Subject: Part 2 of 3 RFA AI-9l-07 NIH Guide 5/3/9l
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Tue, 30 Apr 91 13:59 EST

Hi Paul,
   This should be the final one for this week.  Please post this to
the NIH Listserver as:  RFAAI2-91-07.910503
   Thanks.   Please notify me by phone when these are posted.  Thanks
a million.     Dottie
 ---------------------------- Text of forwarded message -----------------------
Subject:      NIH GUIDE - Vol. 20, No. 18, May 3, 1991 - RFA AI-91-07,
              Part 2 of 3
 
$$XID RFA AI9107 AI-91-07 P2O3 *****************************************
Chief, Clinical Research Management Branch, will provide
assistance, advice, and coordination in supporting recipients
of cooperative agreements during the conduct of an activity.
The role of NIAID will be to facilitate and not to direct
the activities.  The terms described in this section are in
addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS Grant Administration
Regulations in 45 CFR Part 74, and other HHS, PHS, and NIH
grant administration policy statements.
 
NIAID staff will perform the following functions:
 
o The Associate Director, TRP, will assist the ACTG
Executive Committee in establishing the scientific
priorities of the ACTG;
 
o The Chief, Medical Branch, TRP, will assist in
protocol development including the review and approval
for cost effectiveness and appropriate utilization of
resources;
 
o The Chief, Clinical Research Management Branch, TRP,
will assist in promoting the timely implementation and
completion of those clinical trials designated as
priority studies by the ACTG Executive Committee and
NIAID.  This role shall consist of technical advice and
assistance;
 
o The Associate Director, TRP, as a member of the ACTG
Executive Committee, will facilitate the early
termination of a protocol (i.e., for insufficient
accrual, patient safety and noncompliance with 45 CFR
Part 46, inconclusive results when it has been
determined that further accrual will not add
information of scientific value, when the emergence of
new information makes the study question less
relevant, when program objectives have been met, or
when the limitations on the program budget require
that ACTG funds be re-directed to higher priority
protocols);
 
o Coordinate activities among other areas of NIH-
sponsored research and dissemination of results from
clinical trials to the scientific and medical
communities;
 
o The Chief, Operations and Data Management Branch,
TRP, will assist in providing operational and data
management support;
 
o NIAID serves as the sponsor for Investigational New
Drug (IND) applications for conducting studies of
agents under evaluation by the ACTG; also provides updated
information on the safety and efficacy of
investigational new agents supplied to ACTUs under
NIAID INDs.  (Note: the NIAID will not provide
investigational drugs or permit expenditures of NIAID
funds for a study after requesting termination of the
study, except for patients already on study and
requiring continuing treatment);
 
o The Chief, Pharmaceutical and Regulatory Affairs
Branch, TRP, will conduct on-site visits to monitor the
conduct of studies involving the use of
investigational agents, compliance with regulations
for Institutional Review Board (IRB) approval and
informed consent (compliance with 45 CFR 46), accuracy
of data recording, completeness of reporting adverse
drug reactions, and quality control (including
periodic audits for quality assurance, investigational
drug handling, and drug accountability); and
 
o The Chief, Clinical Research Management Branch, will
conduct periodic on-site visits to review protocol
accrual, administrative, technical, and fiscal
management.
 
For activities described herein that require approval
by the Associate Director, TRP, during performance of
this cooperative agreement (e.g., protocol review and
approval, early termination of a protocol, reports
intended for inclusion in IND applications and
clinical brochures, distribution of investigational
agents from the government, etc.), NIAID will
establish an arbitration process to resolve major
differences of opinion.  An arbitration panel,
composed of one ACTU designee, one NIAID designee, and
a third designee with expertise in the relevant area
and chosen by the other two will be formed to review
any scientific or administrative issue and to
recommend an appropriate course of action to the
Director, DAIDS. This arbitration process in no way
affects the right of an award recipient to appeal an
action in accordance with PHS regulations in 42 CFR
Part 50, Subpart D, and HHS regulations in 45 CFR,
Part 16.
 
