDS staff and its contractors.

A.  Awardee Rights and Responsibilities

Awardees will have 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 accepts and will abide by the Bylaws of the HVTN, the research
priorities of the HVTN scientific agenda, and accepts the performance standards
established by the HVTN.

2.  The awardee will follow the International Conference on Harmonization's (ICH)
Guideline for Good Clinical Practice (GCP).  In addition, each HVTU will have
experienced physician investigators associated with the project who have
demonstrated expertise in multi-center clinical trials.  Plans for adequate
staffing will be included, such as the required nursing, pharmacy, and data
management and outreach personnel needed to recruit and screen potential
participants, implement clinical research protocols, perform protocol required
assessments, including laboratory assessments, perform protocol specific assays
for safety monitoring, dispense investigational agents and appropriately document
clinical data, to meet all data reporting requirements of the HVTN 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. 
For applicants proposing sub-sites to a main clinical unit, or a consortia of
sites, provide 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.

3.  The awardee will develop and implement strategies for recruitment, retention
and long-term follow-up of study participants for Phase I and Phase II trials of
experimental HIV vaccines, both in the U.S. and/or in foreign countries with high
HIV seroincidence.  The awardee make every effort to recruit volunteers for
domestic or international Phase I trials who are representative of the geographic
region, paying particular attention to gender and members of minority groups
(e.g., in the U.S. inclusion of African-Americans, Latinos/Latinas, Asians and
Pacific Islanders, and Native Americans).  Phase II trials may require
recruitment of both healthy volunteers at low risk of HIV-1 infection, as well
as individuals more representative of the populations at higher risk for
acquiring HIV-1 infection (e.g., men who have sex with men, injection drug users,
and women and men at increased risk due to heterosexual contacts).  Appropriate
HIV counseling of potential volunteers regarding HIV-1 transmission and methods
to prevent transmission shall be provided, as shall mechanisms to educate the
relevant communities about HIV-1 and HIV vaccine trials.

4.  The awardee will provide long-term follow-up for volunteers who become
infected with HIV after trial enrollment.  Each site will refer an infected
volunteer to qualified physicians or clinics for medical care after HIV infection
is determined.  In addition, the awardee will provide information on availability
and location 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 NIAID must comply with all Federal regulations
for investigational agents, and with DAIDS Standard Operating Procedures.  Before
clinical studies are initiated, a unit 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 recording and operating procedures.  These plans are subject to
approval by the HVTN 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 Clinical Laboratory.  The awardee will follow the
standards set forth by the HVTN for laboratory certification.

9.  Participation of New Investigators, Women and, Minorities.  The awardee will
establish procedure 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 Board (CAB).  The awardee will have a CAB as required of
all NIAID funded sites 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 shall 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 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 awardee will adhere to HVTN Executive Committee
policies for reporting.  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.

14.  Publication of Data.  The awardee will comply with the rules and regulations
set forth by the HVTN leadership, DAIDS, and manufacturers, regarding
presentation and publication in 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.

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

B.  NIAID Staff Responsibilities

The NIAID will have substantial scientific and programmatic involvement during
the conduct of this activity, through technical assistance, advice, and
coordination.  The role of DAIDS staff is to assist and facilitate.  Although
communication primarily will be with the Executive Committee of the HVTN,
substantial communication is anticipated with all members of the HVTN.  The
following are specific responsibilities of DAIDS staff in terms of interventional
clinical research, and the NIAID's role as an IND sponsor as defined in 21 CFR
Part 312.

1.  Scientific Role in NIAID Sponsored Clinical Research. The Associate Director
for VPRP, or designee, will be a member of the HVTN Executive Committee to assure
that the research efforts are consistent with the NIAID agenda for HIV clinical
research and complements those of other NIAID and NIH programs.  DAIDS will serve
as a liaison/facilitator between pharmaceutical companies, the FDA, and HVTN
investigators.  DAIDS will serve as a resource of scientific and policy
information related to the goal of the HVTN.  DAIDS will also independently
support a Data and Safety Monitoring Board (DSMB) that will oversee vaccine
trials.

2.  DAIDS 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 DAIDS 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 NIAID research agenda and other
NIAID/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, DAIDS will not provide investigational products
or permit expenditure of NIAID funds for the proposed investigation.

3.  DAIDS Involvement in Investigational New Drug Applications.  DAIDS will have
the option to file an IND on investigational agents evaluated in HVTN studies. 
Appropriate DAIDS staff will advise the HVTU 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.

4. 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 HVTN 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 awardee must provide a Letter of Understanding to DAIDS
acknowledging these rights.

