Full Text AI-94-028

ADULT AIDS CLINICAL TRIALS GROUPS

NIH GUIDE, Volume 23, Number 32, August 26, 1994

RFA:  AI-94-028

P.T. 34

Keywords: 
  AIDS 
  Clinical Trial 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  September 15, 1994
Application Receipt Date:  January 12, 1995

PURPOSE

The Division of AIDS (DAIDS) of the National Institute of Allergy and
Infectious Diseases (NIAID) invites applications for cooperative
agreement (U01) awards from institutions interested in participating in
a cooperative group(s) that will perform Phase I, II, and III clinical
evaluations of promising new interventions for the treatment of HIV
disease, AIDS, and opportunistic diseases resulting from HIV infection
including malignancies and neurologic complications.  The institutions
will conduct multi-center clinical trials involving adult participants.

Each group of collaborating institutions awarded cooperative agreements
as a result of this competition will be referred to as an Adult AIDS
Clinical Trials Group (ACTG).

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 Request
for Applications (RFA), Adult AIDS Clinical Trial 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 "Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202/783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic non-profit and for-profit
organizations, public and private organizations, 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.  Applications from minority
individuals and women are encouraged; funds are being set-aside for
minority institutions (see FUNDS AVAILABLE).

Eligible institutions may apply for one or more of the following types
of awards:

o  Adult ACTG Central Group
o  AIDS Clinical Trials Unit (ACTU)
o  Statistical and Data Management Center

Separate applications must be submitted for each type of award.

Each Adult ACTG Central Group applicant must identify a single
Statistical and Data Management Center with which it is proposing to
work.  Each applicant for an ACTU award must identify in a cover letter
and in the body of the application the Adult ACTG Central Group with
which the applicant ACTU it is proposing to collaborate.  Each
applicant for a Statistical and Data Management Center must identify
both in a cover letter and in the body of the application the Adult
ACTG Central Group with which the applicant is proposing to
collaborate.  (See SPECIAL INSTRUCTIONS FOR THE PREPARATION OF
COOPERATIVE AGREEMENT APPLICATIONS, Identification of Potential
Applicants and Formation of ACTGs, for further details.)

It is the responsibility of potential applicants for an Adult ACTG
Central Group award and a Statistical and Data Management Center award,
as components of the ACTG, to identify themselves to each other and
establish affiliations.  The NIAID will facilitate the formation of an
ACTG by: (1) identifying potential Adult ACTG Central Group applicants
and unaffiliated potential ACTU applicants to each other; and (2)
holding a pre-application meeting on September 28, 1994.

Each applicant for an Adult ACTG Central Group must demonstrate the
ability to recruit and support a minimum capacity of 1,250 new patients
per year.  Each ACTU applicant must demonstrate the capability to
accrue a minimum of 75 new patients per year.

It is anticipated that once the AIDS Clinical Trial Units (ACTUs) are
selected and the ACTG(s) formed, the combined capacity of the ACTG or
ACTGs will allow for accrual of 2,500 to 3,500 new patients per year.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be 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 performance of the activity.  Under the cooperative
agreement, the NIAID purpose is to support and/or stimulate the
recipients' activities by involvement in and otherwise working jointly
with the award recipients in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity.

Details of the responsibilities, relationships and governance of the
studies to be funded under these cooperative agreements are discussed
later in this document under the section "Terms and Conditions of
Award."

The total project period for an application submitted in response to
the present 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.
The anticipated award date is January 1, 1996.

Awards and level of support depend on receipt of a sufficient number of
applications of high scientific merit.  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.

This RFA is a recompetition of an ongoing program (the Adult AIDS
Clinical Trials Group [ACTG]).  Reissuance of this initiative is
uncertain.  If it is determined that there is sufficient programmatic
need for continuation of this program, the NIAID will invite
applications for extension of this program.

FUNDS AVAILABLE

Approximately $60,000,000 total costs will be available in fiscal year
1996 for the first year of support for awards made under this RFA.  Of
this total, at least $3.5 million will be reserved exclusively to
support meritorious clinical trials units (ACTUs) at minority
institutions.  In Fiscal Year 1996, the NIAID plans to fund one or two
ACTG Central Groups, one Statistical and Data Management Center per
Central Group, and 22 to 29 ACTUs.  Minority institutions are defined
as those that have more than 50 percent minority student enrollment and
award an M.D., D.D.S., D.V.M or other doctorate degrees in the health
professions.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of individual awards
will vary.  The level of support will be dependent upon the number of
applications of high merit received and the availability of funds.
Funding beyond the initial budget period at the level awarded in the
first year of support will be contingent on the continued availability
of funds for this purpose, and the continued progress of the ACTG.

RESEARCH OBJECTIVES

A.  Background

The emergence of the AIDS epidemic in the United States has had a major
impact on public health, as well as medical, social, and economic
institutions in this country.  Within the U.S., over 350,000 persons
have developed AIDS and over one million Americans are believed to be
infected with HIV-1.  In addition, it is estimated that 40,000 adults
are newly infected with HIV in the U.S. every year.

Particularly hard hit by the epidemic are urban centers, where an
increasing number of minorities, women, and injection drug users are
being infected.

One critical goal of the NIAID in the field of AIDS research is the
discovery and development of therapies that will improve the quality
and duration of life of HIV-infected individuals.  While the interests
and mission of the pharmaceutical industry and NIAID overlap in the
field of applied therapeutics research and development, NIAID's overall
responsibility is to focus on those research opportunities of utmost
importance to the public health that are not being addressed elsewhere.

Considerable strides have already been made in the clinical development
of antiretroviral therapies, as well as for the treatment and
prophylaxis of a myriad of opportunistic infections that occur in
severely immunosuppressed patients with AIDS.  Nonetheless, the impact
on survival and clinical disease progression of the existing approved
antiretroviral therapies is of limited magnitude and duration.
Furthermore, the current treatments for some of the opportunistic
infections are not always effective, and breakthrough infections occur
despite prophylaxis therapies.

It is apparent that clinical investigations of new, innovative
interventions are crucial in order to make a significant impact on
survival and quality of life of the HIV-infected individual.

B.  Definitions

Adult AIDS Clinical Trials Group (ACTG) - A collaborative group of
institutions composed of a Central Group, AIDS Clinical Trials Units
(ACTUs), and a Statistical and Data Management Center, which together
conduct all phases of clinical trials, and laboratory studies. (see
Organization of ACTG for description of all component parts.) Each ACTG
consists of experienced investigators in multiple disciplines (e.g.
infectious diseases, virology, immunology, clinical pharmacology,
oncology, neurology, gynecology, and biostatistics).

Advanced Technology Laboratory (ATL) - Additional, central laboratory
capabilities that enable the ACTG to investigate the feasibility,
validity, standardization and implementation of state-of-the-art
assays/technologies related to the scientific agenda.  Awards for ATLs
are made through the ACTG Central Group award.

AIDS Clinical Trials Unit (ACTU) - A clinical site that is a member of
the collaborating group of institutions comprising the ACTG.  The ACTU
is required to participate and enroll patients in clinical trials and
conduct or obtain protocol mandated laboratory tests.

Collaborating Institution - An institution that is an ACTG awardee
either as a Central Group, Statistical and Data Management Center, or
an ACTU.

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

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

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

Executive/Steering Committee - The main governing body of the ACTG that
is established and chaired by the Group Leader.  This committee will be
responsible for making the ultimate decisions on all scientific and
operational issues of the ACTG (See Terms and Conditions of Awards).

Group Leader - The individual who directs the development and
implementation of the research agenda and the organizational structure
and governing procedures that form the basis of ACTG operations.  The
Group Leader is responsible for the leadership and coordination of all
ACTG activities both scientifically and administratively, and serves as
the Principal Investigator for the ACTG Central Group award.  The Group
Leader may also be associated with an ACTU.

Operations Office - An administrative unit within the ACTG Central
Group that will take responsibility for coordinating ACTG activities,
including protocol development and distribution, administrative support
for the Group Leader and scientific leadership of the ACTG and of
scientific and other committees, training sites and monitors; assembly
and submission of documents to DAIDS for registration of sites for
individual trials; maintenance of ACTG administrative records and
archives; planning of two national meetings per year, at least one of
which is held in collaboration with the Pediatric ACTG in the
Washington metropolitan region; and, in conjunction with the ACTG
Statistical and Data Management Center, preparation of administrative
reports of ACTG activities as requested by DAIDS.