C. Reporting Requirements and Publication of Research
Findings
 
In addition to the reporting requirements currently in
existence for awardees of traditional NIH research project
grants, the following apply:
 
Reports of data generated by the ACTG or any of its member
ACTUs that are required for the NIAID to fulfill its role as
sponsor of an investigational agent must be submitted by
the Principal Investigator upon request of the Chief,
Pharmaceutical and Regulatory Affairs Branch, TRP.  These
include:  data required for inclusion in IND applications,
clinical brochures (and similar documents), as well as
periodic reports to the FDA and other regulatory agencies.
 
The Associate Director, TRP, will have access to all data
generated under this cooperative agreement and will
periodically review the progress reports.  Information
obtained from the data may be used by NIAID for the
preparation of internal reports on ACTG activities.
However, the awardees will retain rights to the data (see
below).  Publication of major findings is the responsibility
of the investigators in accordance with the publication
policies established jointly by the ACTG investigators and
the Associate Director, TRP. Publication or oral
presentation of work performed under this agreement is the
responsibility of the Principal Investigator and will
require appropriate acknowledgement of NIAID support.
 
D. Additional Information on Access to Data
 
ACTG member institutions will generate clinical trial data
that will be submitted to the SDAC.  In most cases, these
institutional data will represent only a small subset of the
total database for a given clinical trial and therefore,
will have limited scientific value.  The investigators, in
conjunction with the Associate Director, TRP, will establish
policies limiting publication of such institutional data.
These institutional data will remain the property of the
awardee from which they originated, even following
submission to the SDAC.
 
The total database for a particular trial will usually come
from more than one institution.  While physically located at
the SDAC, the use and publication of the data will be
governed by policies established by the ACTG investigators
and the Associate Director, TRP.  The Associate Director,
TRP will have access to the data and will require periodic
special reports of data generated by the ACTG or any of its
members, as described above.  However, while the NIAID will
have access to data generated under these cooperative
agreements, publication or oral presentation is the
responsibility of the ACTG investigators.
 
In the event of a collaboration with a pharmaceutical
company for the evaluation by the ACTG of an investigational
agent, a memorandum of understanding among the Associate
Director, TRP, participating ACTU Principal Investigators
and the company will set forth the details providing for
access by the company to necessary data.
 
FAILURE TO ABIDE BY THESE TERMS OF AWARD MAY RESULT IN
WITHHOLDING OF FUNDS BY THE NIAID.
 
IX. SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF
NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to
include minorities and women in study populations so that
research findings can be of benefit to all persons at risk of the
disease, disorder or condition under study; special emphasis
should be placed on the need for inclusion of minorities and
women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply
to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear
compelling rationale should be provided.
 
The composition of the proposed study population must be
described in terms of gender and racial/ethnic group.  In
addition, gender and racial/ethnic issues should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study.  This information should be
included in the form PHS 398 in Section 2, A-D of the Research
Plan AND summarized in Section 2, E, Human Subjects.
Applicants/offerors are urged to assess carefully the feasibility
of including the broadest possible representation of minority
groups.  However, NIH recognizes that it may not be feasible or
appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority
populations (i.e., Native Americans (including American Indians
or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics).
 
The rationale for studies on single minority population groups
should be provided.
 
For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment
of diseases, disorders or conditions, including but not limited to
clinical trials.
 
The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.
However, every effort should be made to include human tissues
from women and racial/ethnic minorities when it is important to
apply the results of the study broadly, and this should be
addressed by applicants.
 
For foreign awards, the policy on inclusion of women applies
fully; since the definition of minority differs in other
countries, the applicant must discuss the relevance of research
involving foreign population groups to the United States'
populations, including minorities.
 
If the required information is not contained within the
application, the application will be returned.
 
Peer reviewers will address specifically whether the research
plan in the application conforms to these policies.  If the
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 or deficiency in the
study design and will be reflected in assigning the priority
score to the application.
 
All applications for clinical research submitted to NIH are
required to address these policies.  NIH funding components will
not award grants or cooperative agreements that do not comply
with these policies.
 
