HIV VACCINE TRIALS NETWORK LEADERSHIP GROUP

Release Date:  October 23, 1998

RFA:  AI-98-014

P.T.

National Institute of Allergy and Infectious Diseases

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

PURPOSE

The Division of AIDS (DAIDS) of the National Institute of Allergy and
Infectious Diseases (NIAID) is soliciting applications for a HIV Vaccine
Leadership Group (VLG) for a planned HIV Vaccine Trials Network (HVTN) to
conduct clinical research on HIV vaccines.

The development of safe and effective HIV vaccines is of the highest priority,
and is the ultimate goal of vaccine research supported by the NIAID.  The HVTN
will provide the focus of clinical research towards this objective.  The
primary mission of the HIV Vaccine Trials Network will be to identify,
prioritize, and conduct research on promising vaccine concepts for the
prevention of HIV disease worldwide.  The HVTN will require the immediate
capacity/capability to conduct Phase I and Phase II (safety and
immunogenicity) trials of candidate HIV vaccines, domestically and in
developing 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.  Such larger capability should be accomplished by demonstrating
linkages to domestic and international investigators with the capacity and
willingness to perform such studies in close collaboration with the HVTN.

The establishment of the HVTN will occur through two announcements: this RFA
for a VLG and the second RFA for clinical sites that will serve as HIV Vaccine
Clinical Trials Units (HVTUs).  The purpose of this first RFA is to establish
a single 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 PI of the Core.  The
VLG will plan and implement a comprehensive agenda of clinical research on HIV
vaccines within a cooperative network of clinical trial sites (HVTUs).  The
HVTUs, which will implement the approved scientific agenda, will be solicited
at a later date under a separate RFA.  Applicants for the VLG must identify a
Principal Investigator for the Core who will assume overall scientific and
operational leadership of the group.  The VLG should include multi-
disciplinary teams of scientists.

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
various non-vaccine strategies to prevent HIV-1 transmission, domestically and
internationally (RFA AI-98-015, HPTN Leadership Group, will be published in
the NIH Guide in the near future).  Clinical trials of vaccines focused on
questions around perinatal transmission will be conducted within the HPTN in
collaboration with the HVTN and the Pediatric AIDS Clinical Trials Networks. 
Sites funded under the HPTN may 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 Trials Network
Leadership Group, is related to the priority area of HIV infection.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No.
017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, SDMC
20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

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

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for these awards will be
the cooperative agreement (U01).  The cooperative agreement is an assistance
mechanism in which substantial 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 total project period for each award is five years. 
The anticipated award date is September 1999.  The NIAID has not determined
whether and how this solicitation will be continued beyond the present RFA.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for the first
year of support for awards made under this RFA will total $12 million.  The
distribution of funds is projected as follows:  the Core award at
approximately $4 million including a discretionary fund not to exceed $1.5
million; the CL at approximately $5 million; and the SDMC award at
approximately $3 million.  The Core will have responsibility for transitioning
the phase in/phase out of vaccine trials currently underway in the current
AVEG/HIVNET system.  Although a single CL will be designated for the purposes
of co-ordination, it is recognized that the scope of the laboratory
requirement will make it unlikely that a single laboratory will be able to
respond.  Applicants for the CL are encouraged to identify a network of
laboratory sites, which may be potential HVTUs, which have capability and
capacity to carry out the laboratory functions proposed within the research
agenda.

Applications for clinical trial sites (HVTU) within the HVTN will be solicited
under a separate RFA.  Approximately $13 million total costs are expected to
be available for the first year of support for proposed clinical trials and
trial sites under the subsequent HVTU RFA.

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 (5) years
of the grant will be contingent upon satisfactory progress during the
preceding years and availability of funds for this purpose.

DEFINITIONS

AIDS Vaccine Evaluation Group (AVEG) - Multi-institutional clinical
infrastructure currently responsible for the conduct of Phase 1/2 HIV
vaccines.  This contract program is set to expire in fiscal year 2000.

Central Laboratory (CL) - The CL is the central laboratory that will enable
the HVTN to implement state-of-the-art assays and technologies that are
essential for the completion of the vaccine research agenda, as defined in the
HVTN VLG Application.  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.

Collaborating Institution - A collaborating institution of the HVTN may be the
CORE, the CL, the SDMC, or a HVTU.