Participant Subunit -  An institution supported through a
subcontractual agreement with one of the primary, collaborating
institutions.  A subunit may be established to support the scientific
agenda and/or patient 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 ACTG.

Statistical and Data Management Center - The statistical and data
management unit that is responsible to the ACTG for the statistical
aspects of study design and data analyses and management.

Therapeutic Research Program (TRP) - A program within the DAIDS that is
responsible for the scientific, administrative, and operational
management of clinical therapeutic research programs funded by the
division.

C.  Organization of an ACTG

The ACTG Central Group will consist of:

o  Principal Investigator (ACTG Group Leader)
o  Key Scientific and Management Leadership
o  Operations Office
o  Resources for Advanced Technology Laboratories
o  Executive/Steering Committee

The Statistical and Data Management Center will consist of:

o  Principal Investigator
o  Experts in Statistics, Study Design and Analysis
o  Data Management Resources and Facilities

The AIDS Clinical Trials Units (ACTUs) will consist of:

o  Principal Investigator
o  Clinical Facilities and Staff
o  Clinical Laboratory Facilities and Staff
o  Study Subjects

DAIDS staff, DAIDS contractors (such as those for laboratory quality
assurance, clinical site monitoring, and management of virology,
immunology, and pharmacology laboratory data) and a Data and Safety
Monitoring Board will support the efforts of these awardees.  (See
Terms and Conditions of Award for specific on the roles and
responsibilities of each contributing unit.)

D.  Functions of an ACTG

The activities of an ACTG and its component parts awarded under this
RFA are delineated below.  (See "Terms and Conditions of Award" for
further specifications of selected roles and responsibilities of an
Adult ACTG Central Group.)

Specifically, an ACTG Central Group will be responsible for:

1.  Developing, implementing, monitoring, and updating the ACTG's
scientific agenda for therapeutic research consistent with the NIAID
HIV\AIDS Therapeutic Research Agenda.

2.  Provision of the key scientific and managerial leadership required
to carry out the ACTG scientific agenda.

3.  Identification of a Statistical and Data Management Center
responsible for the statistical aspects of study design, and the
collection and analysis of data from the clinical trials conducted by
the ACTG.

4.  Development and management of an Operations Office that will
provide the necessary infrastructure and staff to support the ACTG
Group Leader in the management and administration of the ACTG.

5.  Organizational structures and management mechanisms for effective
communication and collaboration among ACTG components including:
committee structure, bylaws, procedures for protocol development and
modification, performance evaluation, and monitoring of research
progress.

6.  Identification, selection and management of Advanced Technology
Laboratories (ATLs) that will investigate the feasibility, validity,
standardization and implementation of state-of-the-art pharmacologic,
immunologic and virologic assays/technologies for use in support of the
ACTG clinical trials.

7.  Criteria and processes for: assessing the performance of ACTG
components, including individual ACTUs, subunits, ATLs, the operations
office and the statistical and data management center; the addition,
reduction, expansion, or removal of ACTUs based on the needs of the
scientific agenda and the performance of ACTUs; and the modification of
the activities of the ATLs, the operations office and the statistical
and data management center.

8.  Mechanisms to ensure the involvement and participation of community
representatives at all levels of scientific planning and study conduct.

9.  Procedures for encouraging the participation in the proposed
research of new investigators, women and minorities.

Each AIDS Clinical Trials Unit will be expected to perform the
following activities. (See "Terms and Conditions of Award" for further
specification of selected activities of an Adult ACTU).

1.  Participate in single and multi-institutional clinical trials
according to the agenda of the ACTG.

2.  Perform on site and/or obtain (via collaboration) virology,
immunology (including flow cytometry), and pharmacology laboratory
services as required for protocol mandated evaluation of patients
enrolled in ACTG clinical trials.

3.  Identify and recruit HIV-infected patient populations to support
patient accrual, with a minimum of 75 new patients per ACTU per year.

4.  Enroll and retain ethnically diverse patient populations that are
representative of the local community and the population(s) most
affected by HIV and AIDS, including women.

5.  Provide or have access to gynecological and outreach related
resources to assist in evaluating the efficacy of treatments for and to
address the needs of women infected with HIV.

6.  Obtain input and involve community representation of the
populations most affected by HIV and AIDS in the planning, conduct and
dissemination of information on clinical trials.

7.  Encourage the participation of new investigators, women and
minorities in scientific and managerial aspects of the ACTU.

8.  Agree to follow the organizational structures and managerial
mechanisms of the ACTG.

The Statistical and Data Management Center for an ACTG will be
responsible for the following activities.  (See "Terms and Conditions
of Award" for further specifications of selected roles and
responsibilities of a Statistical and Data Management Center.)

1.  Statistical aspects of study design, data analyses and data
management.

2.  Development and maintenance of systems for registration and
randomization of participating patients into Phase 1, 2, and 3 clinical
trials.

3.  Centralized storage, security, processing and retrieval of ACTG and
ACTU information.

4.  Design and implement procedures for the collection, reporting and
quality control of data (including standardized case report forms) and
for submission of information by the ACTG, the ACTUs and collaborating
institutions.

5.  Training of clinical site staff and external site monitors
(external site monitoring is performed by a DAIDS contractor) in the
areas of data management and clinical trials methodology.

6.  Receipt, recording, and reporting of adverse experience reports
from the ACTUs to DAIDS and the FDA.

7.  Analyses for IND annual reports to the FDA, and interim reports for
NIAID, FDA, and DSMB review.

8.  Agree to follow the organizational structures and managerial
mechanisms of the ACTG.

E.  Objectives and Scope

The primary goal of this initiative is to evaluate, in Phase 1, 2, and
3 clinical trials, innovative therapeutic strategies and interventions
for HIV infection and its complications.  These interventions will be
based on emerging knowledge of the biology and potential therapeutic
targets of HIV and associated pathogens, the pathogenesis of HIV
infection and resulting opportunistic diseases, and factors influencing
disease progression and treatment outcome.  This initiative is
specifically designed to strengthen the coordination of the ACTG
research agenda with progress in basic research and it emphasizes the
rapid utilization of these discoveries in multi-disciplinary clinical
research.  The goal is to allow the ACTG to capitalize on the latest
insights into the biology of HIV and its associated pathogens and into
host-pathogen relationships for the purpose of developing more
effective treatments while enhancing knowledge of the pathogenesis of
HIV disease and its complications.

The NIAID HIV/AIDS Research Agenda comprehensively documents the
Institute's major scientific programs, priorities, and plans in each of
five broad scientific areas:  pathogenesis, epidemiology and natural
history, therapeutics research and development, vaccine research and
development, and pediatric disease.  The Agenda is the basis for
NIAID's scientific planning, program management and evaluation, and
communication on the scope and nature of the Institute's efforts in HIV
research.

Through the performance of clinical trials, the ACTG will play a
critical role in helping to fulfill the goals and priorities
delineated in the Therapeutics Section of the Institute's HIV/AIDS
Research Agenda as summarized below.  Copies of the Therapeutics
Section of the NIAID HIV/AIDS Research Agenda are available from the
program staff listed under INQUIRIES.

The ACTG Central Group will identify the highest priority research
questions from the major therapeutic areas, and develop a comprehensive
clinical trials agenda consistent with the HIV/AIDS Therapeutics
Research Agenda.  The ACTG will be responsible for addressing the major
areas in the NIAID's Agenda and establishing areas of emphasis.

1.  Primary Disease Therapeutics.  Considerable progress has been made
in developing, evaluating, and instituting into clinical practice
nucleoside analogues that inhibit HIV-1 replication and enhance disease
free survival in infected individuals.  However, the clinical utility
of these agents are of limited duration and magnitude.  Therefore, it
is crucial to base further progress in primary disease therapeutics on
additional knowledge of HIV life cycle and pathogenesis.  Innovative
approaches should focus on the following:

o  Development of antiretroviral therapies aimed at interfering with
the life cycle of HIV as well as therapeutic strategies to treat the
primary disease processes of HIV infection.  These approaches should
complement the efforts of industry and should be targeted to the entire
spectrum of immunodeficiency, from acute infection through the chronic
asymptomatic stage, and the stages of AIDS-related complications.

o  Determination of the clinical implications of the development of
resistance of HIV-1 and the role of viral phenotypes.

o  Identification and validation of surrogate markers both as
indicators of biologic activity and as predictors of overall clinical
outcome.

o  Improvements in the therapeutic index of existing and/or approved
anti-HIV therapies through the use of novel combinations of agents,
alternative dosage schedules, or improved drug formulations, including
antiviral and immunomodulators in combination.