X. REVIEW PROCEDURES
 
Incomplete and nonresponsive applications will be returned to
the applicant without review.
 
Examples that will result in the application being
considered as nonresponsive include, but are not limited to:
(1)  failure to address all items of the Adult ACTU
component; and (2) submission of optional components that are
not presented as separate narratives with separate budgets.
 
Depending upon the number of applications received, triage
of applications (screening of applications by peer
review to make a preliminary evaluation of their scientific
and technical merits) may be conducted.  Comprehensive
evaluation of applications will be conducted by a Special
Review Committee (SRC), consisting of primarily non-Federal
scientific experts.  Each component will be evaluated and
rated based on the review criteria described in this RFA, as
follows:
 
o The adult component (A) and the pediatric component
(B, if present) will be reviewed at one SRC session,
but these components will be rated separately;
 
o Applications for the adult ACTU component judged to
be most meritorious by the first SRC and containing
Part C will be forwarded to the second SRC for
evaluation of the laboratory components (C.1 - 6);
 
o The priority score assigned to the application will
be based solely on the score received by the adult
ACTU component (A).  The merit assigned to the optional
pediatric (B) and laboratory (C) components will be used by
NIAID to guide funding decisions with respect to these
latter components.
 
REVIEW PROCEDURES SPECIFIC FOR PART C
 
Applications for part C that are complete and responsive may
also be subjected to triage by a peer review group to
determine their scientific merit relative to the other
applications received in response to each project outlined
in this portion of the RFA.  The NIH will withdraw from
competition those components judged by triage to be
noncompetitive for award and notify the principal
investigator and institutional official.
 
Only applications of sufficient merit to receive
consideration for receiving an award after the review of
Part A will be eligible for review of part C.  If an
application will not receive funding consideration based on
the score of Part A, components under part C may not be
reviewed.  Each component under part C will be evaluated
independently.
 
Subsequently, applications will receive a second-level
review by the National Advisory Allergy and Infectious
Diseases Council.
 
XI. REVIEW CRITERIA
 
PARTS A AND B
 
The following factors will be considered in the
scientific and technical review of the application:
 
o     Adequacy of the technical approach and
understanding of the problem as evidenced by the
potential effectiveness of the proposed plan in
meeting program requirements;
 
o     The qualifications and the expertise of the
Principal Investigator and key personnel in
scientific areas emphasized by the program and
their past experience in conducting all phases
of clinical trials;
 
o     Adequacy of the available patient population;
 
o     Adequacy of the available physical facility and
institutional support;
 
o     Establishment of ancillary support linkages;
 
o     Quality of the accrual and retention plan,
staffing requirements, and reasonableness of the
budget of each component of the application;
 
o     The availability of resources necessary to
perform the research;
 
o     Capability of the applicant to conduct clinical
trials in a cost efficient manner; and
 
o Inclusion of a representative proprotion of
women and minority subjects in proposed clinical
trials.
 
PART C
 
COMPONENTS C.1 and C.2
 
The following factors will be considered in the
scientific and technical review of the applications
for components C.1 (Virology Core Laboratory) and C.2
(Pharmacology Core Laboratory):
 
      o     Adequacy of the scientific/technical approach
      o     Understanding of the problem
      o     Demonstrated ability to perform the minimum
number of required assays
o     Prior participation or experience in relevant
quality control programs
o     Adequacy of the proposed procedures for receipt,
storage and handling of samples from other
sites, and for timely reporting of data
o     Qualifications, expertise, experience and time
commitment of the Principal Investigator and key
personnel
o     Adequacy of the available resources
o     Reasonableness of cost
 
COMPONENTS C.3 to C.6
 
The following factors will be considered in the
scientific and technical review of the applications
for C.3 (Virology Developmental Research), C.4
(Pharmacology Developmental Research), C.5 (Immunology
Developmental Research), and C.6 (Other Clinical
Developmental Research):
 
o     Adequacy of the scientific/technical approach
o     Scientific merit of the proposed research
o     Orginality and uniqueness of proposed research
o     Relevance of the proposed research to the
clinical objectives of the ACTG
o     Availability of required clinical samples
o     Qualifications, expertise, experience and time
commitment of the Principal Investigator and key
personnel
o     Adequacy of the available resources
o     Reasonableness of cost
 