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

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

CORE Principal Investigator (PI)  - The CORE Principal Investigator is
responsible for the leadership and coordination of all HVTN activities both
scientifically and administratively, and serves as the Principal Investigator
for the CORE Award.  The CORE PI may or may not be associated with a HVTU. 
The CORE PI responsibility may be transferred during the period of the award
according to election procedures outlined by HVTN bylaws, in which case a new
PI will be nominated and voted upon by the HVTN Executive Committee to lead
the CORE.

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

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

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

HIV Network for Prevention Trials/HIV Network for Efficacy Trials (HIVNET) -
Multi-institutional clinical infrastructure currently responsible for the
conduct of Phase 1-3 clinical trials of non-vaccine prevention modalities and
Phase 2/3 vaccines.  This contract program will expire in Fiscal Year 2000.

HIV Prevention Trials Network (HPTN) - The HPTN will be a collaborative
network of institutions involved in the conduct of all phases of non-vaccine
HIV prevention.  Included in this scope of activities are clinical studies
evaluating topical microbicides, interruption of perinatal transmission,
behavioral studies with biological endpoints, preventive treatment of sexually
transmitted diseases, and chemoprophylaxis.

HIV Vaccine Trials Network (HVTN) - The HVTN will be a collaborative network
of institutions comprised of the CORE, CL, HVTUs, and the SDMC.  This group
conducts all phases of HIV vaccine clinical trials and laboratory studies.

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

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

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

Prevention Sciences Review Committee (PSRC) -  An internal DAIDS review
committee with the responsibility of  evaluating clinical protocols in the
context of relevance to the mission of NIAID as well as on the basis of sound
methodology, reasonable feasibility, safety and ethics.

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 under the fiscal and
managerial umbrella of a HVTN.  Subunits may be established to support the
scientific agenda and/or accrual goals.  All subunits are subject to the same
policies and procedures mandated by Federal regulations, DAIDS and NIAID
policies, and the bylaws of the HVTN.

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.  Other members of the VLG group may
be designated by the HVTN in the future.

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

SOLICITATION PROCESS

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

When applying for VLG components (CL or SDMC), each applicant must identify
the VLG CORE with whom they propose to work and must coordinate the
preparation of their application with all other components of the VLG. 
Unaffiliated applications will not be accepted.

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

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

RESEARCH OBJECTIVES

BACKGROUND

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 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 await Phase I testing.  One Phase II
trial has been completed.  This trial enrolled nearly 300 volunteers from
heterogeneous populations, including volunteers at high risk of exposure to
HIV, and studied two HIV-1 gp120 subunit vaccines, comparing their
immunogenicity and effect on high-risk activity in populations at risk for
acquiring HIV-1 infection.  A second Phase II trial, studying the safety and
immunogenicity of live recombinant canarypox-HIV constructs (ALVAC vCP205 -
Pasteur Merieux Connaught) with or without vaccination with HIV-1 SF2
recombinant gp120 (Chiron Vaccines), is underway with 420 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, ADCC and CTLs against selected HIV
epitopes.  Studies have also demonstrated that certain adjuvants are useful
for inducing increased levels of antibody response.

In spite of these advances, many critically important questions remain
unanswered including: 1) whether a vaccine product or combination of vaccine
products can elicit protective immune responses; 2) whether immunological
responses can prevent the establishment of HIV-1 infection following exposure;
3) whether vaccine-induced immunological responses can inhibit HIV replication
in individuals who become infected with HIV; and 4) the relevance of viral
(e.g., clade) and host (e.g., HLA) genetic factors in the development of HIV
vaccines.

RESEARCH OBJECTIVES AND SCOPE

The objective of this RFA is to establish a Vaccine Leadership Group (VLG) for
a comprehensive multi-centered HIV Vaccine Trials Network (HVTN).  The VLG
will have the expertise to set the overall scientific agenda to guide the HVTN
in addressing the questions listed above as well as other key questions
regarding HIV vaccine development and testing, leading to the development of
effective HIV vaccines.  Research to be implemented by the HVTN, under the
leadership of the VLG should address the following broad scientific needs and
considerations:

Clinical Trials of HIV Vaccines

o  Identify and prioritize the clinical evaluation of vaccine concepts and
adjuvant formulations, as well as routes of administration, and dosage
schedules that can elicit broad and long-lasting humoral and/or cellular
immune responses to homologous and heterologous strains of HIV-1 at systemic
and/or mucosal levels to achieve protection from infection or disease;

o  Conduct Phase I and II multi-site trials, domestically and internationally,
to evaluate the safety, toxicity, immunogenicity and efficacy of experimental
HIV vaccines under Investigational New Drug applications;

o  Perform clinical trials of candidate HIV vaccines in populations at risk
for acquiring HIV infection, both domestically and internationally, to
determine whether underlying health conditions or other factors in these
populations will affect the safety or immunogenicity of candidate vaccines;

o  Develop plans for community outreach, education, and participation on HIV
vaccines in communities where HIV vaccine clinical trials will be conducted;

o  Prepare for and conduct large-scale, Phase II/III and Phase III vaccine
clinical trials, in U.S. and in developing countries.  Such plans should
include:

-- proposing linkages with sites capable of performing large-scale, Phase
II/III and Phase III vaccine efficacy trials (including the criteria used to
select these sites);

-- ensuring that the key investigators from selected sites outside the HVTU
will be integrated within the HVTN organizational structure  (e.g., will be
familiar with the participating HVTN investigators, the HVTN bylaws and
decision-making process, and the data arising from HVTN studies relevant to
implementing a large vaccine trial; and

-- identifying and addressing the needs associated with implementation of
large scale vaccine studies, including methodological research on trial
design.

HIV Vaccine Research within the Context of Clinical Trials

o  Identify and test improved, standardized, quantifiable, reproducible and
accurate methods to evaluate immunological responses to vaccination through
basic and clinical studies;

-- Conduct laboratory studies to identify correlates of immune protection
against establishment of HIV infection or disease progression, utilizing data
and specimens obtained from the vaccine trials conducted by the HVTN and the
most advanced methodology available;

-- Expand the scope of the current global HIV vaccine effort.  For example,
investigate the relevance of viral (e.g. clade) and host (e.g. HLA) genetic
factors in the development of HIV vaccines.

-- Identify and develop practical and reliable laboratory assays to screen
vaccine trial participants for HIV infection, and to assess suppression of
infection in vaccine recipients who become infected, both domestically and in
the developing world; and

-- Collaborate with investigators using simian models of retroviral infection
and disease to systematically address the correlative relationship between
human and animal studies.  While it is not the intent of NIAID to fund simian
based vaccine research within this award, collaborations which may assist in
the ultimate development of an HIV vaccine may strengthen an application for
the VLG

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

The cooperative agreement funding mechanism will require collaboration among:
the DAIDS Associate Director for VPRP, the CORE PI, the Principal Investigator
of the CL and the Principal Investigator of the SDMC.  The DAIDS will assist
in coordinating the activities of the HVTN as defined below and will
facilitate the exchange of information.

I.  Awardee Rights and Responsibilities

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

A.  Vaccine Leadership Group (CORE) Responsibilities

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

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

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

4.  Executive Committee -- An Executive Committee will be established as the
main governing body of the HVTN and must include at least one DAIDS staff
representative.

5.  Administrative Support -- The VLG will be responsible for coordinating,
administrating, and supporting all research activities.  These activities
include but are not limited to: (i) protocol development, distribution of
information, and training; (ii) administrative support for the VLG, the
Executive Committee, community advisory board, and all other HVTN committees;
(iii) maintenance of group administrative records and archives; (iv)
coordination of efforts with DAIDS regarding group meetings; and (v)
preparation of administrative and scientific reports.

6.  Protocol Development -- The VLG will have the responsibility to assure
that the HVTN will initiate the development of protocols only when there is
sufficient commitment among the HVTN Principal Investigators and other
scientific leaders within the group to proceed expeditiously.  Early
notification that the HVTN is considering a trial must be provided to the
DAIDS to allow for comment on scientific rationale, feasibility, costs, and
compatibility with overall NIAID research priorities and activities.  The HVTN
must have clear procedures for designating members of protocol teams,
selecting sites for limited-site trials, and providing protocol-specific
training.  The HVTN must develop a mechanism to monitor progress, from study
initiation through publication, and provide status reports to the DAIDS, on
each study, in a mutually agreed upon format and on a schedule.