2.  Immune Based Therapeutics/Immune Reconstitution.  The development
of immunodeficiency in HIV-1 infection can be evident at its earliest
stages, far in advance of clinically apparent disease.  The
immunodeficiency is relentless in its progression, ultimately leading
to opportunistic infections and malignancies.  The infected individual
generates a myriad of immunological responses to HIV-1, however, it
remains unclear which, if any, of these responses is protective.  In
addition, recent gains in our understanding of HIV pathogenesis have
identified many factors contributing to the progressive
immunosuppression, including CD4+ T-cell depletion, CD4+ T-cell
qualitative dysfunction, loss and dysfunction of T-cell precursor cells
and the developmental microenvironment, cytokine dysregulation,
abnormal immune activation, apoptosis, and superantigen effects.
Therefore, strategies could include the:

o  Development of immune-based approaches to the treatment of HIV
disease and reconstitution of the immune system, e.g., passive and
active immunotherapies, cytokines/cytokine modulators, adoptive cell
transfer/stem cell therapies, and inhibitors of immune activation.

3.  Treatment and Prevention of HIV-Related Opportunistic Infections.
The morbidity and mortality caused by the multiple opportunistic
infections (OIs) associated with HIV infection are substantial.
Several of these pathogens have been associated with other
immunocompromised states.  However, the frequency and severity of some
HIV-related OIs surpasses previous experience.  For most OIs, there are
only a limited number of agents effective in prophylaxis or treatment,
many of which have significant toxicities associated with their use.
There are no known effective therapies for some OIs including
cryptosporidiosis and the emergence of drug resistance will limit the
effectiveness of currently available agents.

Support of basic, preclinical and clinical research on HIV-related OI
pathogens is viewed as an important role of the NIAID.  Innovative
strategies may include, but are not limited to:

o  Develop approaches to provide safe and effective simultaneous
prophylaxis against multiple OIs, recognizing that long term utility of
these regimens will be dependent on patient acceptability and
tolerance.  Risks and benefits of widespread prophylaxis, including the
development of drug-resistant organisms, pharmacokinetic interactions,
and additive toxicity must also be specifically evaluated.

o  Assess markers for the optimal initiation of prophylaxis.  Evaluate
new methods for more rapid diagnosis of opportunistic infections,
determine drug susceptibility, and evaluate response to therapy,
including predictors of relapse.

o  Evaluate the use of active/passive immunization, cytokine
modulation, and other immune based therapies as adjunctive therapies in
the management of selected opportunistic infections.

o  Develop improved agents for the treatment and prevention of
HIV-associated CMV, disseminated Mycobacterium avium Complex, enteric
pathogens, and azole-resistant candida.

o  Develop new agents and combinations for the prophylaxis and
treatment of disease caused by Mycobacterium tuberculosis infection,
including strains that are resistant to standard agent(s).  Develop and
evaluate regimens, formulations or delivery vehicles that enhance
patient compliance through convenience or improved tolerance.

o  Evaluate the role of OIs, for example CMV, MAI, TB, as cofactors in
the progression of HIV-disease.

4.  Oncology Treatment Research.  Proposed research could focus on
development and implementation of a coordinated research agenda in
conjunction with the National Cancer Institute that will address the
development of better therapeutic strategies to treat Kaposi's sarcoma,
lymphoma, CNS lymphoma and human papilloma-virus associated
malignancies in HIV-infected individuals.

5.  Neurology Treatment Research.  Proposed research could focus on
development and implementation of a coordinated research agenda with
the National Institute of Neurologic Diseases and Stroke that will
facilitate the development of therapeutic strategies for the neurologic
manifestations of AIDS, including AIDS dementia complex, neuropathy,
progressive multifocal leukoencephalopathy, CNS lymphoma, and CMV
encephalitis.

NOTE:  In addition the National Institute of Mental Health is
interested in receiving applications, independent of this RFA, that
will advance the development of therapeutics for the neuropsychiatric
and neuropsychological manifestations associated with HIV infection,
including early cognitive impairment, AIDS Dementia Complex, and
associated mania, psychosis, depression and anxiety disorders.
Methodological studies focused on the identification of markers of
disease progression to AIDS-associated cognitive and motor impairment
are strongly encouraged.  For further information contact Dr. Walter L.
Goldschmidts, Office on AIDS, NIMH, (301) 443-7281.

6.  Women's Health Treatment Research.  Proposed research could focus
on development and implementation of a research agenda that will
facilitate better understanding and treatment of women's specific
health issues of HIV infection, such as drug pharmacokinetics in women,
cervical neoplasia, pelvic inflammatory disease and vaginal
candidiasis.

7.  Pharmacology.  Proposed research could focus on development of a
research agenda that will define the pharmacokinetics and
pharmacodynamics of new drugs and study the interactions of drugs used
in combination to treat HIV and opportunistic infections.

8.  Methodology for Trials.  Using data from group trials increase the
understanding of HIV/AIDS and related diseases and improve the design
and conduct of trials.

SPECIAL REQUIREMENTS

In the terms and conditions of award listed below, reference is made to
other research programs in AIDS, principally funded through NIAID
cooperative agreements and contracts.  Information concerning these
programs will be discussed at a pre-application meeting scheduled for
September 28, 1994.  For additional information contact Dr. Frederick
H. Batzold at the address listed under INQUIRIES.

A.  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 special Terms of Award are in addition to, and 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 this concept, the dominant role and prime
responsibility for the activity resides with the awardees for the ACTG
as a whole, although specific tasks and activities in carrying out the
study will be shared among the awardees and the NIAID and its
contractors.

The cooperative agreement funding mechanism will require collaboration
between the DAIDS Associate Director of the Therapeutics Research
Program (TRP), and the Group Leader(s) of the ACTG(s).  The DAIDS will
assist in coordinating the activities of the ACTG(s) as defined below
and will facilitate the exchange of information.

B.  Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the details for
the project within the guidelines of the RFA and for performing the
scientific activity, and agree to accept close coordination,
cooperation, and participation of NIAID staff in all aspects of
scientific and technical management of the project.  Specifically,
awardees have primary responsibilities as described below.

1.  Responsibilities of the ACTG Central Group

a.  Research Agenda

The Principal Investigator (Group Leader) of an ACTG Central Group, in
collaboration with other investigators constituting the scientific
leadership of the ACTG, is responsible for the development and
implementation of a comprehensive clinical trials research agenda,
consistent with the research goals and priorities established in
NIAID's HIV/AIDS Therapeutic Research Agenda and complementary to the
research conducted by the Community Programs for Clinical Research on
AIDS (CPCRA), the Division of AIDS Treatment Research Initiative
(DATRI), NIAID Division of Intramural Research, and other AIDS clinical
trials mechanisms.  These research goals will be reviewed and discussed
quarterly with DAIDS staff.

b.  Bylaws/Operating Procedures

The Group Leader will be responsible for ensuring that there are
well-documented policies and operating procedures guiding all aspects
of ACTG activities (e.g., protocol development, review, initiation,
conduct, and closure, data collection, publication, etc.) and bylaws
delineating the requirements and expectations of collaborating
institutions, membership criteria and process for new site
consideration by the ACTG, standards of performance, and procedures for
removing institutions due to poor performance.

c.  Executive/Steering Committee

The ACTG will establish this governing committee that will be chaired
by the Group Leader.  At a minimum the committee will include
representatives from the Statistical and Data Management Center, the
Operations Office, and a member of the community.  In addition, there
will be one voting member of the committee from the DAIDS Therapeutics
Research Program.  This committee will be responsible for overseeing
all scientific and operational activities of the ACTG including, but
not limited to: scientific direction, policies and bylaws, standards of
performance, study oversight, evaluation of collaborating institutions,
and criteria and review procedures for distributing discretionary
funds.