XII. AWARD CRITERIA
 
Scientific merit and technical proficiency, based on the
demonstrated and projected capabilities described in the
application in response to this RFA, will be the predominant
criteria for determining funding priorities.  However, after
applications have been approved by the National Advisory
Allergy and Infectious Diseases Council, NIAID staff
reserves the right to give consideration to the following
additional factors in the final selection of applications to
be funded: inclusion of populations currently
underrepresented in the adult ACTUs (women, minorities,
former IVDUs, and  persons with hemophilia) so that the ACTG
reflects the demographic features of the nation-wide HIV
epidemic; HIV-AIDS incidence/geographic distribution; and
cost effectiveness of conducting ACTG clinical trials.
 
XIII. METHOD OF APPLYING
 
Preapplication Meeting
 
Optional preapplication meetings will be held on June 3, 4, and 5, 1991
in Bethesda, Maryland, San Francisco, California, and Dallas, Texas,
respectively, to provide a forum during which prospective applicants may
ask questions and obtain information.  The meeting dates and locations
will also be announced in the NIH Guide for Grants and Contracts.  In
addition, Dr. Batzold may be called at (301) 496-8214 after May 6, 1991
to obtain specific information about the meetings.
 
Receipt Date
 
The deadline for receipt of applications is August 6, 1991.
Applications received after this date will be considered as
nonresponsive to this RFA and returned without review.
Applications that, upon staff review, are considered non-
responsive to this RFA, will also be returned without
review.
 
Submission
 
The research grant application form PHS 398 (rev. 10/88,
Reprinted 9/89) must be used in applying. These forms are
available at most institutional business offices and from:
 
Office of Grants Inquiry
Division of Research Grants
National Institutes of Health
Westwood Building, Room 449
5333 Westbard Avenue
Bethesda, MD  20892
 
It is important to follow the instructions for preparing the
application as described in both the form PHS 398 and in
this RFA. Failure to do so will result in an application
with insufficient information for appropriate scientific
review. Part A and Optional Components must be submitted in
a single package. Each component of the application will
receive a separate review.
 
Submit a signed, typewritten original of the application,
and 6 exact, single-sided photocopies (including the
Appendix), in one package to:
 
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
o Use the mailing label (amended to show the room
number) contained in the application package.
 
o Submit 17 exact, single-sided photocopies
of the application, in one package
directly to:
 
Dr. Allen Stoolmiller
AIDS Review Section
NIAID/DEA/PPRB
Westwood Building, Room 3A-07
5333 Westbard Avenue
Bethesda, MD  20892
 
In order to ensure that the application is identified with
this RFA and is processed appropriately,
 
o THE RFA LABEL AVAILABLE IN FORM PHS 398 (REV. 10/88.
REPRINTED 9/89) MUST BE AFFIXED TO THE BOTTOM OF THE FACE
PAGE OF THE ORIGINAL SIGNED APPLICATION. FAILURE TO USE THIS
LABEL COULD RESULT IN DELAYED PROCESSING OF THE APPLICATION
SUCH THAT IT MAY NOT REACH THE COMMITTEE IN TIME FOR REVIEW.
 
o Designate the PHS component as NIAID/DAIDS/TRP.
 
