Subject: RFA AI-9l-07 Part l of 3 5/3/9l NIH Guide
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Tue, 30 Apr 91 13:42 EST

Hi Paul,
   This is six of seven.  Please post this to the NIH Listserver as:
 RFAAI1-91-07.910503
   Thanks.   Dottie
 ---------------------------- Text of forwarded message -----------------------
Subject:      NIH GUIDE - Vol. 20, No. 18, May 3, 1991 - RFA AI-91-07,
              Part 1 of 3
 
$$XID RFA AI9107 AI-91-07 P1O3 *****************************************
 
REQUEST FOR APPLICATIONS
 
RFA:  AI-91-07
 
ADULT AIDS CLINICAL TRIALS UNITS
 
P.T. 34; K.W. 0715008, 0755015
 
National Institute of Allergy and Infectious Diseases
 
Letter of Intent Receipt Date:      June 5, 1991
Preapplication Meetings:            June 3, 4 and 5, 1991
Application Receipt Date:           August 6, 1991
 
The NIAID invites applications for the recompetition of the
adult AIDS Clinical Trials Units (ACTUs).
 
The NIAID plans to continue its support of the adult AIDS
Clinical Trials Units.  Reissuance of this initiative in
future years is not anticipated until the end of the project
period to be funded under this competition.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit by June 5, 1991,
a letter of intent (maximum of three pages) that includes a
descriptive title of the proposed research, the name
and institution of the Principal Investigator, and a brief
description of proposed research for each component in which
participation is planned.  A copy of the form, "APPLICATION
COMPONENTS" (Appendix I) should be appended to the letter of
intent.  Names of prospective co-investigators and other key
personnel should be included.  The letter of intent is
requested in order to provide an indication of the number
and scope of applications to be reviewed.
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:
 
Frederick Batzold, Ph.D.
Clinical Research Management Branch
Treatment Research Program, Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 208P
Bethesda, MD  20892
Telephone:  (301) 496-8214
 
               GLOSSARY OF ABBREVIATIONS
 
ACTG        AIDS Clinical Trials Group
ACTIS       AIDS Clinical Trials Information Service
ACTU        AIDS Clinical Trials Unit
AIDS        Acquired Immunodeficiency Syndrome
ATEU        AIDS Treatment Evaluation Unit
CAB         Community Advisory Board
CPCRA       Community Program for Clinical Research on AIDS
CRPR        Clinical Research Products Repository
CSG         Clinical Study Group
CTCC        Clinical Trials Coordinating Center
DAIDS       Division of Acquired Immunodeficiency Syndrome
DEA         Division of Extramural Affairs
FDA         Food and Drug Administration
GCRC        General Clinical Research Center
GMB         Grants Management Branch
HIV         Human Immunodeficiency Virus
HRSA        Health Resources and Services Administration
IND         Investigational New Drug
IRB         Institutional Review Board
NCI         National Cancer Institute
NIAID       National Institute of Allergy and Infectious
            Diseases
NICHD       National Institute of Child Health and Human
            Development
NIDA        National Institue of Drug Abuse
NIH         National Institutes of Health
PHS         Public Health Service
PHS 398     Application for Public Health Service Grant
QA          Quality Assurance
RFA         Request for Application
SDAC        Statistical and Data Analysis Center
SMSA        Standard Metropolitan Statistical Area
SRC         Special Review Committee
SSS         Social and Scientific Systems
TRP         Treatment Research Program
 
I. INTRODUCTION AND RESEARCH OBJECTIVES
 
The Division of AIDS (DAIDS) of the NIAID, in cooperation
with the AIDS Clinical Trials Group (ACTG), administers a
major AIDS clinical trials program.  The ACTG consists of a
network of U.S. academic institutions [designated as AIDS
Clinical Trials Units (ACTUs)], the DAIDS Treatment Research
Program (TRP), and DAIDS supported contracts (Statistical
and Data Analysis Center and the Operations Office).  The
research objectives of the ACTG are: to provide an effective
and efficient system to evaluate the safety and efficacy of
therapeutic interventions against HIV infection, AIDS, and
its associated conditions; to ensure that studies, selected
primarily by the ACTG investigators, address questions of
highest scientific priority; to develop new agents from
initial trials in human subjects to their final approval by
the Food and Drug Administration (FDA); and to help transfer
effective therapies from the research setting to routine
patient care.
 
The research objectives are accomplished through the accrual
of patients to ACTG trials, submission, analysis and
publicaton of data, and by participation of ACTU
investigators in the committees of the ACTG.  These are the
Scientific, Resource and Executive Committees.  The conduct
of all studies and the publication of data is the
responsibility of the investigators.  Within this
cooperative framework, individual ACTUs participate in some
or all of the ACTG studies and contribute to the ACTG's
efforts.
 
For a complete description of the current structure and
function of the ACTG, see Appendix II.  Applicants are
strongly encouraged to read this Appendix before preparation
of their application.
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, Recompetition of the
Adult AIDS Clinical Trials Units, 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, D.C. 20402-9325 (telephone 202-783-3238).
 
II. PURPOSE
 
The purpose of this RFA is to recompete the adult component
of the AIDS clinical trials program.  Existing adult ACTUs
and new applicants are invited to apply.  Successful
applicants will comprise the new network of adult ACTUs.
This network will be composed of investigators from a
variety of disciplines with demonstrated experience and
expertise in conducting clinical trials.  It is expected
that the awardees will have the capability to participate in
all phases of clinical trials in the areas of primary HIV
infection and associated opportunistic infections.  Both
areas will be given high priority.  Because of the
increasing incidence of HIV-related malignancies, applicants
will have the opportunity to describe their capability to
conduct oncologic trials or plans to develop such
capability.  The need for additional support for studies of
neurologic complications of HIV infection is recognized and
applicants will be able to apply for such.  Strong emphasis
will be placed on the enrollment of study participants from
populations currently underrepresented in clinical trials
(e.g., women, minorities, and substance abusers) and on
studies directed towards these populations.
 
In addition, applicants may elect to apply for the following
OPTIONAL components: participation in pediatric clinical
trials (available only to existing ACTUs that currently
have a pediatric component); protocol-mandated virology and
pharmacology laboratory testing; and developmental
laboratory research.  FAILURE TO APPLY FOR AN OPTIONAL COMPONENT WILL
NOT AFFECT THE REVIEW OR FUNDING OF THE ADULT CLINICAL
TRIALS COMPONENT.
 