d.  Protocol Development

The ACTG will initiate development of each protocol only when there is
sufficient commitment among the principal investigators of clinical
units and other scientific leaders to proceed expeditiously to write
the protocol, complete accrual, and analyze and publish the study
results.  Early notification that the ACTG 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 in other clinical trials programs.  The ACTG
must have clear procedures for designating members of protocol teams
and for selecting sites for limited-site trials.  The ACTG must develop
a mechanism to actively monitor progress, from initiation through
publication, and must provide status reports to the DAIDS on each
study, in a format and on a schedule to be mutually agreed upon.

e.  Administrative Support

The Operations Office will be responsible for coordinating,
administering, and supporting all research activities at the direction
of the Group Leader or designee.  These activities include, but are not
limited to:  protocol development; administrative support of scientific
and other committees; assembly, review, and submission of regulatory
documents for registration of sites for clinical trials; maintenance of
group administrative records and archives; organization/support of, at
a minimum, one annual national group meeting in collaboration with the
Pediatric ACTG; and in conjunction with the group's Statistical and
Data Management Center, preparation of administrative and scientific
reports.

f.  Data Management and Analysis

Each ACTG will develop standard procedures to ensure that data
collection and management are: (1) adequate for quality control and
analysis and (2) as simple as appropriate in order to minimize data
collection burden on the part of the clinical sites.

g.  Protocol Submission

Prior to implementation of a clinical trial, the ACTG leadership must
submit a final draft to DAIDS for review and approval based on
consistency with the NIAID HIV/AIDS Therapeutic Research Agenda and
overlap with other NIAID clinical trial programs.  DAIDS will
communicate all decisions in writing to the ACTG; it will be the ACTG's
responsibility to disseminate this information to member investigators
and others as appropriate.  Implementation may not proceed in the case
of disapproval.  (See "B.  NIAID Staff Responsibilities" below for
additional information on the approval and appeal processes.)

h.  Quality Assurance:  Data Management

The ACTG's Statistical and Data Management Center will design and
implement systems to promote and ensure the quality of clinical trials
data.  The center will develop quality assurance procedures to be
employed by staff at each clinical site and the managers of the central
database, including types of manual and computerized procedures and
edit checks that will be used to identify and correct data errors, the
process that will be used to verify that eligibility criteria have been
met, the process that will be used to verify endpoint data, and the
average time period that erroneous computerized data will remain
on-line before errors are corrected.  Procedures will be developed to
assure data security and recovery in the event of lost data.

i.  Quality Assurance:  Laboratory Quality Control and Data Management

All virology, immunology, and pharmacology laboratories supported
through the ACTG (i.e., laboratories performing protocol-mandated
testing and Advanced Technology Laboratories) should adhere to
methodological and analytic guidelines set forth by the scientific
committees of the ACTG.  All laboratories must participate in quality
assurance programs supported under contract with the DAIDS and overseen
jointly with the ACTG (See. "B.  NIAID Staff responsibilities").  In
addition, all ACTG-supported laboratories should utilize a laboratory
data management system for specimen tracking and data transmission
provided by a contractor to the DAIDS.

j.  Advanced Technology Laboratories

The Group Leader, in consultation with the Executive/Steering Committee
of the ACTG, will be responsible for identifying the centralized
advanced technology laboratory capabilities required in virology,
immunology and pharmacology to support the ACTG research agenda.  With
the designated funds awarded to the ACTG Central Group, the
Executive/Steering Committee will identify suitable laboratories,
determine appropriate distribution of resources, develop a mechanism to
monitor laboratory performance and annually assess allocation of the
ATL funds.

k.  Study Oversight Responsibility

The ACTG leadership must establish procedures to assure adequate
protection of the rights and safety of volunteers involved in its
clinical investigations, and for the quality and integrity of these
studies and resulting data.  This study oversight by the ACTG includes
compliance with all Federal regulations and NIAID policies and
procedures.  The ACTG must also maintain accurate and timely
information on the progress of each study it conducts.

l.  ACTG Compliance with Federal Regulatory Requirements

The ACTG 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 ACTG must be able to demonstrate that each
institution conducting ACTG trials has a current, approved Assurance
Number on file with the NIH Office for the Prevention of Research Risks
(OPRR), that each protocol and informed consent is approved by the
responsible Institutional Review Board (IRB) prior to patient entry,
that each investigator has a current Food and Drug Administration Form
1572 and curriculum vitae on file at DAIDS, and that each patient (or
legal representative) gives written informed consent prior to entry on
study.  The ACTG must assure timely reporting of all serious and
unexpected toxicities to DAIDS in accordance with DAIDS established
policy and procedures delineated in the "ACTG Adverse Experience
Reporting Manual."

m.  Reporting Requirements

The ACTG Group Leader will submit to the DAIDS an annual progress
report summarizing data on protocol performance by the ACTG as a whole
and by each participating clinical unit.  These reports will include,
at a minimum: patient accrual and retention rates; patient
demographics; timeliness and completeness of all data, including
adverse events; timeliness of IRB approvals of new protocol versions;
completeness and quality of laboratory data; and scientific
contributions, including publications.  These data should be compiled
across all studies and by protocol, as appropriate.

Reporting requirements will be in agreement with Federal regulations
and NIAID procedures.  The ACTG Group Leader will submit to the NIAID
data summary reports prior to the due dates to the Food and Drug
Administration (FDA) required of IND sponsors.  At the time of protocol
review, for each clinical study DAIDS will identify the types and
frequencies of reports needed to monitor the safety and clinical
effectiveness of the therapeutic interventions.  These reports may
include (1) a line listing and summary tables of all serious adverse
events submitted as frequently as every two weeks; (2) a report on
patient status submitted every two weeks for each Phase I and I/II
study; (3) a quarterly and annual report summarizing adverse events and
patient status for each protocol, including unblinded analysis for the
DAIDS medical monitor with the approval of the Data and Safety
Monitoring Board.

The ACTG 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 ACTG.

n.  Publication of Data

Prompt and timely presentation and publication in the scientific
literature of major findings is required.  Publications or oral
presentations of work done under this cooperative agreement will
require acknowledgement of NIAID support to the ACTG.  Prior to the
submission of manuscripts for publication the ACTG will provide a
preprint to the Division of AIDS.  Although the awardee will retain
custody and primary rights to the data consistent with current HHS, PHS
and NIH policies, DAIDS will have access to all data generated under
this cooperative agreement and may periodically review it.

o.  Progress Review

The ACTG Executive/Steering Committee will establish procedures for
regularly evaluating the performance of its members including data
management/quality, accrual of adequate numbers of patients, adherence
to requirements for enrolling women and minorities, observance of
protocol requirements, scientific contributions/participation, and
timely publication of data.  This mechanism will include a procedure
for recommending to DAIDS an adjustment of institutional funds within
the group as appropriate for the level of contribution and performance.

p.  Interaction with DAIDS

The ACTG Group Leader will meet with the Associate Director, TRP
quarterly.  The purpose of the meeting will alternate as follows:
semi-annual meetings will be held to discuss research progress,
establish priorities, and plan future activities.  Also, semi-annual
meetings will be held with investigators representing other NIAID
clinical trials programs to ensure coordination of research agendas.
Additional meetings between DAIDS and the ACTG Group Leader may be held
as needed.

q.  National Meetings

It is expected that an ACTG will hold two national meetings per year,
at least one of which is held in conjunction with the Pediatric ACTG
and located in the Washington metropolitan area.  These meetings will
be open to the public.  Through calendar year 1996, the DAIDS will
provide logistical support for two national meetings (and one smaller
meeting of ACTG leadership), e.g., contracting with local hotels and
vendors; however, the ACTG will be responsible for organizing the
scientific content and format of the meeting.  As of 1997, funds will
be transferred to the ACTG Operations Office to cover the costs
associated with all aspects of meeting planning, including logistics
(e.g., hotel, scheduling).

r.  Conflict of Interest

The ACTG will develop, establish, monitor and enforce a Conflict of
Interest (COI) Policy, acceptable to NIAID, for addressing and
resolving any conflict of interest issues that may arise through
financial ties between members of the ACTG and the private sector.

A report on the ACTG's activities regarding COI issues will be part of
the biannual review.

s.  Discretionary Fund

The Operations Office will maintain and manage a Discretionary Fund.
The Executive/Steering 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 funding 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.