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

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

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

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

a. Administrative: The VLG, under the leadership of the CORE PI will assume
responsibility for assuring required administrative information is submitted
to DAIDS.  Types of information will include, for example, lists of
investigators and other key personnel, affiliated sites, protocol abstracts
and tracking data, patient accrual and demographics, and publication
information.  Some information such as protocol enrollment/accrual status may
be required weekly, some less often.  Submission by electronic means, whenever
possible, is preferred.

b. Performance: The Executive Committee will establish procedures for
evaluating the performance of all HVTN components and provide DAIDS with
reports.  Procedures will include processes for the addition, reduction,
expansion or elimination of clinical sites, labs or other components based on
scientific contribution, protocol participation, observance of protocol
requirements, data management/quality, and subject accrual/retention.  This
mechanism will include a procedure for recommending to DAIDS an adjustment of
institutional funds based on level of contribution and performance.  A system
for establishing such procedures in a timely manner must be implemented by the
VLG.

c. Annual Report:  The VLG will submit to DAIDS an annual report summarizing
HVTN activities (including accrual and demographic data), accomplishments,
performance evaluations and future directions.  A system for providing such
information in a timely manner must be implemented by the VLG.

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

11. Publication of Data -- Prompt and timely presentation and publication in
the scientific literature of major findings is essential.  Publications or
oral presentations of work performed under this cooperative agreement will
require acknowledgment of NIAID/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 under this cooperative agreement will have access to
all data generated and may periodically review it.

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

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

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

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

16. Linkages with HIV Prevention Trials Network -- The HIV Prevention Trials
Network (HPTN) will be established contemporaneously with the HVTN.  The HPTN
may be a unique scientific resource and offer a desirable capacity for
conducting population-based studies.  It is likely that any large-scale study
of HIV vaccines will involve at least some HPTN sites.  The VLG, in concert
with the leadership of the HPTN (PLG) will develop and maintain linkages
between the HVTN and the HPTN.  These linkages will allow for ongoing exchange
of information and planning to allow for rapidly including HPTN Sites in
studies, should that be desired.  The VLG may propose a number of different
mechanisms and approaches to meet this need.  These mechanisms may include
ongoing activities such as having joint membership in leadership groups or
identifying specific individuals responsible for assuring information sharing. 
There may also be specific activities such as joint protocol development or
common scientific meetings.

B.  Central Laboratory Responsibilities

1.  Conduct of Laboratory Assays and Research -- The Central Laboratory will
be responsible for the following:  (i) performing timely laboratory studies as
needed for specific clinical trials; (ii) providing laboratory based
scientific leadership and consultation for the HVTN and collaborating
institutions and organizations; (iii) collaborating at all stages of protocol
development concerning laboratory testing and implementation; (iv)
conducting/overseeing quality assurance of laboratory assays performed at HVTN
clinical and laboratory sites in order to improve the planning, design,
conduct and interpretation of HVTN trials; and (v) work with the statistical
center to assure transfer of quality laboratory data to the data center for
preparing summary tables and data analyses for use in NIAID and IND annual
reports as well as interim submissions to the NIAID, FDA, and the DSMB.

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

These laboratories may include, but are not limited to, cellular, humoral,
mucosal immunology studies, viral studies, as well as assay and reagent
development.  The scope of the laboratory research should include immunologic
and virologic assays relevant to HIV vaccine development.

The CL will coordinate and oversee the quality assurance of assays performed
at subsites and assure that a common laboratory data management system is
utilized for specimen tracking and data transmission.

C. Statistical and Data Management Center (SDMC) Responsibilities

1.  Study Design, Conduct, Analyses, and Publications -- The SDMC will be
responsible for:  (i) providing statistical leadership for the HVTN and for
all stages of protocol development and conduct; (ii) performing timely interim
analyses of safety and efficacy for protocol teams and/or DAIDS and/or DAIDS
DSMB; (iii) generating executive summaries of preliminary analyses for use by
the protocol team, DAIDS, DSMBs, and collaborators; (iv) conducting final
analyses and participating on publication writing teams; (v) producing study
monitoring reports (such as accrual and AERs) for the VLG and DAIDS; (vi)
conducting analyses and summaries for annual and interim reports for DAIDS
INDs; and (vii) suggesting and, when agreed upon by VLG leadership, performing
additional analyses of data obtained from HVTN vaccine trials, based upon the
intimate familiarity of SDMC investigators with both the HVTN data set and the
key scientific issues relevant to HIV vaccine development.