III. OVERVIEW OF CLINICAL TRIALS COMPOSITION
 
The adult component of the ACTG will be composed of the
network of adult ACTUs funded under cooperative agreements
as a result of this RFA.  The clinical trials units may or
may not contain the optional component features.
 
Investigators and staff at ACTUs will participate in the
ACTG effort by enrolling patients into ACTG protocols, by
participating in ACTG activities, and by developing concept
sheets for studies to advance the scientific agenda for HIV
infection and its complications.
 
Under the terms of this RFA, funds will be provided to ACTUs
on the basis of the essential personnel, equipment, patient
care costs, and supplies necessary to enroll an agreed-upon
number of patients onto an array of protocols each year.
For the first year of funding, examples of existing
protocols, provided in this RFA, will be used to construct
budgets. In future years, the cost of new
protocols will be estimated in advance so that budgets will
reflect the number of new patients,
and the cost of the individual
protocols in which the unit will be participating.  This
funding is designated as Clinical Core Funding.  The
majority of this funding will be dispensed at the beginning
of each annual funding period.  Following a mid-period
review of accrual and other performance factors, a decision
will be made by NIAID staff about releasing the balance of
the Clinical Core funding for that budget period.  In
addition, at the time of the annual non-competing
application, budgets for Clinical Core Funding will be
reviewed and may be adjusted depending on the complexity and
cost of protocols to be undertaken by the ACTU, in accordance
with the priorities of the ACTG and NIAID.
 
For each budget period, a portion of the total ACTG budget
may be set aside and designated as Incentive Funding.  These
funds will be awarded as administrative supplements or
competing supplements, consistent with NIH and NIAID
policies, during a budget period and will support activities
including, but not limited to, the following: 1)
augmenting awards to ACTUs able to accrue a greater than
expected number of patients into high priority protocols, 2)
initiating in mid-period new priority protocols established
by the ACTG and the NIAID that require funding not included
in the Clinical Core Funding budget; and 3) providing
limited support to institutions whose investigators
contribute a substantial amount of uncompensated time and
effort to ACTG committees or other program activities.
 
All applicants MUST apply for the Adult ACTU component (PART
A).  APPLICANTS MAY NOT APPLY FOR ANY OTHER COMPONENT UNLESS
THEY HAVE APPLIED FOR PART A.  The Pediatric component (PART
B) and the Laboratory Component (PART C) are OPTIONAL.
 
IV.  SPECIAL INSTRUCTIONS FOR PREPARING ACTU APPLICATIONS
 
A. This section supplements the instructions for
preparing a grant application form PHS 398 (rev.
10/88, reprinted 9/89).  Additional information is
provided on the organization of the application to
accomodate the multicomponent structure of this RFA.
The cooperative agreement application should be
assembled and paginated as one complete application.
However, each component of the application will
require a separate narrative and itemized budget with
justification. Specific instructions for preparing
each component are found in the individual
descriptions in Sections V.(A and B) and VI.(C) of
this RFA.
 
The following is a summary of the components of the
application:
 
Part A-     Adult Clinical Trials Unit (REQUIRED)
Part B-     Pediatric Component (OPTIONAL - LIMITED TO
            EXISTING ADULT ACTUs WITH A PEDIATRIC COMPONENT)
Part C-     Laboratory Component (OPTIONAL)
            C.1 - Protocol Mandated Virology (OPTIONAL)
            C.2 - Protocol Mandated Pharmacology (OPTIONAL)
            C.3 - Developmental Research in Virology
            (LIMITED TO APPLICANTS FOR C.1)
            C.4 - Developmental Research in Pharmacology
            (LIMITED TO APPLICANTS FOR C.2)
            C.5 - Developmental Research in Immunology (OPEN
            TO ALL APPLICANTS)
            C.6 - Other Microbiological Developmental
            Research (OPEN TO ALL APPLICANTS)
 
B.    Page 1 of Form PHS 398
 
Complete items 1-18 as instructed.  Please note
that this should be page one for the entire
application and that all succeeding pages should
be numbered consecutively.
 
Item 2: Enter the number and title of the RFA
and the optional components, if any, in the
application.
 
Items 7 & 8: The budgets requested should
represent the TOTAL budget of the entire
application including Clinical Core Funding
(Part A) and all Optional Components (Parts B
and Part C).
 
Item 12: Only domestic organizations are
eligible to apply and applicant organizations
may not include an international component,
including subunits, as part of the application.
 
C.    Page 2 of Form PHS 398
 
The abstract should contain a brief summary of
the proposed work and objectives for all
components in the application.
 
Under 'Key Personnel Engaged on Project' list
the Principal Investigator of the ACTU and the
Program Director for each component.
 
D.    Page 3 Form PHS 398
 
Prepare a detailed Table of Contents that will
enable reviewers to readily locate specific
information for each component.
 
E.    Page 4 Form PHS 398
 
The application must contain an overall
Composite Budget for the first 12-month budget
period.  The Composite Budget must include the
subtotals from the individual detailed budgets
for the first 12-month budget period for each
component in the application.  The subtotals for
each category (e.g., Personnel, Equipment, and Supplies)
on the Composite Budget page must be
identified by the activity (e.g., Part A, Part B, C.1,
C.2).  Justification for budget elements
should be presented in the individual
components.
 
F.    Page 5 Form PHS 398
 
A summary total budget by category (e.g., Personnel,
Equipment, and Supplies) for all years of
requested support must be presented on page 5.
The total budget for all future years of
requested support is a composite of the
individual budgets contained in each component.
Justification for the budget elements
must be presented in the individual
components.
 
G.    Biographical Sketches
 
Prepare biographical sketches for all
professional personnel participating in the
adult ACTU (Part A) and any other components for
which support is requested, using the
appropriate page from form PHS 398 and
applying the same page limitations. The
biographical sketches, with the Principal
Investigator first and those of the other key
professional personnel following in alphabetical
order, must be placed at the end of the
application, appropriately numbered and
referenced in the Table of Contents.
 
V.    PART A. CLINICAL TRIALS UNIT
 
The structure and functions of the ACTG (ACTUs, TRP, SDAC,
and the Operations Office) will be retained, as described in
Appendix II.  However, the major change will be the linkage
between ACTU performance and funding.  The key elements of
this change are the establishment of procedures for costing
protocols and revision of the administrative framework of
the ACTU.
 
PROCEDURES FOR COSTING PROTOCOLS
 
Protocols will be developed following the same
procedures outlined in Appendix II; i.e.,
proposed studies summarized as concept sheets,
that are reviewed, approved and prioritized by
the appropriate ACTG Scientific Core Committee,
the Executive Committee, and NIAID.  Approved
concept sheets are then developed into
protocols.
 