2.  Responsibilities of AIDS Clinical Trials Units (ACTUs)

a.  Staffing

Each ACTU must have experienced physician investigators associated with
the project who have demonstrated expertise in multi-center AIDS
clinical trials.  Adequate staffing must also include nursing,
pharmacy, data management and outreach personnel to recruit and screen
potential patients, implement clinical research protocols, perform
protocol required assessments, dispense investigational agents and
appropriately document clinical data, meeting all data reporting
requirements.

b.  Clinical Studies

Each ACTU will be required to have the capability to accrue a minimum
of 75 patients per year, and develop and implement a community outreach
program.  All clinical trials conducted at each ACTU must be in
compliance with the policies and bylaws of the ACTG.

c.  Routine Laboratory Assays

For those laboratory studies that will not be carried out in
centralized ATLs, each ACTU must have the capability to perform and/or
obtain (via collaboration) virology, immunology (including flow
cytometry) as required for evaluation of patients enrolled in the
ACTG's clinical trials.  Plans may entail arrangements including both
on-site and off-site testing.  Applicants proposing to obtain
laboratory testing from off-site collaborators (outside of their
institution) must provide the appropriate documentation (e.g., letters
of agreement) to substantiate the collaborative arrangement.  Use of
existing DAIDS-certified laboratories in the same community, whenever
possible, is strongly encouraged.  All laboratories performing protocol
mandated tests must participate in relevant laboratory quality
assurance programs.

d.  Quality Assurance:  Investigational Drug Management

Investigators performing trials under cooperative agreements must be
NIAID registered investigators (Form 1572 and curriculum vitae on
record with DAIDS) and must comply with requirements described in the
DAIDS Standard Operating Procedures.  Investigators must comply with
the "Pharmacy Guidelines and Instructions for ACTG" for storage,
dispensing and accountability of investigational agents and must comply
with all Federal regulations for investigational agents.

e.  Quality Assurance:  Internal Quality Control

Each ACTU must establish an internal quality control program to assess
the quality of its research records, which must be approved by and
consistent with the quality control policies developed by the ACTG.
These policies should include, but are not limited to, quality control
measures for collection, reporting and recording of data.  Each ACTU's
internal audit plan should apply to the main unit as well as any
subunits that might be established in affiliation with it.

Each clinical unit must submit a pharmacy plan to the Chief,
Pharmaceutical and Regulatory Affairs Branch (PRAB) for approval for
compliance with FDA requirements.  Upon approval, sites must register
for each protocol sponsored under an NIAID IND by submitting a package
of regulatory documents.  This package will be verified complete and
accurate by the ACTG Operations Office.  Once a site is registered for
a protocol, drug will be supplied by the NIAID Clinical Research
Products Management Center, and patients can be enrolled.

Each ACTU will be required to cooperate with the DAIDS Clinical Site
Monitoring Contractor, which will conduct external site monitoring to
assure site compliance with all Federal regulations and NIH policies
with respect to patient safety, data completeness and accuracy.

3.  Statistical and Data Management Center Responsibilities

a.  Study Design, Conduct, Analysis and Publication

The statistical staff will be responsible for providing statistical
scientific leadership for the ACTG; collaborating with other protocol
team members in all stages of protocol development and implementation;
performing timely interim analyses of safety and efficacy results for
review by protocol teams and/or the DAIDS Data and Safety Monitoring
Board; performing final analyses for publication, participating in the
writing of scientific papers and publish study results in conjunction
with other protocol team members;  producing timely study monitoring
reports, deliverable to the Group Leader and DAIDS; conducting
secondary analyses of ACTG data to improve the planning, design,
conduct and interpretation of ACTG trials; and summary tables and data
analyses for use in IND annual and interim submissions to the FDA and
function in accordance with the policies and bylaws of the ACTG.

b.  Data Management

The data management staff will provide for central registration and
randomization of patients on all studies; develop case report forms;
develop standardized criteria for verification of clinical endpoints;
design and implement a system to provide for the efficient transfer of
study results from clinical sites to a central database, using either
a centralized or distributed data entry approach; in conjunction with
the laboratory data management project and the NIAID AIDS Specimen
Repository, provide support for tracking and identification of
laboratory specimens; provide for processing, storage in a central
database and retrieval of study results; provide limited online access
for ACTUs to their own blinded data in the central database; prepare
selected, significant public access datasets, with adequate
documentation, deliverable to a location designated by DAIDS; provide
for an electronic mail system, capable of exchanging messages through
the Internet, to facilitate communication among clinical sites, other
ACTG components, and DAIDS; provide data management training of the
clinical unit staff and external site monitors; and develop reports
detailing site performance in data management, deliverable to the Group
Leader and DAIDS.  The data management staff should function in
accordance with policies and bylaws of the ACTG.

c.  Collaboration

When circumstances require the ACTG to collaborate with one or more
other clinical trial groups (e.g., CPCRA), the ACTG will agree to
follow procedures for trial conduct to be determined by DAIDS in
consultation with the leadership of each clinical trials group.
Normally, one group will be given the lead responsibility by DAIDS and
its procedures will be followed by all other collaborators.

In addition, the Statistical and Data Management Center will be
required to provide registration and randomization of patients for, and
accept data from, any organization funded by NIAID to participate in
adult ACTG trials, such as the National Hemophilia Foundation.
(Oversight for the performance of such organizations will be the
responsibility of the NIAID.)  Annual patient accrual to ACTG protocols
by other programs will not exceed five percent of the total ACTG
accrual.

4.  NIAID Staff Responsibilities

The NIAID will have substantial scientific/programmatic involvement
during the conduct of this activity, through technical assistance,
advice and coordination above and beyond normal program stewardship for
grants, as described below.

The role of the DAIDS staff as described throughout these terms of
cooperation is to assist and facilitate, but not to direct the research
activities.  Communication and interaction will occur primarily with
the Group Leader and the scientific leadership of the ACTG; however,
DAIDS will also interact directly with the Principal Investigator of
any of the collaborating institutions as needed.  This project is part
of a larger program of therapeutics research supported by NIAID.  Each
of the DAIDS staff listed below has specific responsibilities in terms
of investigational drug research and the role of the DAIDS as a drug
sponsor as defined in 21 CFR Part 312.

a.  DAIDS' Scientific Role in NIAID-Supported Clinical Research

The Associate Director, TRP and/or designated staff will work closely
with the ACTG Executive/Steering Committee to assure that the research
efforts of the ACTG are consistent with the NIAID agenda for
HIV-related clinical research and are complementary to those of the
other clinical trials mechanisms supported by DAIDS, specifically the
CPCRA and DATRI.

DAIDS will serve as a resource, and will disseminate information
regarding promising new agents, therapeutic strategies, or
developments.  DAIDS staff will advise the clinical investigators, as
requested or needed, of results from other trials (e.g., adverse
experiences and early terminations) that could influence the design,
development, or conduct of clinical trials and will serve as the
liaison between the pharmaceutical company representatives, the FDA and
the ACTG investigators.

b.  DAIDS Role in Protocol Review and Development

In order for a clinical trial to be initiated by an ACTG, the study
proposal must be mutually approved by the ACTG and the DAIDS Clinical
Science Review Committee (CSRC), chaired by the Associate Director,
TRP, DAIDS.  Once notified that a trial is under serious consideration
within the ACTG, DAIDS will evaluate the priority of the proposed trial
in relation to the NIAID HIV/AIDS Therapeutic Research Agenda, to other
NIAID trials, likelihood of timely completion; patient safety;
compliance with Federal regulatory requirements; plans for interim
monitoring of results; and resource requirements.  DAIDS staff will
also estimate the costs associated with the protocol.  The Associate
Director, TRP will return comments and recommendations in writing to
the ACTG within 30 days.

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

In the event a protocol is disapproved, the Associate Director, TRP
will work with the ACTG Executive/Steering Committee to resolve
specific concerns and ensure consistency between the research
interests, abilities and priorities of the ACTG and NIAID.
Nonetheless, DAIDS will not provide investigational materials or permit
expenditure of NIAID funds for a protocol that has not been approved.