2.  Data Management -- The SDMC will: (i) provide central registration and
randomization for all study subjects; (ii) develop case report forms and
standardized criteria for clinical endpoint verification; (iii) design and
implement systems for the efficient tracking and transfer of clinical and
laboratory data from clinical sites to the central database; (iv) provide data
management training to the clinical sites and DAIDS' Clinical Site Monitoring
Contractor; (v) provide for central storage, security, processing and
retrieval of study results; (vi) demonstrate the means by which it will ensure
that all data, patient questionnaires, consent forms, and all other records
containing the volunteers name will be maintained in a confidential and secure
manner at all times (e.g., no materials containing the volunteers name may be
sent to vaccine manufacturers or to other individuals outside the HVTN); (vii)
prepare selected public access databases for DAIDS, as provided for in the
approved plan for providing public access in a reasonable time after the
primary analysis and publications (see 1. above); (viii) provide for an
electronic mail system capable of exchanging messages through the Internet, to
facilitate communication among HVTN's, other HVTN components and DAIDS; (ix)
provide recruitment, retention and other relevant summary data to the sites
and protocol teams as designated by the VLG; and (x) assume responsibility for
ongoing maintenance of the modified ICD system for classifying and coding the
types of serious adverse experiences.

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

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

D. HVTU Clinical Sites

While the HVTU Clinical Sites will be solicited under a separate RFA, the VLG
applicants should be aware that HVTU responsibilities will include:

1. Volunteer enrollment, retention and follow-up;
2.  Standard clinical laboratory assays (e.g. CBC) for patient assessment;
3.  Individual quality assurance plans for Investigational Drug Management and
internal data generation; and
4.  Community Advisory Board plans.

II.  NIAID Responsibilities

The NIAID will have substantial scientific programmatic involvement during the
conduct of this activity, through technical assistance, advice, and
coordination.  The role of DAIDS staff described throughout these terms of
cooperation is to assist and facilitate.  Although communication primarily
will be with the VLG Leader, substantial communication is anticipated with all
members of the HVTN Executive Committee.  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 Executive Committee to
assure that the research efforts are consistent with the NIAID agenda for HIV
clinical research and complement those of other NIAID and NIH programs.  The
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 protocol must be approved by the Associate Director, VPRP. 
Once notified that a study is under consideration, the Prevention Sciences
Research Committee (PSRC) will evaluate the proposal relative to: (i) the
NIAID 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
after review.  If a 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 -- The DAIDS
will have the option to file an IND on investigational agents evaluated in
HVTN studies.  Appropriate DAIDS staff will advise the investigators on
specific regulatory requirements for IND sponsorship.  In situations where
DAIDS is the IND sponsor, they will also assemble, review, and submit the
required regulatory documents to the FDA.  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) -- When a pharmaceutical collaborator
provides an investigational agent to DAIDS, a CTA will be negotiated
describing respective responsibilities and rights.  The agreement will
include, but is not limited to, IND sponsorship, safety and data monitoring,
and access to data.  The VLG Core PI generally will be consulted on the terms
prior to the execution of the CTA.  Pharmaceutical collaborators generally
request that patentable inventions discovered in the studies be brought to
their attention, and the company has rights of first refusal provided that the
collaborator has rights to the background patent.  In general, terms in the
CTA covering data access and sharing will conform to policies developed
jointly by the VLG and DAIDS.

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

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

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

10. SAE Reporting -- In order to provide for consistent reporting of serious
adverse experiences across clinical trial groups, DAIDS has established
policies and procedures delineated in the "Serious Adverse Experience
Reporting Manual for the Vaccine and Prevention Research Program."

III.  Collaborative Responsibilities

1.  Group Governance -- The VLG will establish an Executive Committee as the
central decision making body for the Group.  The Committee will include the
Associate Director, VPRP, or designee, as a voting member.  A Chairperson,
other than the DAIDS Official, will be elected by the Group membership as
defined in the Bylaws.