Protocol development will be modified in that
the total per capita cost of each patient
accrued to the study for its duration will be
determined for a new protocol before initiation
of the study. Thus, consideration of cost
effectiveness and appropriate utilization of
available resources will be a part of the NIAID
approval process for new protocols.
 
For the first year, applicants will provide
budgets based on costs determined for the 5
sample protocols provided in the RFA. For future
budgets, as new costed protocols are introduced,
costs for a new study will be determined by
relating the new study to one of the 5 sample
protocols to which it is most closely related
and for which the applicant has previously
submitted a cost estimate.
 
REVISION OF THE ACTU ADMINISTRATIVE FRAMEWORK
 
o Clinical Care Funding
 
Clinical Core funding consists of the resources
required to maintain an infrastructure sufficient to
accrue a projected minimum number of new patients each
year.  Clinical Core funding will include costs for
personnel, supplies/equipment, patient care,
laboratory support for protocol-mandated
immunophenotyping, and costs for virology and/or
pharmacology tests if these are to be performed at
another site.
 
Clinical Core funding will be based on the projected
number of new patients to be accrued.  For existing
ACTUs which are recompeting, the budget should include
funds for continuing patients accrued prior to
recompetition and who are still being actively
followed as part of an ACTG protocol.  Applicants
should prepare a clinical core budget sufficient to
accrue a MINIMUM of 60 to a MAXIMUM of 150 new
patients per year.  The budgets will be constructed
using the cost of individual ACTG protocols
expected to be accrued to that protocol (see below
for additional details on the costing of protocols and
directions for construction of the budget). Clinical
Core funding for new patients must include the total
cost of follow-up for the entire duration of his/her
time on the study.
 
Clinical Core funding will be administered as follows:
the majority of the funding will be released at the
beginning of the budget year.  At mid-year, the
performance of the unit will be assessed by NIAID
staff, using accrual and other measures of
performance.  This assessment will be based on an
Interim Progress Report submitted by the Principal
Investigator.  If unit performance is satisfactory,
the remaining increment of funding will be released.
In the event of unsatisfactory ACTU performance (e.g.,
failure to meet accrual goals without adequate
justification), the remaining funds will be reduced or
withheld. Continued inadequately justified poor
performance during the remaining months of the budget
period may result in reduction of Clinical Core
funding for the following budget period or
interruption of support.
 
o Incentive Funding
 
A portion of the total ACTG budget may be set aside
each year for Incentive Funding.  These funds will be
used to support activities such as:
 
a.    funding for personnel or patient care costs for
ACTUs that are able to EXCEED the target accrual
goal to ACTG and NIAID-designated high priority
protocols; upon approval of the NIAID, the ACTU
may apply for incentive funding;
b.    initiating a high priority protocol or to focus
on a scientific area during a budget year for
which resource needs exceed the clinical base
funding of individual ACTUs; and
c.    funding for awardee institutions to supplement
costs incurred as a result of substantial
uncompensated participation by investigators in
ACTG activities (e.g., travel or other program
work, such as a chair of an ACTG scientific
committee).
 
Incentive funding will be awarded as administrative
supplements after an NIAID staff review of requests or as
competing supplements.
 
ADULT CLINICAL TRIALS UNIT - INSTRUCTIONS FOR PHS FORM 398
 
[THE FOLLOWING INSTRUCTIONS REPLACE THOSE GIVEN IN FORM 398;
OTHERWISE INSTRUCTIONS IN THE FORM MUST BE FOLLOWED]:
 
SPECIFIC INSTRUCTIONS - SECTION 1.
 
(Page 4)
 
Construction of Detailed Budget for Part A:
 
Appendix III contains guidelines for Core
Budgets (Adult Units).  Appendix IV contains
descriptions of 5 current ACTG protocols of
varying complexity and scope, from small phase I
studies to large phase III efficacy studies.
These 5 protocols represent the range of costs
of ACTG protocols, from uncomplicated outpatient
studies to complicated labor-intensive inpatient
studies. Using the form "COST OF CLINICAL
TRIALS" (Appendix IV), applicants must
calculate and list the institutional direct cost
per patient for each of the five protocols.
 
The Clinical Core funding budget will be
constructed by projecting the total number of
patients expected to be accrued to one or more
of the five given protocols (or any existing ACTG
protocol of similar phase, complexity, scope,
and resource requirements). Appendix V contains
a listing of ACTG protocols by title that are
currently open to enrollment as examples of the
the scope of studies performed by the ACTG.  The
Clinical Core budget total provided by
applications from existing ACTUs should include
support for continuing patients.  The budgets for
continuing patients should be presented on a
separate PHS Form 398 budget page.
 
Clinical Trials Units may be formed through
consortium arrangements with other insitutions
or health care agencies. The goal of such
arrangements would be to contribute
substantially to the performance of the awardee
institution (the Main Unit) by providing access
to patient populations not well represented at
the Main Unit. These collaborating institutions
would be designated as Subunits, although
ultimate financial and scientific responsibility
would reside with the Main Unit. (Appendix VI
contains Guidelines for Establishment of
Subunits).
 
If the applicant does not apply for the optional virology or
pharmacology support laboratories, the Clinical Core budget
must include costs required to:
 
a. collect, log, process, store and ship
clinical specimens to designated ACTG-
certified virology and pharmacology core
laboratories, as required by ACTG
protocols; and
 
b. maintain ACTG specimen inventories and
storage facilities and cooperate in all
ACTG batch testing efforts by shipping
specimens to designated ACTG-certified
virology and pharmacology core
laboratories, as required by ACTG
protocols.
 
Efficient use of funds for clinical trials will
be a major determinant of award levels.
 
SPECIFIC INSTRUCTIONS - SECTION 2.
 