Disagreements arising pursuant to protocol approval may be
submitted to an arbitration panel for resolution.  A panel
composed of one ACTG designee, one DAIDS designee, and a
third member with HIV/AIDS clinical trials expertise chosen
by the other two members will be formed to review the DAIDS
decision and recommend an appropriate course of action to
the Director, DAIDS.  These special arbitration procedures
in no way affect the awardee's right to appeal an adverse
determination in accordance with PHS regulations at 42 CFR
Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.
For protocols under a DAIDS IND, DAIDS will be responsible
for filing the protocol to the IND.

d.  DAIDS Role During Protocol Conduct

For ongoing clinical trials, DAIDS Medical Officer will
monitor the safety and efficacy of the treatment being
evaluated.  Therefore, interim and final reports on efficacy
and toxicity for all sponsored clinical trials will be
routinely provided to the DAIDS Medical Officer.  In
addition, for protocols in which the DAIDS is the IND
sponsor, DAIDS will assign medical monitors who will review
blinded and unblinded safety and efficacy data with the
protocol statistician on behalf of the DAIDS Data and Safety
and Monitoring Board to permit appropriate monitoring.

e.  DAIDS Role in Protocol Closure

The Associate Director, TRP and/or designated staff will
monitor the progress of ACTG trials by reviewing reports
periodically submitted to DAIDS, through the Data and Safety
Monitoring Board which consists of experts from several
disciplines, and through semi-annual meetings with ACTG
leadership.  DAIDS may deem it necessary to deny access to
further investigational drug supplies and deny the
expenditure of additional NIAID funds (except where
volunteers are already enrolled) if any of the following
reasons apply:  (a) risk of patient safety, (b) scientific
question no longer relevant, (c) slow accrual, or (d) study
will not answer question.  Appeal of such a decision by the
ACTG would proceed in the same manner as an appeal regarding
the disapproval of a protocol prior to opening.

f.  Access to Data

The Chief, Coordinating Centers Branch (CCB) and/or designated
monitoring contractor staff will have access to all data generated
under these cooperative agreements and may periodically review the data
as recorded on case report forms and/or maintained in the central
database.  Data must be available for external checking against
original source documents as required by NIAID policy and Federal
regulations relative to the responsibility of DAIDS as an IND sponsor.
The awardees will retain custody and primary rights to the data
consistent with current HHS, PHS, and NIH policies, including a policy
to provide public access to selected, significant data sets generated
with the use of public funds, within a reasonable period of time after
primary analysis and publication by the ACTG.

g.  Clinical Trials Agreements

It is expected that for most clinical trials, a pharmaceutical company
collaborator will provide investigational agents for the trials.  In
order for the ACTG, DAIDS and the company to understand their
respective responsibilities and rights, a Clinical Trials Agreement
(CTA) will be negotiated and signed by DAIDS and the company.
Important terms of the agreement include IND sponsorship, safety and
data monitoring, and access to trial data.  Concurrence with the ACTG
Group Leader will normally be obtained prior to execution of the final
agreement.  In general, terms in the CTA covering data access and
sharing will conform to policies developed jointly by the group
leadership and DAIDS.

h.  Laboratory Quality Assurance and Data Management

The DAIDS will provide the ACTG with contractual support for virology,
immunology and pharmacology laboratory quality assurance services.
Administrative, fiduciary and other aspects of contract management will
be the responsibility of DAIDS.  Scientific and technical oversight for
these quality assurance programs will be provided by DAIDS in
conjunction with advisory groups comprised of ACTG and other
investigators, and the Chief, Drug Development and Clinical Sciences
Branch working in a cooperative manner.

The DAIDS will also provide the ACTG with contractual support for the
management of virology, immunology and pharmacology laboratory data.
Given the complex nature of these data, the large volume to be
collected and the highly technical aspects of its collection, this
activity will be supported by its own project, distinct from, but
coordinated with, the group's data management system/facility.

i.  DAIDS Involvement in Investigational New Drug Applications

The DAIDS will have the option to cross file or independently file an
IND on investigational drugs evaluated in the ACTG clinical trials.
The Chief, PRAB will advise investigators of specific requirements and
changes in requirements concerning IND sponsorship that the FDA may
mandate.  Investigators performing trials under cooperative agreements
will be expected, in cooperation with the DAIDS, to comply with all FDA
regulations associated with investigational drug studies.

j.  DAIDS Review of ACTG Compliance with Federally Mandated Regulatory
Requirements

The Chief, PRAB will advise the ACTG regarding mechanisms to meet (1)
FDA regulations for DAIDS-sponsored studies involving investigational
agents, and (2) the NIH Office for Protection from Research Risks
(OPRR) regulations for the protection of human volunteers.

For DAIDS-sponsored trials with investigational agents, the DAIDS has
established an external DAIDS Clinical Site Monitoring Contract to
document good clinical research practices, including regulatory
compliance, proper protocol implementation, and test agent
accountability.

The DAIDS Clinical Site Monitoring contractor will visit ACTUs on a
quarterly basis (approximately five days per visit) to review specific
priority protocols, train in specific protocols, review, internal
quality assurance plans, audit pharmacies, and document error
resolution.

In order to provide for consistent reporting of adverse experiences
across clinical trials groups, DAIDS has established policies and
procedures delineated in the "ACTG Adverse Experience Reporting
Manual."   The ACTG, as the largest of the groups, will have the
responsibility for ongoing maintenance of the modified ICD-9 system for
classifying and coding the types of adverse experiences reported.  This
will require collaboration with staff from the DAIDS and other trials
groups.

k.  DAIDS as a Resource for Site Evaluation

The Chief, Clinical Site Management Branch (CSMB) will assist the ACTG
in developing criteria to evaluate the performance of the collaborating
institutions.  The Chief, CSMB will also provide ongoing data
pertaining to each site's performance as well as data on the cost of
the ACTG's research activities, including protocol specific costs.

l.  Review of Performance

The performance of the ACTG as a whole and that of the individual
institutions will be reviewed at least annually by the Associate
Director, TRP on the basis of information provided in annual progress
reports, evaluations of site performance conducted by the
Executive\Steering Committee, and site monitoring reports provided to
DAIDS by its contractor.

Substandard data management/quality, insufficient patient accrual,
inadequate progress in executing the research agenda, or noncompliance
with the Terms and Conditions of Award may result in a reduction in
budget, withholding support, suspension, or termination of award.

m.  DAIDS Review of Quality Control and Study Monitoring Procedures

The Chief, PRAB will periodically conduct a review of the ACTG and its
sites for the reliability of and compliance with clinical and
regulatory systems, and will advise on the same.

STUDY POPULATIONS

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 sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 1003-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations) which have been in effect
since 1990.  The new policy contains some new provisions that are
substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23,
Number 11.  A copy is also available through the NIH Grant Line (data
line (301) 402-2221).  Investigators may obtain copies from these
sources or from Dr. Frederick H. Batzold (see "INQUIRIES") who may also
provide relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 15, 1994, a
letter of intent that includes a descriptive title of the proposed
application (Adult ACTG Central Group, Adult ACTU, or Adult ACTG
Statistical and Data Management Center); the name, address, and
telephone number of the Principal Investigator; the number and title of
this RFA; a list of the key investigators and their institution(s); and
for Adult ACTU and Statistical and Data Management Center applicants,
the identity of the ACTG Central Group with which the applicant plans
to affiliate.

The letter of intent is requested to provide an indication of the scope
and number of applications that will be received and to promote early
interaction among potential applicants and between the applicants and
NIAID staff.  Letters of intent from potential applicants for ACTG
Central Group awards will be used by DAIDS program staff to refer
unaffiliated potential applicants for ACTUs to potential ACTG Central
Groups.  The letter of intent does not commit the sender to submit an
application, nor is it a requirement for submission of an application.
The letter of intent is to be sent to Dr. Peter Jackson at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  For purposes of identification
and processing, item 2a on the face page of the application must be
marked "YES" and the RFA number and the words "ADULT ACTG - CENTRAL
GROUP" or "ADULT ACTG - ACTU" or "ADULT ACTG - STATISTICAL AND DATA
MANAGEMENT CENTER", as appropriate must be typed in.

The research grant application form PHS 398 (rev. 9/91) must be used in
applying.  These forms are available at most institutional offices of
sponsored research and may be obtained from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 594-7441.

The RFA label in the form PHS 398 must be affixed to the bottom of the
face page.  Failure to use this label could result in delayed
processing of the application.  Submit a signed, typewritten original
of the application, including the Checklist, and three signed exact
photocopies.  Each application for the ACTG Central Group, Statistical
and Data Management Center, and each ACTU must be submitted separately.

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

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

Peter Jackson, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C14
6003 Executive Boulevard  MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-8426
FAX:  (301) 402-2638

The deadline for the receipt of applications is January 12, 1995.
Applications received after this date will be considered as
non-responsive to this RFA and will be returned without review.