IV.  Arbitration

Any disagreement that may arise on scientific or programmatic matters (within
the scope of the award) between award recipients and the NIAID may be brought
to arbitration.  An arbitration panel will be composed of three members: one
selected by the Executive Committee (with the NIAID member not voting) or by
the individual awardee in the event of an individual disagreement, a second
member selected by the NIAID, and the third member with expertise in the
relevant area selected by the first two members to review any scientific or
programmatic issue that is significantly restricting progress.  While the
decisions of the Arbitration Panel are binding, these special arbitration
procedures will in no way affect the awardee's right to appeal an 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/not94-105.html.

Investigators may obtain copies from these sources or from Dr. Margaret
Johnston at the address listed under INQUIRIES.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.  All investigators proposing research involving
human subjects should read the "NIH Policy and Guidelines on the Inclusion of
Children as Participants in Research Involving Human Subjects" that was
published in the NIH Guide for Grants and Contracts, March 6, 1998, and is
available at the following URL address:
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 November 30, 1998, a letter of
intent that includes a descriptive title of the overall proposed research; the
name, address and telephone number of the Principal Investigator; and the
number and title of this RFA.  Although the letter of intent is not required,
is not binding, does not commit the sender to submit an application, and does
not enter into the review of subsequent applications, the information that it
contains allows 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

The individual applications that together make up the VLG package must be
submitted on the standard research grant application form PHS 398 (rev. 5/95). 
Application kits are available at most institutional offices of sponsored
research and may be obtained from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda MD 20892-7910 telephone (301) 435-0714, Email:
grantsinfo@nih.gov.

The RFA label available in the PHS 398 application form must be affixed to the
bottom of the face page of the application.  Failure to use this label could
result in delayed processing of the application such that it may not reach the
review committee in time for review.  In addition, the RFA title ("HVTN
LEADERSHIP CORE" and/or "HVTN CENTRAL LABORATORY" and/or "HVTN STATISTICAL AND
DATA MANAGEMENT CENTER") and number (AI-98-014) must be typed on line 2 of the
face page of the application for and the YES box must be marked.

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

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

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

Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C07, MSC 7610
Bethesda, MD  20892-7610

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

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

SPECIAL INSTRUCTIONS FOR THE PREPARATION OF COOPERATIVE AGREEMENT APPLICATIONS

I.  Identification of Potential Applicants and Formation of the VLG

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

II.  Pre-Application Meeting รพ November 23, 1998

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

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

III.  Application Preparation

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

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

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

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

A key feature of this RFA is that it requires a CORE application to be
submitted by a CORE Principal Investigator of the HVTN CORE.  The Central
Laboratory and Statistical and Data Management Center components should be
submitted as separate applications within the same VLG package.  The use of
tables (e.g., accrual and protocol type), diagrams, and organization and flow
charts is strongly encouraged throughout the preparation of all applications.

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

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

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

The CORE application is not subject to the page limitations in the PHS 398
Form.  This section of the application should not exceed 150 pages.  When
preparing your application use the topics listed below and the items under
Vaccine Leadership Group (CORE) Responsibilities (Special Requirements, Terms
and Conditions of Award) as a guide for writing the research plan in lieu of
items a-d on pages 16-17 of the PHS 398 application kit.  However, the "Gender
and Minority Inclusion for Research Involving Human Subjects", "Participation
of Children" and  "Human Subjects" must be included in the Research Plan.  The
PI of the CORE should take overall responsibility in the CORE application for
ensuring that the overall representation of study population, HVTN-wide, will
be appropriately inclusive of under-represented populations.

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

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

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

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

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

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

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

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

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

a. Community Advisory Boards [REQUIRED]: U.S and international
b. HIV Prevention Trials Network Leadership [ENCOURAGED]:
c. Acute Infection and Early Disease Research Network [ENCOURAGED]
d. Centers For AIDS Research (CFARs) [ENCOURAGED]
e. International Research Groups [ENCOURAGED] - UNAIDS/WHO, IAVI, etc

B.  Central Laboratory Application

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

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

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

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

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

C.  Statistical and Data Management Center Application

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

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

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

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

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

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

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for responsiveness by 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 of the HVTN CORE, CL, and SC
applications will focus on each applicant's ability to contribute to the HVTN
scientific agenda, as well as the ability to provide leadership and expertise
in the conduct of vaccine clinical trials.  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