IN PLACE OF ITEMS A-D OF THE RESEARCH PLAN, PLEASE ADDRESS
THE FOLLOWING 9 AREAS:
 
1. PROFICIENCY IN THERAPEUTIC CLINICAL TRIALS (2-3 pages)
 
The applicant should describe the extent and scope of
previous clinical trials experience, especially that
involving HIV infection and its complications.
Information needed for the evaluation of proficiency
should include the following:
 
a.    Applicants not previously associated with the
ACTG:
 
1)    describe clinical trials experience in
terms of kinds of studies; number and type
of patients, including disease state and
demographic features;
2)    describe how data management was performed
and the data quality assurance program in
effect;
3)    list all related publications; and
4)    describe the level of scientific
participation in the study [e.g., protocol
design, oversight, analysis of data and/or
presentation and publication of results].
 
b.    Applicants that are existing ACTUs:
 
[NIAID will provide to the Review Committee
copies of ACTU Institutional Evaluation Reports
and accrual statistics]
 
(1)   describe in detail scientific contributions
to the ACTG including chairing or
participating on committees, protocol
chairs, concept sheet
submissions, laboratory effort and serving
on working groups; and
(2)   relate any extenuating circumstances or
other situations that might have affected
the site's performance, as reflected in the
evaluations.
 
c.    Applicants that are subunits of existing ACTUs:
 
1)    describe in detail scientific
contributions to the ACTG including
chairing or participating on committees,
protocol chairs, concept sheet
submissions, laboratory effort, and
serving on working groups;
2)    provide the total accrual of the parent
ACTU and state what proportion was
contributed by the subunit;
3)    list the ACTG protocols in which the
subunit participated including the number
and demographic features of patients
accrued; and
4)    describe the system of data management
used (i.e., data entry at the site or
transfer of case report forms or other data
to the parent unit) and the quality assurance
program in place at the subunit.
 
2. ORGANIZATIONAL STRUCTURE FOR CONDUCT OF CLINICAL STUDIES
(6-8 pages)
 
The applicant should detail the essential features
necessary for performance of clinical studies
including organizational structure, qualifications of
key personnel, and facilities. The narrative must
specifically address the following:
 
a. organization - structure of the clinical trials unit and
its administrative relationship with the parent
institution.  Describe whether the clinical trials unit
is an integral part of the patient care activities of
the institution or is constituted as a separate
reseach unit. The applicant must describe how studies
of acute illness requiring inpatient care will be
conducted in addition to the plan for outpatient
studies.
 
b. facilities - a description of the space available for
performing both outpatient and inpatient clinical
studies should be included.  Describe the patient care
area where study subjects would receive non-protocol
related care if different from the clinical trials
unit. The availability of a GCRC for the clinical
trials should be noted.
 
c. personnel -  in addition to personnel listed on
budget page 4, describe the type, number, and
qualifications of any other personnel who might assist
in the conduct of the studies, e.g., physicians and/or other
health care personnel in training, institution-
supported administrative or health care personnel,
state or municipal supported personnel, volunteers, or
others.
 
3. TYPES OF STUDIES (3-5 pages)
 
Studies of treatment and prophylaxis of primary HIV infection and
opportunistic infections will continue as high priority areas and ALL
applicant institutions must participate in such studies.  Because of the
increasing frequency of HIV-related malignancies and the recognized
importance of neurologic complications of HIV infection, the ACTG will
also emphasize studies in oncology and neurology.  Applicants will not
be penalized by the Review Committee for failure to include a focus on
oncology or neurology.  Sites that have suitable expertise and
appropriate patients for any of the above areas should include support
for necessary personnel in the Clinical Core budget.  In this section
the applicant should address the following:
 
a. describe the plan for participation in high
priority areas:
 
      1) primary HIV infection
      2) opportunistic infections
      3) HIV-associated malignancies
      4) neurologic complications of HIV
      infection
 
b. qualifications of key personnel necessary for
each area of emphasis (in addition to personnel
described in l.c. above and on budget page 4)
[For this purpose, key personnel include the
Principal Investigator (PI), Co-Investigators,
and other Physicians]
 
c. special scientific expertise, facilities, and
other unique features the proposed site might
offer to the ACTG effort in reference to the
designated scientific areas of emphasis.
 
4. TYPES OF PROTOCOLS (2-3 pages)
 
ACTG protocols vary both in terms of type (i.e., phase
I, I/II, II, or III) and in complexity. It is NIAID's
expectation that each ACTU will mainly accrue patients
across the range of phase II/III studies. Certain
applicants may elect to focus primarily on phase I
studies. This section should address the following:
 
a. estimate how the projected total accrual of
patients in the first year will be distributed
among the types of clinical trials (i.e., phase
I, I/II, II, and III); and
 
b. in the event of a heavy emphasis on one type
of study, e.g., phase I, applicants must
describe the unique personnel, facilities,
patients, or other features that would justify
this special focus.
 
5. ACCRUAL AND RETENTION PLAN:  GENERAL REQUIREMENTS FOR
INCLUSION OF WOMEN AND MINORITIES (3-5 pages)
 
Each applicant must project a minumum
number of patients to be accrued in the first year, a
number that defined the size of the budget. Accrual
of a minimum of 60 adult patients/year to ACTG studies
is necessary to qualify as a prospective clinical
trials unit (see below for information on minimum and
maximum accrual goals).
 
a. The applicant must document the ability to
accrue the projected number of patients into
ACTG studies. This documentation should also
address the following:
 
1) primary source of study subjects, i.e.,
inpatient or outpatient units providing
primary care, consultative services, HIV
testing sites, referrals from community-
based physicians or agencies, or other;
 
2) if referral, describe policies and
procedures for communication, provision of
non-protocol related care, follow-up by
research staff or primary care provider,
and transfer of care back to primary care
provider upon completion of study;
 
3) the amount of primary care provided by
the research staff; and
 
4) for new applicants, past records of
clinical trials or data from inpatient or
clinic records showing number of patients
under care (or projected) and an
estimation of percentage suitable for ACTG
studies.
 
b. Describe the demographic features of patients
in the catchment area, including number of AIDS
cases, HIV seroprevalence data, sex,
race/ethnicity, and risk transmission
categories. If available, include a
categorization of HIV status (asymptomatic,
symptomatic, and AIDS) for patients currently
being seen or anticipated.
 
c. Describe the plan for the inclusion of
women, minorities, substance abusers, and
persons with hemophilia.  Individuals from these
populations are currently underrepresented in
NIAID clinical trials. This plan MUST project
inclusion of women and minorities in numbers
that are consistent with the demographic
features of HIV infection among persons in the
applicant catchment area. Note
that this plan is an important element in the
review criteria.  If the required
information is not contained in the application,
the application will be returned.  Peer
reviewers will address specifically whether the
research plan in the application conforms to
these policies.  If representation of women or
minorities in a study design is inadequate to
answer the scientific question(s) addressed AND
the justification for the selected study
population is inadequate, it will be considered
a scientific weakness of the study design and
will be reflected in assigning the priority
score to the application.
 
d. The applicant must describe the strategy
for interaction with community health care
providers or agencies that have led, or is
likely to lead, to referral of HIV-infected
women and minorities for clinical studies. The
number and type of staff who are culturally
sensitive to the needs of these populations
must be included.
 
e. The applicant may consider the establishment
of subunits at patient care sites that provide
care for large numbers of HIV-infected women and
minorities (see Appendix VI for Guidelines for
Establishment of Subunits).
 