Special Instructions for the Preparation of Cooperative Agreement
Applications

A.  Identification of Potential Applicants and Formation of ACTGs

It is the responsibility of potential applicants for an ACTG Central
Group award, ACTU award, and Statistical and Data Management Center
award as components of an ACTG to identify themselves to each other and
establish affiliations.  In addition to the standard communication
channels among investigators, the NIAID will facilitate the formation
of an ACTG by:  (1) providing the identity of potential ACTG Central
Group applicants to unaffiliated potential ACTUs applicants and the
names of unaffiliated potential ACTU applicants to potential ACTG
Central Group applicants based on the letters of intent; and (2)
holding a pre-application meeting on September 28, 1994.

B.  Pre-Application Meeting - September 28, 1994

The purpose of this meeting, to be held in the Bethesda, MD area, 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 (when these have not already been
established).  For further information contact:  Dr. Frederick H.
Batzold at the address listed under INQUIRIES.  Potential applicants
that request the RFA but are unable to attend the pre-application
meeting will be sent a summary of the discussion and any materials that
are distributed.

C.  Application Preparation

All applications must be submitted on the form PHS 398 (rev. 9/91).
Successful applications for each ACTG component (ACTG Central Group,
Statistical and Data Management Center, and ACTUs) 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.

All applications, including that of the ACTG Central Group, the
Statistical and Data Management Center, and the ACTUs should describe
the scientific and administrative experience of key personnel.

On page 2 of the PHS 398 form, in the section entitled PERSONNEL
ENGAGED ON PROJECT, it is imperative that all applicants list all
individuals and their institutions participating in the scientific
execution of the project in the format as specified 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.

The key feature of this RFA for the Adult ACTG(s) is that it requires
an ACTG Central Group application to be submitted by a Group
Leader/Principal Investigator of the ACTG Central Group.  All ACTUs
seeking membership in a collaborative group must submit a separate
application identifying the Central Group to which they are seeking
membership.  The Statistical and Data Management Center application
must be submitted separately, and must also identify the ACTG Central
Group with which it is affiliated.

In summary, for each ACTG being proposed, applications in response to
this RFA must include the following elements:

o  Adult ACTG Central Group Application

o  Scientific Agenda and Research Plan Operational/Management Plan
Plan/Budget for Advanced Technology Laboratories Outreach Plan
Operations Office Procedures

o  AIDS Clinical Trials Unit Application  Principal Investigator
Association with One ACTG Central Group Ability to Contribute to the
Scientific Agenda Demonstrated Clinical Trials Capabilities and
Expertise Ability to Provide Protocol Mandated Laboratory Tests Accrual
Potential Demographic Diversity/Community Outreach Plan

o  Statistical and Data Management Center Application

o  Principal Investigator Association with One Central Group Ability to
Provide Expertise in Statistics and Study Design and Analysis Data
Management Capabilities

The specific requirements for each application are listed below.

1.  Adult ACTG Central Group Application

The Group Leader is required to assemble the scientific leadership
required to produce a comprehensive research agenda on behalf of an
ACTG, and identify the scientific and managerial leadership required
for the ACTG to effectively and efficiently carry out its research
plan.

The ACTG Central Group application is not subject to the page
limitations as stated in the form PHS 398.  However, the Research Plan
(see pages 19 through 23 of the PHS 398 application brochure) must be
limited to 250 pages. (Note:  the Research Plan includes the scientific
agenda, the key scientific and managerial leadership, the
organizational and governance structure, the Operations Office
procedures, and the plan for establishing ATLs.)  The application
should be as concise as possible to ensure a thorough review.  The use
of tables, diagrams, organization and flow charts is strongly
encouraged.

Suggested format and page limitations for the Central Group
Application.  Applicants may request reallocation of the page limits
from Dr. Frederick H. Batzold (see INQUIRIES).

Scientific Agenda and Research Plan:  130 pages including
identification of the Group Leader/Principal Investigator, key
scientific leadership and a statistical and data management center.

Operational/Management Plan:  25 pages including organizational chart,
governance structure, plans for establishing bylaws, and key managerial
leadership.

Advanced Technology Laboratory Plan/Budget:  35 pages

Outreach Plan:  10 pages including plans for ensuring access to
under-represented populations especially women and minorities, for
involving community representatives in ACTG activities.

Operations Office Procedures:  50 pages including plans for developing,
implementing, and monitoring protocols, and plans for carrying out
regulatory responsibilities to the extent possible these plans can be
included as appendices.  Otherwise, these procedures should be
described in detail within the text of the application.

In addition to the support needed for the Operations Office, this
application should include a budgetary request by the Group Leader for
administrative/managerial support.

The application should also include a budget request for central ATLs.
The total budget request and planned distribution among virology,
immunology and pharmacology should be based on the scope of activities
proposed directly in support of the ACTG research agenda.

The Group Leader may also request a discretionary budget in this
application that will be used to fund innovative pilot studies, to
supplement the budgets of collaborating institutions, which are
undertaking resource intensive studies, to 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 $2,000,000 and the application must describe the criteria
and review procedures that will be used by the Executive/Steering
Committee for distributing these funds.

In addition to the proposed detailed overall first year budget and
summary budgets for future years, the applicant should identify the
annual budgets for the following four categories of activities:  (1)
administrative support for the Group Leader and scientific leadership
of the ACTG; (2) the Operations Office; and, within the Operations
Office, (3) the Advanced Technology Laboratories and (4) the
Discretionary Funds.

2.  Adult AIDS Clinical Trials Unit (ACTU)

Each application requesting support as an ACTU is subject to the page
limitations (25 pages) for the Research Plan as specified in the Form
PHS 398. (Note:  the Research Plan should include the information
requested below.) Appendices should be limited to no more than 60
pages.  Applications exceeding the page limitation will not be provided
to the Initial Review Group and will be returned to the applicant.

ACTU applicants must specify the ACTG Central Group application with
which it is proposing to affiliate.

Budget requests for clinical units cannot exceed $1,700,000 in TOTAL
COSTS per year for all activities at the unit including recruitment and
retention of new patients, protocol mandated virology and
immunophenotyping, and costs associated with the follow-up of patients
continuing on ACTG protocols at incumbent applicant institutions.

Budget justifications must be based on the projected types of studies
to be conducted, number of patients to be accrued, and the number and
type of personnel required relative to the above projections.

Historically, the protocol specific mean costs per patient per year for
ACTG Phase I, Phase II, and Phase III studies have been approximately
$6,300, $7,500, and $4,300, respectively.  The mean annual protocol
specific costs include:  all personnel time directed toward patient
care (e.g., physicians, nurses, and pharmacists), all laboratory costs,
and all clinical procedures.  The mean costs do not include resources
devoted to patient recruitment, screening and ancillary services, data
management, quality assurance, program administration or supplies.

The ACTU application should include, but is not limited to, the
following information:

a.  Expertise of key staff and nature of proposed scientific
contributions, consistent with the ACTG research agenda described in
the ACTG Central Group application;

b.  Evidence of past accomplishments relative to multi-center HIV
clinical trials;

c.  Organizational structure and responsibilities of key personnel;

d.  Evidence of the ability to accrue a minimum of 75 HIV-infected
patients per year;

e.  Evidence of the ability to enroll and retain ethnically diverse
patient populations, and plans to ensure the inclusion of
under-represented populations from within the applicant's catchment
area and the populations most affected by HIV and AIDS, especially
women and minorities (demographic data on the institution's catchment
area must be provided);

f.  Evidence of effective community linkages and plans for involving
community representatives in research activities;

g.  Procedures for the protection of human subjects;

h.  Internal quality assurance programs for regulatory compliance and
data management;

i.  Experience in conducting protocol mandated virologic and
immunologic assays;

j.  Plans to encourage the participation of new investigator, women,
and minorities in the scientific and managerial aspects of the ACTU.

3.  Statistical and Data Management Center

The application for the Statistical and Data Management Center must be
associated with only one ACTG Central Group application, and the ACTG
Central Group with which the Center is proposing to affiliate must be
stated in a cover letter and in the application.

The Statistical and Data Management Center application is not subject
to the page limitations as stated in the form PHS 398.  However, the
Research Plan (see pages 19 through 23 of the PHS 398 application
brochure) must be limited to 110 pages.  (Note:  the Research Plan
should include the information requested below.)  The application
should be as concise as possible to ensure a thorough review.