Coordinating and Operations Center (CORE) Application

1.  Significance.  Does this study address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?
-- Quality of the scientific research agenda to address current and evolving
needs in vaccine development, including the proposed ranking of the research
priorities and justifications.
-- Evidence that the research agenda reflects a broad understanding of HIV
vaccine research within the changing context of the HIV/AIDS epidemic and of
the implications/consequences of vaccine 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?
-- Adequacy of the proposed research plans including the approach to
set/redirect priorities, initiate studies, transition ongoing clinical trials,
and govern Group activities, and criteria for affiliated HVTN clinical sites
nationally and internationally.
-- Adequacy of proposed procedures for protocol development, implementation,
and oversight; committee management; and fiscal management.
-- Strength and adequacy of the proposed management plan including:
-- bylaws for governance including the election of HVTN Leadership and
committee membership;
-- mechanism for effective communication;
-- operational plans for the delegation of authorities, decision making, and
fiscal management; and
-- performance evaluation plans and standards for participating institutions
including corrective measures and principles of resource reallocation.
-- Adequacy of outreach plan to ensure the inclusion of women, children,
minorities and community representatives in all aspect of the proposed
research and Group activities.
-- Adequacy and feasibility of plans to foster participation of new
investigators, especially women and racial/ethnic minorities, in activities at
all levels of the HVTN.
-- Adequacy of the plan for establishing and maintaining linkages with sites
capable of performing Phase II/III and III HIV vaccine trials domestically and
internationally, and for the plans to rapidly implement such Phase II/III and
III trials when they become necessary.

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 research agenda addresses innovative approaches to the
development and clinical evaluation of HIV vaccines, and the ability to
respond to changing scientific priorities nationally and internationally.

4.  Investigator.  Are the investigators appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers?
--Adequacy of the qualifications, research experience, and time commitment of
the PI for the CORE award.  Adequacy of the qualifications and research
experience of the proposed scientific leadership, including but not limited
to, previous experience with design, administration, management, and
coordination of multi-center clinical trials.

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

Central Laboratory Application

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

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?
-- Adequacy of the plans for achieving the proposed CL scientific
contributions, including and the criteria for the selection and expertise of
the proposed laboratories..
-- Adequacy of the proposed linkage among the various components that comprise
the HVTN, as well as the ability to carry out the proposed responsibilities.
-- Adequacy and quality of the CL network management plan, if appropriate.

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?
-- Quality of the plan to develop and implement new assay technologies.

4.  Investigator.  Are the investigators appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers?
-- Adequacy of the qualifications, experience and availability of the key
personnel to achieve the stated scientific goals and administrative
responsibilities of the CL.

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

Statistical and Data Management Center Application

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

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?
-- Adequacy of the proposed linkage among the various components that comprise
the HVTN, as well as the ability to carry out the proposed responsibilities.
-- Quality of the plan for both clinical and laboratory database designs,
administration, data collection, security, and site-specific training; quality
of sample protocols.
-- Adequacy of the plan, including sample protocols, for developing and
maintaining systems for patient randomization; receiving, recording and
reporting of adverse events, and providing timely data analysis.
-- Adequacy of plans to ensure the inclusion of women, children, minorities
and community representatives in all aspect of the proposed research and Group
activities.

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

4.  Investigator.  Are the investigators appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers?
-- Strength of the qualifications and experience of the Principal Investigator
and staff in providing statistical, analytical and data management expertise
for multi-center clinical studies.
-- Availability of the proposed SDMC director as well as other biostatisticans
and data system personnel to provide statistical leadership.

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

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

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, animals or the environment, where such are involved.

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

AWARD CRITERIA

The predominant criteria for funding priorities will be the scientific and
technical merit of the group package as determined by peer review. 
Consideration will be given to the cost-effectiveness of the proposed studies,
the availability of funds, and the ability of the VLG/HVTN to adequately
address all needs of the scientific agenda.

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:

Margaret I. Johnston, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2A07
Bethesda, MD  20892-7620
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 496-8200
FAX:  (301) 480-4582
Email:  pj7p@nih.gov

Direct inquiries regarding regulatory affairs and oversight information to:

MaryAnn Luzar, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building
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 (For express mail or courier us 20852)
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 496-5601
FAX:  (301) 480-3780
Email:  ad22x@nih.gov

Schedule

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

AUTHORITY AND REGULATIONS

This program is described in the 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.


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