6. DATA MANAGEMENT PLAN (3-5 pages)
 
[For existing ACTUs, please highlight any changes from the
existing data management system].
 
a. Describe the plan for managing the clinical
trials data from both inpatient and outpatient
studies, i.e., collection, entry, maintenance,
monitoring, storage, and transmission.
 
The plan for data storage must take into account that
Federal regulations require the retention of research
records for investigational drugs for two years after a
marketing application is approved for the drug. If an
application for the drug is not approved, the records must
be retained for two years following discontinuation of
shipment and delivery of the drug and after the FDA has been
notified.
 
The plan should include establishing procedures for:
 
1) staff education and training on the requirements of
specific protocols;
 
2) completion of the forms required for patient study
visits (the time from patient visit to data entry
should be noted);
 
3) transcription of laboratory data from lab slips to
data forms in preparation for data entry;
 
4) data entry into the ACTG PC-based distributed data
entry system in a timely fashion;
 
5) design and maintenance of filing systems for the
patient chart and completed data forms and ensuring
the security of these files; and
 
6) provision of adequate resources with respect to
both staff and PC hardware and software to accomplish
these responsibilities.
 
The Data Manager should have a basic knowledge of PC
hardware, software and DOS.
 
b. Describe a plan for establishing on-site quality
assurance procedures to assess the accuracy and
completeness of all research records, compliance with
Federal regulations regarding clinical trials (e.g.,
Institutional Review Board approval and informed
consent process).  Assignment of dedicated personnel
(e.g., 0.5 FTE research nurse or 0.5 FTE data manager
with supervision by a research nurse) is strongly
encouraged.
 
c. A list of computer equipment that will be required
for a clinical trials unit is located in Appendix VII.
Required equipment may be requested as part of the
application.
 
7. PHARMACY PLAN (3-5 pages)
 
Each application must include a pharmacy plan that
addresses the development and maintenance of the
investigational drug control system.  The pharmacy
plan must include the guidelines set out in the ACTG
Pharmacy Manual (available upon request from the NIAID
Operations Office) and FDA regulations involving the
use of investigational drugs:
 
a. technical procedures for control of drug
ordering;
b. procedures for dispensing;
c. procedures for accountability; and
d. drug storage.
 
The plan should contain separate sections
describing the details applicable to each
clinical trials site included in the
application.  Letter(s) of agreement in support
of the plan(s) from pharmacy personnel at the
participating institutions should be included.
 
Guidelines for levels of pharmacy commitment
based on projected accrual are included on the
form, "ACTU CORE BUDGET", in Appendix III.  In
addition, the cost of the pharmaceuticals and
supplies that are not provided by the ACTG
should be included; e.g.,  parenteral solutions,
irrigation solutions, IV tubing, other supplies
and materials, as well as costs associated
with preparation of these medications.
 
8. LABORATORY CAPABILITY (3-5 pages)
 
a. Immunophenotyping
 
Applicants must demonstrate the capability of
performing two-color flow cytometric
immunophenotyping using whole blood samples with
analysis on a laser-based instrument. Based on a
projected accrual of 60 patients, laboratories
should be capable of analyzing a minimum annual
number of 500 samples including, but not
limited to, CD4, CD8, CD3, CD19, CD45, CD14, and
others (e.g., CD25, CD38, and DR), as required
in ACTG protocols.
 
Awardee laboratories will be required to
participate in the ACTG quality assurance (QA)
program.
 
The narrative description should contain the
following:
 
      1) prior laboratory experience with flow
      cytometry;
      2) description of equipment;
      3) qualifications of key laboratory
      personnel;
      4) description of internal QA program; and
      5) involvement in multicenter QA efforts.
 
b. Virology and Pharmacology
 
      Applicants have the option of applying for funds to
      support laboratories for protocol-mandated virology
      and/or pharmacology tests.
 
If this option is not selected, or if an application
for a core laboratory is not funded, awardees will be
required to arrange (through a subcontract or other
mechanism) to have protocol-mandated virology and
pharmacology testing performed by an  ACTG-certified
laboratory.
 
9. ANCILLARY SUPPORT (3-5 pages, plus supporting letters)
 
The following support linkages are either REQUIRED
or ENCOURAGED:
 
a. Community Advisory Board [REQUIRED]. The purpose of
a Community Advisory Board (CAB) is to foster
inter-action between the ACTU staff and HIV-infected
individuals in the community in addition to community
health care providers and advocacy groups.  The goal
of this interaction is to communicate information
about the ACTU, the clinical trials, and the
availability of investigational therapies and to
receive input about study design or any factor that
might impact on patient acceptance or compliance.
Describe the role and relationship of the Community
Advisory Board (CAB) to the research and operations of
the applicant institution. Specify the composition of
the CAB, including AIDS-related expertise of the
participants, functions performed for the ACTU, and
proposed meeting schedule.  Inclusion of women and
minorities is required; their participation on the CAB
should be reflective of the demographics of HIV-
infected persons in the catchment area.
 
b. CPCRA [REQUIRED].  Establish a formal communication
linkage with a CPCRA site if one is located within the
same SMSA (see Appendix VIII). The purpose of this
linkage is to make certain that the most
appropriate clinical trials mechanism is available to
HIV-infected individuals in a community and to avoid
needless competition for study subjects. Include a
letter of agreement in the application that should be
co-signed by the Principal Investigator of the
applicant institution and the CPCRA site. The letter
should describe: agreed upon procedures for screening,
recruitment, and accrual of patients; assignment
of patients to NIAID protocols; and whether and how
facilities, staff, and resources will be shared.
 
c. General Clinical Research Center (GCRC)
[ENCOURAGED]. Applicants from institutions that have
a GCRC funded by the National Center for Research
Resources may wish to identify the GCRC as a resource
for conducting the proposed research. In such a case,
a letter of agreement from either the GCRC Program
Director or the Principal Investigator should be
included with the application.
 
d. HRSA AIDS Demonstration Project [ENCOURAGED].  An
establishment of linkage with a HRSA project, if one is
located within the same SMSA, is encouraged and a
letter of agreement describing the relationship should
be included. [Appendix IX contains a listing of HRSA
AIDS Demonstration Projects].
 
e. National Institute on Drug Abuse (NIDA) Treatment
and Research Centers [ENCOURAGED].  NIDA and NIAID
collaborate in funding ACTG trials in order to
increase the number of HIV-infected drug users in ACTG
protocols. Applicants are strongly encouraged to
establish linkages with NIDA Treatment and Research
Centers located in the same community. [Appendix X
contains a listing of the NIDA Treatment and Research
Centers].
 