XIV.  INQUIRIES
 
Written or telephone inquiries concerning this RFA are
encouraged.
The following NIAID staff will be available to answer
questions regarding the preparation of the application in
response to this RFA:
 
Review Requirements:          Responsiveness to RFA:
 
Allen Stoolmiller, Ph.D.      Frederick Batzold, Ph.D.
Address as indicated          NIAID/DAIDS/TRP/CRMB
above                         6003 Executive Blvd., Room 207P
                              Rockville, MD  20892
Telephone:  (301) 496-7966    Telephone:  (301) 496-8214
 
Budget Questions
 
Ms. Mary Kirker
Chief, AIDS Grants Management Section
Grants Management Branch/NIAID
Westwood Building, Room 706
Bethesda, MD  20892
Telephone:  (301) 496-7075
 
XV.   SCHEDULE
 
Letter of Intent:                   June 5, 1991
Preapplication Meetings:            June 3, 4, and 5, 1991
Application Receipt Date:           August 6, 1991
Special Review Committee:           October 6, 1991
Other ad hoc Reviews of Components: To be announced
NIAID Advisory Council Review:      January 20, 1992
Anticipated Award Dates:            March 1 and April 1, 1992
 
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, Title IV,
Section 301 as amended, Public Law 78-410; Public Law 97-
219; Public Law 99-500; and Report 99-711 to accompany HR
5233 and administered under PHS grant policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.
 
                         APPENDICES
 
   I. Application Components Form
 
  II. Structure and Functions of the ACTG
 
 III. Guidelines for Adult Clinical Core Budget (Part A)
      Guidelines for Pediatric Clinical Core Budget (Part B)
 
  IV. Sample ACTG Protocols and Costing Forms
 
   V. ACTG Protocols
 
  VI. Guidelines for Establishing Subunits
 
 VII. Required Computer Equipment
 
VIII. CPCRA Sites
 
  IX. HRSA Demonstration Projects
 
   X. NIDA Drug Abuse Treatment Research Units and Centers
 
                                   APPENDIX I
 
                           APPLICATION COMPONENTS FORM
 
INDICATE EACH COMPONENT APPLIED FOR BY PLACING AN (X) IN THE APPROPRIATE
BOX.
 
BOX         PART        COMPONENT
 
/  /         A          Adult Clinical Trials Unit (Required)

 
/  /         B          Pediatric Component (Optional)
 
__________
 
/  /         C          Laboratory (Optional)
 
__________
 
/  /                    1.  Support for Protocol-Mandated Virology
 
__________
 
/  /                    2.  Support for Protocol-Mandated Pharmacology
 
__________
 
/  /                    3.  Developmental Research in Virology
                            (Limited to applicants for virology support
labs)
 
__________
 
/  /                    4.  Developmental Research in Pharmacology
                            (Limited to applicants for pharmacology
support lab)
 
__________
 
/  /                    5.  Developmental Research in Immunology
                            (Open to ALL applicants)
 
__________
 
/  /                    6.  Developmental Research in Other Areas
                            (Open to ALL applicants)
__________
                         APPENDIX II
 
             STRUCTURE AND FUNCTIONS OF THE ACTG
 
A.    Background
 
      A.1.  Establishment of the AIDS Clinical Trials Group
            (ACTG)
 
B.    Current Structure and Function of the ACTG
 
      B.1.  AIDS Clinical Trials Units (ACTUs)
 
      B.2.  Treatment Research Program (TRP)
 
      B.3.  Statistical and Data Analysis Center (SDAC) and
            Operations Office
 
      B.4.  ACTG Interactions
 
      B.4.a.   Committees
 
      B.4.b.   Protocol Development
 
C.    Major Strengths and Accomplishments of the ACTG
 
D.    Community Program for Clinical Research on AIDS
 
E.    Supplementary Resources Funded Under Different
      Mechanisms
 
      E.1.  SDAC
 
      E.2.  Operations Office
 
      E.3.  Site Monitoring
 
      E.3.a.      Clinical Site Monitoring
 
      E.3.b.      Laboratory Quality Assurance
 
      E.4.  Clinical Research Products Repository (CRPR)
 
      E.5.  AIDS Clinical Trials Information Service (ACTIS)
 
APPENDIX II
 
A. Background
 
The National Institute of Allergy and Infectious Diseases,
Division of AIDS (DAIDS), has broad responsibility for
research in the areas of therapeutic intervention, vaccine
development, pre-clinical drug development and pathogenesis,
and epidemiology and natural history of HIV.  DAIDS is
composed of two programs and two branches: the Treatment
Research Program (TRP); the Basic Research and Development
Program (BRDP); the Epidemiology Branch; and the
Biostatistics Research Branch.  The two components of TRP-
sponsored research are the AIDS Clinical Trials Group (ACTG)
and the Community Programs for Clinical Research on AIDS
(CPCRA).  The ACTG is a national network of collaborative
clinical trials that comprises AIDS Clinical Trials Units
(ACTUs), TRP staff, and several contractors who provide data
and operations support.
 