Suggested format and page limitations for the Statistical and Data
Management Center:

Organizational Structure/Management Plan:  10 pages including
organizational chart, procedures for communicating with collaborating
institutions, availability of experienced biostatisticians and other
key statistical scientific leadership.

Statistical Expertise:  30 pages to the extent possible plans and
standard operating procedures for providing timely interim analyses of
safety and efficacy and final analyses for publication, procedures for
supplying scientific, administrative and regulatory reports to the
Executive/Steering Committee and DAIDS should be included as
appendices.  Samples of protocols should also be provided in appendices
to demonstrate experimental design, methods of analysis, and sample
size calculation.  If the SOPs and protocols are not available, this
information should be described in detail in the text of the
application.

Data Management Capabilities:  70 pages SOPs that address plans for
database design and administration, procedures for data collection,
management, analysis and quality control, plans for
developing/maintaining patient registration/ randomization systems,
centralized storage and retrieval of data, plans for tracking
laboratory specimens, plans for training site personnel and site
monitors, and plans for providing an electronic mail system should be
included in the appendix.  If they are not available they should be
described in detail in the text of the application.

REVIEW CONSIDERATIONS

A.  Review Procedures

Applications will be reviewed by the Division of Research Grants (DRG)
for completeness and by the NIAID staff to determine responsiveness to
the RFA.  Incomplete 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.  As part of the initial merit review, a process (triage) may be
used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response to
the RFA.  Applications judged to be competitive will be discussed and
be assigned a priority score.  Applications determined to be non-
competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.  A second level of review will be
provided by the National Advisory Allergy and Infectious Disease
Council.

The review will be conducted in two stages.  A review panel will review
the ACTG Central Group application(s), focusing on the merit of the
proposed scientific agenda and the factors that will affect the group's
ability to achieve its stated goals and objectives.  The review panel
also will review the application from the Statistical and Data
Management Center associated with each ACTG Central Group application.

The review of the ACTU applications will focus on each unit's ability
to contribute to the ACTG Central Group's scientific agenda, as well as
the ability and expertise to conduct AIDS clinical trials, including
accruing 75 or more demographically representative patients/year.

B.  Review Criteria

The basic review criteria for this RFA are the same as those for
unsolicited research project grant applications, namely:

a.  Scientific, technical, or clinical significance and originality of
the proposed research; each project will be rated on its own merit.

b.  Appropriateness and adequacy of the experimental approach and the
methodology proposed to carry out the research.

c.  Qualifications and research experience of the Group Leader and key
staff in the area of the proposed research.

d.  Availability of necessary resources to conduct the research.

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

f.  In clinical studies, if there is inadequate representation of women
and/or minorities in a study design AND this affects the potential to
answer the scientific question(s) addressed, such inadequacy will be
considered to be a weakness or deficiency in the study design.  This
weakness will be reflected in the priority score assigned to the
project, unless a convincing justification is provided by the
investigator to explain the inadequate representation.

In addition, applicants are expected to address criteria specific to
the objectives of this RFA.  These criteria include:

1.  ACTG Central Group Application

a.  Scientific, medical, and technical significance of the proposed
research agenda; proposed plan to effectively accomplish the scientific
priorities outlined in the Adult ACTG research agenda; and the
strategies to integrate the clinical and laboratory activities of the
Adult ACTG.

b.  Adequacy of the proposed plan and budget for Advanced Technology
Laboratories to accomplish the research goals and priorities outlined
in the Adult ACTG Central Group application.

c.  Availability, qualifications and research experience of the Group
Leader, and named scientific leadership, including but not limited to,
previous experience with design, administration and management of
multi-center clinical trials.

d.  Plans for overall group management and operations, including the
structure and mechanism for effective communication and collaboration
among the group members including committee structure, an outline of
proposed bylaws, procedures for protocol development, data analysis,
delegation of responsibilities, performance evaluation and monitoring
of research progress, and management actions to improve performance or
eliminate inadequate performers.

e.  Plans for effective interaction and coordination among
participating institutions, with DAIDS, and with other research groups
conducting HIV/AIDS clinical trials.

f.  Adequacy of the available resources and personnel for administering
the group.  Evidence of Operations Office capabilities in research
administration, protocol development, and management of regulatory
documents.

g.  Adequacy of plans for appropriate inclusion of women and
under-represented minority groups in the clinical trials.

h.  Adequacy of plans for inclusion of community representation in
research and organizational activities.

i.  Adequacy of plans to encourage participation of new investigators,
especially women and minorities in activities at all levels of the
ACTG.

2.  AIDS Clinical Trials Unit Application

a.  Qualifications of key personnel, and scientific merit of the
proposed contributions to the cooperative group consistent with the
Adult ACTG Central Group's scientific agenda.

b.  Experience in multi-center HIV/AIDS clinical trials research.

c.  Demonstrated experience in conducting or obtaining virologic,
immunologic and pharmacologic assays in support of AIDS clinical
trials, and adequacy of laboratories internal quality assurance plan.

d.  Adequacy of available facilities and time availability of the
investigators and key personnel.

e.  Availability of a minimum of 75 patients per year and evidence of
the ability to accrue such patients.

f.  Adequacy of drug control procedures and pharmacist support to
ensure appropriate dispensing of study product.

g.  Adequacy of provisions for the protection of human subjects.

h.  Previous experience and adequacy of plans for the inclusion of
women and minority patients and for participation of new and minority
investigators.

i.  Previous experience and adequacy of plans for involving community
representatives in the sites' research activities.

3.  Statistical and Data Management Center Application

a.  Availability of experienced biostatisticians and other key
personnel to provide statistical scientific leadership for the design
and analysis of multi-center clinical trials.

b.  Organizational structure, responsibilities, and procedures for
communicating with collaborating institutions.

c.  Plans for database design and administration, and procedures and
policies for data collection, management, analysis, and quality
control.

d.  Plans for developing and maintaining systems for patient
registration/randomization and for centralized storage, processing, and
retrieval of data.

e.  Procedures for providing timely interim analyses of safety and
efficacy and final analyses for publication.

f.  Procedures for supplying scientific, administrative, and regulatory
reports to DAIDS.

g.  Plan to provide for an electronic mail system for all collaborating
ACTG institutions and DAIDS capable of exchanging messages through
Internet.

h.  Evidence of ability to collaborate with one or more other clinical
trial groups as needed.

i.  Plan for tracking laboratory specimens.

j.  Plan for training clinical (ACTU) site staff and external site
monitors in data management and clinical trials methodology.

AWARD CRITERIA

The predominant criteria for funding priorities will be the scientific
and technical merit of applications in response to this RFA.
Consideration will also 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; and (2)
cost-effectiveness of proposed studies.

Of the total funds available a minimum of $3.5 million will be reserved
for awards for ACTUs at minority institutions.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope of
this RFA are strongly encouraged and may be directed to the staff
listed below.

Requests for the "NIH GUIDELINES FOR INCLUSION OF WOMEN AND MINORITIES
AS SUBJECTS IN CLINICAL RESEARCH" and the "NIAID HIV/AIDS Research
Agenda" as well as inquiries regarding programmatic issues may be
directed to:

Frederick H. Batzold, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2A03
6003 Executive Boulevard MSC 7620
Bethesda, MD  20892-7620
Telephone:  (301) 496-8214
FAX:  (301) 480-5703

Inquiries regarding review criteria and procedures:

Peter Jackson, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C14
6003 Executive Boulevard MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-8426
FAX:  (301) 402-2638

Inquiries regarding fiscal issues to:

Kathryn Phillips
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B33
6003 Executive Boulevard MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Schedule

Letter of Intent Receipt Date:  September 15, 1994
Pre-Application Meeting:        September 28, 1994
Application Receipt Date:       January 12, 1995
Special Review Committee:       May 1, 1995
NIAID Advisory Council:         September 11, 1995
Anticipated Award Date:         January 1, 1996

AUTHORITIES AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases Research and
93.855 - Allergy, Immunology and Transplantation Research.  Grants are
awarded under the authority of the Public Health Service Act, Section
301 (42 USC 241) and administered under the PHS grants policies and
Federal Regulations, most specifically at 42 CFR Part 52 and 45 CFR
Part 74.  This program is not subject to the intergovernmental review
requirements of the Executive Order 12372 or Health Systems Agency
review.

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American People.

.

Return to RFAs Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.