Applicants are strongly encouraged to form other linkages,
including but not limited to: community-based organizations
that serve populations at increased risk for HIV infection,
designated State AIDS Centers, NCI lymphoma network, and
community-based AIDS clinics.  A letter of agreement for
each linkage should be included with the application.
 
COMPLETE THE REMAINDER OF SECTION 2, PARTS E THROUGH I
 
V. PART B. PEDIATRIC COMPONENT OF AN ADULT ACTU (OPTIONAL)
 
The history of the pediatric component as part of the adult
ACTUs is described in Appendix II.A.  In general, these
components were established in communities where the
incidence of HIV-infected children was not sufficiently high
to warrant a free-standing pediatric ACTU.  In an effort to
maintain this participation of adult ACTUs in pediatric
clinical trials, adult units with existing pediatric
components may apply for funding to continue support of that
component.
 
THIS OPTION IS AVAILABLE ONLY TO EXISTING ADULT ACTUs THAT
ALREADY HAVE A PEDIATRIC COMPONENT.  FUNDING TO ESTABLISH
NEW PEDIATRIC COMPONENTS OF ADULT UNITS SHOULD BE PURSUED
THROUGH OTHER INITIATIVES.
 
Patients accrued to ACTG pediatric clinical trials by the
pediatric component must be considered IN ADDITION to the
minimum number of 60 adult patients required as an adult
ACTU.
 
                   INSTRUCTIONS FOR PART B.
       PEDIATRIC COMPONENT OF AN ADULT ACTU (OPTIONAL)
 
THIS COMPONENT REQUIRES A SEPARATE DESCRIPTION AND BUDGET.
IT SHOULD CONTAIN THE FOLLOWING SECTIONS: PROGRESS REPORT,
RESEARCH PLAN, ACCRUAL AND RETENTION PLAN, STAFFING
REQUIREMENTS, AND BUDGET.  USE THE APPROPRIATE SECTIONS OF A
SEPARATE FORM PHS 398 FOR THE APPLICATION OF THE PEDIATRIC
COMPONENT.
 
SPECIFIC INSTRUCTIONS - SECTION 1
 
Construction of a Detailed Budget for Part B
 
The budget for this component can not exceed an amount
representing 10 percent (direct costs) of the proposed adult
ACTU budget for the first year.  Guidelines for level
of effort are found in Appendix XI.
 
SPECIFIC INSTRUCTIONS - SECTION 2
 
IN PLACE OF ITEMS A-D OF THE RESEARCH PLAN ADDRESS THE
FOLLOWING AREAS:
 
1. The applicant must describe the history of the
pediatric component and the productivity in terms of
accrual of children and scientific contributions of
ACTU investigators including publications,
presentations, and participation in ACTG activities;
 
2. Proposed research plan for the component including
the types of ACTG protocols to be implemented;
 
3. Organization and operation of the pediatric
component including:
 
a. a description of the interrelationship with
and the services provided by the adult ACTU;
 
b. a description of procedures in place for
enrolling HIV-infected women who are mothers of
children participating in ACTG clinical trials;
 
c. ancillary support available to the pediatric
component (e.g., social worker, state or local
HIV clinic); and
 
d. institutional support provided to the
pediatric component by the relevant departments,
such as Pediatrics, Obstetrics/Gynecology, and
Perinatology.
 
4. Accrual and retention of pediatric patients:  Gender
and Ethnic Status
 
This section should contain information about the
number of potential study subjects in the catchment
area as well as evidence of past ability to accrue a
minimum of 5 new children/yr to ACTG studies.
Screening and recruitment procedures should be
described. Problems that have been encountered should
be identified and solutions discussed. The procedures
for retaining children on ACTG studies should be
described. In keeping with NIH general requirements
for inclusion of women and minorities, the gender and
minority status of each child must be identified; and
 
5. Staffing requirements:
 
List the staff currently supported at the pediatric
component and provide justification for proposed
changes in staffing levels.
 
Relationship with NICHD
 
Applicants from institutions that have a site
conducting clinical trials on pediatric AIDS funded by
the National Institute of Child Health and Human
Development (NICHD) or have such a site within the
same SMSA will be required to include a letter of
agreement from the Principal Investigator of the NICHD
site in which the relationship beteween the two sites
is described. The following items should be included:
screening/recruitment procedures for HIV-infected
children; whether facilities, resources, and/or
personnel are shared; whether both sites are or will
be participating in ACTG protocols, and if so, how
assignment to ACTG protocols is or will be made.
 
VI.  PART C. OPTIONAL LABORATORY COMPONENTS (C1-C6)
 
BACKGROUND
 
A major goal of the ACTG is to maintain the capability to
address all aspects of clinical drug evaluation.  This
requires that laboratory and clinical investigators
coordinate their efforts to assure accurate collection and
interpretation of clinical data using state-of-the-art,
quality controlled laboratory methods.
 
The objectives of these optional laboratory components are
three-fold:  (1) to provide participating ACTG clinical
investigators funded under parts A and B with quality
controlled laboratory services required to appropriately
evaluate clinical samples, e.g., protocol-mandated testing;
(2) to assure that these laboratory services remain state-
of-the art throughout the grant period;  and (3) to assure
appropriate utilization of clinical samples acquired during
ACTG protocols in addressing clinically relevant questions
anticipated to provide information that will result in
improved diagnosis and treatment of HIV infection and its
sequelae.
 
There are six optional components for which investigators
may apply.  EACH COMPONENT REQUIRES A SEPARATE DESCRIPTION
AND BUDGET (SEE INSTRUCTIONS FOR PART C).  The components
are:
 
      C.1 Virology Core Laboratory
      C.2 Pharmacology Core Laboratory
      C.3 Virology Developmental Research
      C.4 Pharmacology Developmental Research
      C.5 Immunology Developmental Research
      C.6 Other Microbiological Developmental Research
 
In order to maintain the ACTU as an integrated
clinical/laboratory research environment, applicants are
encouraged to utilize on-site institutional laboratories.
Research to be conducted under the core laboratories
includes protocol-mandated testing and implementation of
state-of-the-art technologies.  Research permitted within
the developmental research areas may be broader in scope but
must be of high clinical relevance and anticipated to
require the use of clinical samples collected during ACTG
protocols.
 