5.  DAIDS Role during Study Conduct.  DAIDS will provide Regulatory Training at
an annual meeting held in the Washington, D.C. area.  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.

6.  DAIDS Role in Protocol Closure.  The Associate Director, 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
VLG Leadership.  NIAID, 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.

7.  Access to Data.  The Associate Director, 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.  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 awardee 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.

9.  Review of Performance.  The performance of all sites will be reviewed at
least annually by the Associate Director, VPRP, other VPRP staff, and the HVTN
Executive Committee using the comprehensive annual progress report, clinical site
evaluations developed by the HVTN Executive Committee, and site monitoring
reports provided to DAIDS by its contractor.  DAIDS staff will assist the HVTN
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 VLG will establish an Executive Committee as the
central decision-making body for the HVTN that will include the PI's of the three
VLG components: the Core, Statistical Center, CL, as well as representative HVTU
PIs.  The PI of the Core will serve as the chairperson.  The Committee will also
include the Associate Director, VPRP, or designee, as a voting member. 
Additional membership and any change in the chairperson will be accomplished as
defined in the HVTN Bylaws.

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

D.  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 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 the 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
http://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:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

For the purpose of this RFA, adults are defined as persons 18 years of age and
older.  The NIH has other programs for HIV clinical research in children under
18 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

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

Each competing HVTU 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 Vaccine
Leadership Group (VLG) award will not have been made at the time applications are
due in response to this HVTU RFA.  It is also possible that the research agenda
of the VLG awardee will 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;
see under INQUIRIES for how to contact Dr. Jorge Flores for further information. 
In addition, HVTU 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 VLG research agenda.  Further
guidance from NIAID on vaccine research needs, can be found in the HVLG 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) 435-0714, Email: 
grantsinfo@nih.gov.  Applications are also available on the internet at
http://grants.nih.gov/grants/forms.htm

Each application requesting support as an HVTU 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 Vaccine Trial Units) and number (AI-99-009) 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 (but no 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 appendices must 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.  Contribute to the HVTN research agenda.  Applicants should describe their
expertise, experience and capacity to conduct vaccine research in the U.S. and
foreign countries, as it relates to the HVTN scientific agenda.  Applicants
should demonstrate their ability to lead, contribute to, and prioritize vaccine
clinical research, including their scientific contributions to the design and
conduct of HIV vaccine or related trials and the conduct of laboratory research
ancillary to HIV vaccine trials, such as the development or applications of new
assays, or addressing basic research questions utilizing vaccine trial specimens.

2. Phase I and II Vaccine Trials. The capability and experience to implement and
manage a Phase I and/or II vaccine clinical trial based in the U.S. and/or a
foreign country as it relates to the HVTN scientific agenda should be described. 
Applicants should assume that they will be participating in four to six domestic
phase I trials and one phase II domestic trial at any time, and/or in one phase
1 or phase II trial at international sites, at any time.

3. Efficacy trials.  Applications should describe a plan for transition from
Phase I and II vaccine study activity to vaccine efficacy trial recruitment,
enrollment, immunization, and short-term and long-term follow-up, consistent with
the requirements of the HVTN 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.  Note that for AVEG
or HIVNET sites conducting vaccine clinical trials, the HVTN leadership group
will develop a plan for transition of these studies to the HVTN.  Current AVEG
or HIVNET awardees that apply for awards under this RFA should include in the
budget the costs for completion of these current studies, and any new studies
that may be implemented under the HVTN. 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 a typical Phase I and II vaccine trial.  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 HVTN'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. 
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?

-  Scope and quality of the proposed scientific contributions of the applicant
to the HVTN research agenda
-  Quality of the operational contribution to the HPVN research agenda
-  Evidence that the scientific contribution reflects a broad understanding of
HIV vaccine 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 vaccine trials, particularly minority
populations for U.S. sites and subsites (if applicable)
-  Strength and adequacy of plans and mechanisms for recruitment and retention
of clinical trial participants from relevant populations
-  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 plan to implement Phase II/III and III HIV vaccine trials
including ability to expand
-  Adequacy of 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 HVTN incorporates
innovative approaches to the development and clinical evaluation of HIV vaccines
-  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 Phase II/III vaccine trials
utilize innovative approaches for expanding recruitment and ensuring adequate
retention
-  Evidence that the proposed plans for community education for HIV preventive
vaccine trials incorporate 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 HVTN 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:

Jorge Flores M.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A11
Bethesda, MD  20892-7620
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 435-3578
FAX:  (301) 402-3684
Email:  jf30t@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. Ann Devine
Grants Management Branch
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B23
Bethesda, MD  20892-7610
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 496-5601
FAX:  (301) 480-3780
Email:  ad22x@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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