EACH COMPONENT WITHIN PART C REQUIRES A SEPARATE DESCRIPTION
AND BUDGET.  INVESTIGATORS SHOULD COMPLETE PHS 398 (rev.
10/88 or 9/89).
 
Investigators are limited to submission of only one
application for each of the six laboratory components
described in Part C.  Applications containing more than one
application for any one component within part C will be
returned without review.
 
INVESTIGATORS WHO WISH TO APPLY FOR VIROLOGY DEVELOPMENTAL
RESEARCH FUNDS (C.3) MUST ALSO APPLY FOR AND BE AWARDED
SUPPORT FOR A VIROLOGY CORE LAB (C.1) AND AN ADULT ACTU
(PART A).
 
INVESTIGATORS WHO WISH TO APPLY FOR PHARMACOLOGY
DEVELOPMENTAL RESEARCH FUNDS (C.4) MUST ALSO APPLY FOR AND
BE AWARDED SUPPORT FOR A PHARMACOLOGY CORE LAB (C.2) AND AN
ADULT ACTU (PART A).
 
INVESTIGATORS APPLYING FOR AN ADULT ACTU (PART A) ARE
ELIGIBLE TO APPLY FOR DEVELOPMENTAL RESEARCH FUNDS FOR
IMMUNOLOGY (C.5) AND/OR OTHER MICROBIOLOGICAL RESEARCH AREAS
(C.6).
 
EACH PROJECT WILL BE REVIEWED INDEPENDENTLY AND SHOULD
CONTAIN SUFFICIENT INFORMATION AND DETAIL TO ASSURE A
THOROUGH REVIEW.
 
SPECIFIC INSTRUCTIONS - SECTION 1
 
It is anticipated that core laboratory awards will not
exceed $140,000 direct costs per year per laboratory and
that developmental research awards will not exceed $100,000
direct costs annually per application.
 
SPECIFIC INSTRUCTIONS - SECTION 2
 
APPLICANTS FOR CORE LABORATORY SUPPORT IN VIROLOGY AND/OR
PHARMACOLOGY SHOULD ADDRESS THE ITEMS LISTED UNDER SCOPE OF
PROGRAMS FOR COMPONENTS C.1 AND C.2. IN SECTION 2 (RESEARCH
PLAN) OF THE PHS 398 FORM.
 
APPLICANTS FOR THE DEVELOPMENTAL RESEARCH COMPONENTS (C.3-
C.6) SHOULD FOLLOW THE INSTRUCTIONS IN SECTION 2 (RESEARCH
PLAN) OF THE PHS 398 FORM.
 
SCOPE OF PROGRAMS IN PART C
 
Component C.1 Virology Core Laboratory
 
Protocol-mandated testing required of virology core
laboratories will include measurement of p24 antigen levels
and culture of HIV from clinical samples.  The measurement
of other viral or surrogate markers and incorporation of new
technologies will also be required as diagnostic methods
improve and/or require evaluation.  Applicants should
demonstrate a capability to measure clinically relevant
viral markers using a variety of methodologies.
 
Applicants should describe and document their:
 
(1)   procedures for culturing HIV from clinical
samples and for performing p24 antigen
determinations;
 
(2)   procedures for the storage of samples
anticipated to be received from other ACTUs and
for maintenance of specimen inventories;
 
(3)   capability to conduct a minimum of 500 HIV
cultures and 2600 HIV p24 antigen determinations
per year;
 
(4)   prior participation and performance in quality
assurance programs; and
 
(5)   capability to develop new virological markers by
describing their past experience in developing
and evaluating new clinically relevant
techniques.
 
Laboratories will be required to use the DataWorks
software for participation in the QA program.
 
Component C.2  Pharmacology Core Laboratory
 
Pharmacology core laboratories will perform protocol-
mandated measurement of drug levels in clinical samples.
New technologies will also be implemented as pharmacologic
detection procedures improve and/or require evaluation.
Applicants should demonstrate a capability to conduct
therapeutic drug level monitoring using a variety of
methodologies.
 
Applicants should describe and document their:
 
(1)   procedures to conduct pharmacokinetic analysis
of agents utilized in the treatment of HIV
infection and the opportunistic infections
associated with AIDS;
 
(2)   procedures for the storage of samples
anticipated to be received from other ACTUs and
for maintainance of specimen inventories;
 
(3)   capability to perform a minimum number of 500-
1000 drug level determinations per year for an
experimental agent such as a nucleoside analog;
 
(4)   prior participation and performance in quality
assurance programs; and
 
(5)   capability to develop new pharmacologic assays
by describing their past experience in
developing and evaluating new clinically
relevant techniques.
 
Component C.3-C.6 Developmental Research
 
Applicants for the Virology Core Laboratory are eligible to
apply for Developmental Virology Research support.
Applicants for the Pharmacology Core Laboratory are eligible
to apply for Developmental Pharmacology Research support.
Only one developmental research support application in each
subject area (e.g., virology, immunology, pharmacology, and
others) is permitted per ACTU application.
 
Access to significant numbers of clinical samples from
patients with detailed medical histories provides a unique
resource to support developmental research studies of HIV
and AIDS-related viral opportunistic pathogens.  The
objective of the developmental research funding is to
stimulate investigators to answer clinically relevant
therapeutic questions that require the utilization of
clinical samples generated under ACTU protocols.  Emphasis
in these studies should be on specific issues that make the
best use of resources that are available through clinical
trial sites and that address scientific questions that arise
from the performance of clinical trials.  Investigators who
seek support for research that does not require the
utilization of ACTU samples at some point in the research
project are encouraged to seek funding through the R01
mechanism.
 
Component C.3 Developmental Virology Research
 
Developmental Virology Research projects are
encouraged in, but are not limited to, the following
areas:
 
(1) identification and validation of new virological
markers correlating with clinical progression and/or
anti-retroviral effects;
 
(2) quantitative determination of the amount and
infectivity of HIV virions or cell-associated virus in
bodily fluids/tissues and their correlation with other
clinical and immunological parameters of HIV infection
and disease;
 
(3) development of improved methodologies to screen
for resistance and to design and evaluate strategies
to counteract drug resistance;
 
(4) characterization of mechanisms of resistance,
stability and virulence of the drug resistant
phenotype, including development of propagation
procedures for optimal cultivation of resistant
isolates from potentially heterogeneous viral
populations;
 
(5) evaluation of the effect of single and combination
therapies on the emergence of drug-resistant HIV
and/or viral opportunistic pathogens; and
 
(6) elucidation of the potential role of host factors
in the development of resistance.
 
Component C.4 Developmental Pharmacology Research
 
Treatment of HIV disease and its sequelae has involved
clinical administration of a diverse group of
compounds.  Novel compounds with different sites of
action will move into clinical trials in the near
future.  This presents unique opportunities for
examining the pharmacologic and toxicologic properties
of these new agents and their combinations.  Research
is encouraged in, but not limited to, the following
areas:
 
(1) drug-drug interactions for combination therapies;
 
(2) pharmacokinetics and pharmacodynamics in diverse
patient populations;
 
(3) effect of disease state on drug toxicities,
pharmacokinetics or metabolism;
 
(4) levels of active drug in target cells/tissues; and
 
(5) improved methodologies for monitoring drug levels
in plasma and urine.
 
Component C.5 Developmental Immunology Research
 
Research in the identification and validation of
immunologic surrogate markers that correlate with
disease status or drug efficacy is encouraged.
Examples include but are not limited to:
 
(1) characterization of immune cell phenotype and
function (HIV-specific CTLs, HIV or other antigen
specific proliferation, cytokine production, and others);
 
(2) characterization of soluble products of immune
activation (beta 2-microglobulin, neopterin, soluble
CD8, HIV specific antibodies, and others);
 
(3) evaluation of the immune response to AIDS-
associated opportunistic pathogens; and
 
(4) evaluation of the immune response to therapeutic
agents.
 
Component C.6 Other Clinical Developmental Research
 
Areas of developmental clinical research that require
interdisciplinary research approaches but do not fall
specifically into the category of immunology,
pharmacology or virology research include, but are not
limited to:
 
(1) interactions of the human host and opportunistic
pathogens;
 
(2) culture or propagation of patient-derived
Pneumocystis carinii, Cryptosporidium, Microsporida
and other relevant pathogens;
 
(3) determination of the frequency and mechanism(s)
of drug resistance in opportunistic pathogens;
 
(4) diarrhea-wasting syndrome with emphasis on
undetected infectious agents; and
 
(5) development and validation of rapid, sensitive
diagnostic methods for opportunistic pathogens,
including surrogate markers.
 
VII. MECHANISM OF SUPPORT
 
Awards will be made as cooperative agreements (UO1).  Assistance
provided through a cooperative agreement differs
from the traditional research grant in that the Government
component (NIAID) anticipates substantial programmatic
involvement during performance of the award.  The
interaction of NIAID staff with the investigators is
expected to assist and facilitate the research.  There is no
intent, real or implied, for staff to direct an ACTU's
activities or to limit the freedom of investigators.  The
nature of staff participation is described in Section VIII
of this RFA under "TERMS OF AWARD:  NATURE OF PARTICIPATION
OF NIAID STAFF".  The Principal Investigator has the
responsibility for the planning, direction, and execution
of the proposed project, as well as publishing the results
in a timely manner.  All policies and requirements that
govern the grant program of the U.S. Public Health Service
and the National Institutes of Health apply.
 
It is anticipated that 20 to 25 adult ACTUs will be funded.
The approximate amount of funds available for the first year
of support for the adult ACTUs will total $48 million.
This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit
and availability of funds.  Awards will be made for a 12-
month budget period within a total project period of four
years.  Continuation awards for new budget periods within an
approved project period will be made on the basis of
satisfactory performance and availability of funds.  The
anticipated award dates will be March 1 and April 1, 1992.
It is anticipated that the NIAID will continue this program
after the initial project period through a competitive
renewal of the cooperative agreements; however, continuation
is contingent upon available funds and NIAID priorities.
 
Although this program is provided for in the financial plans
of the NIAID, the award of cooperative agreements pursuant
to this RFA is also contingent upon the continuing
availability of funds for this purpose.
 
Interim progress reports will be required.  In each budget
period, a report on scientific and technical progress will
be required at the end of five months following the budget
period start date on the notice of award.  The information
requested for inclusion in these reports will be issued by
NIAID staff.  Scientific and fiscal review must be completed
before the funds for the remainder of the budget period are
released.  Interim funding adjustments within the budget
period may also be made.
 
VIII. TERMS OF AWARD
 
      A. General Considerations
 
The ACTG investigators will be responsible for the overall
conduct of the studies performed.  ACTU investigators and
professional staff will establish and serve on all ACTG
Committees.  The adult ACTU investigators will be
responsible for developing concept sheets for studies,
protocol development, the accrual of new patients, retention
of patients enrolled on protocols, accrual to high priority
protocols, production of high quality data, and the analysis
and publication of the research results.  ACTU performance
in each budget period will determine the core budget award,
release of increments of the core budget, and the amount of
incentive funding awarded during that budget period.
Accordingly, the adult ACTU will submit interim progress
reports, due at the end of five months after the beginning
of the budget period.  In addition, the amount of the award
made in future award years will be contingent upon ACTU
performance.  Inadequately justified performance, such as
not meeting minimum accrual goals without justification or
poor quality of data, during a budget period may result in
reduction of future year awards or interruption of support.
 
The ACTG clinical trials are assisted through four contracts
that provide technical and logistical support to the ACTUs
(see Appendix II.E.).  These contracts that are administered
by the TRP include:  1) a Statistical and Data Analysis
Center (SDAC); 2) an Operations Office; 3) Clinical Site
Monitoring; and 4) a Clinical Research Products Repository.
The SDAC, at the request of the ACTG Executive Committee,
assists the ACTUs in the statistical analysis and in the
management of data resulting from the participating ACTUs
conducting studies.  The Operations Office, at the request
of the ACTG Executive Committee, assists the investigators
in the development of protocols, tracking the progress of
studies and the development of and maintenance of Standard
Operating Procedures of the ACTG.  Clinical Site Monitoring,
at the request of the Executive Committee, conducts periodic
site monitoring to assess the quality and completeness of
the data collected at each ACTU.  The Clinical Research
Products Repository manages inventories of investigational
drugs and ships these drugs to the ACTU investigators at
their request.
 
In addition, the Principal Investigators and other key ACTU
personnel  will attend regularly scheduled ACTG meetings in
the Washington, DC area (or at a site designated by NIAID),
approximately three times per year.
 
      B. Nature of Participation of NIAID Staff in the ACTG
 
NIAID will assist the investigators as a member of the ACTG
and will be represented by the TRP staff of the DAIDS.  The