The TRP has responsibility for administering the major
portion of the DAIDS clinical trials efforts.  The program
has four primary goals: 1) to establish and support a
national network of institutions to evaluate potential
therapies for HIV infection and its associated conditions;
2) to ensure that treatments of highest priority are being
tested; 3) to participate in drug development from initial
human trials to final Food and Drug Administration (FDA)
approval; and 4) to expedite the transfer of new therapeutic
advances from the research setting to the treatment of HIV
infected patients.  The TRP is composed of five branches
encompassing medical and clinical sciences, pharmaceutical
and regulatory affairs, operations and data management, and
site management functions.
 
The first major extramural initiative in this effort
established the AIDS Treatment Evaluation Units (ATEUs), a
group of 19 contracts supporting clinical investigation in
1986.  In addition, data management support and site
monitoring were provided by the Clinical Trials Coordinating
Center (CTCC), established by NIAID through a separately
awarded contract to Research Triangle Institute (RTI) in
September 1986.  In 1987, this network was expanded to
include 17 new sites, called Clinical Study Groups (CSGs),
that were funded as cooperative agreements.  Two of the
CSGs had pediatric studies as their clinical focus.  In
addition to therapeutics, CSGs were also awarded funds to
perform basic HIV-related research and outreach activities.
 
Since only two of the participating institutions were
devoted to the pediatric population, a new initiative was
released to specifically target this population.  In
September 1988, 12 new awards were made to institutions to
establish pediatric clinical trial units.  An additional
award was made to a pediatric ACTU in 1989.  Also, several
of the earlier funded institutions that were initially doing
work with adult populations only began participating in the
pediatric clinical trial effort.  As of May 1991, there are
15 pediatric ACTUs and 12 adult ACTUs with pediatric
components participating in pediatric clinical trials.
 
The pediatric components are located in adult ACTUs where
the incidence of HIV infection among children is usually too
low to justify a separately funded pediatric ACTU.  Their
contribution to the overall pediatric clinical trial effort
is recognized as significant.
 
The clinical trials program was reviewed in July 1987 by an
ad hoc NIAID Clinical Trials Advisory Panel.  The Panel
recommended that: 1) the AIDS Program adopt a highly
interactive collaborative cooperative group structure that
encompassed the ATEUs and CSGs; 2) protocols should be
developed by the cooperative group with substantial
involvement of AIDS Program staff; and 3) the CTCC be
revised to include a) senior biostatisticians with
multistudy, multicenter experience, b) computerization of
those data relevant to the conduct and analysis of each
study (as required by the FDA), and c) the adoption of a
relational database management system.
 
      1. Establishment of AIDS Clinical Trials Group (ACTG)
 
The ACTG was established in December 1987.  Adopting the
recommendations of the Panel, when first organized, the ACTG
was composed of three components: 1) the ATEUs and CSGs,
renamed ACTUs; 2) the NIAID AIDS Program Office; and 3) the
CTCC.  In order to provide additional resource support for
the ACTG, an Operations Office was established through a
contract awarded by TRP to Social and Scientific Systems,
Inc. (SSS) of Bethesda, MD in December 1987 (coincident with
the establishment of the ACTG). The Operations Office
provides expertise and support in the development and
evaluation of proposed clinical trial protocols, the
implementation, conduct, and completion of protocols, and
support to the ACTG committees.
 
To fulfill the goal of establishing a collaborative
cooperative group, the original ATEU contracts were
converted to cooperative agreements in June 1988.
In addition to the two pediatric ACTUs (originally funded as
CSGs), 13 additional pediatric ACTUs were funded as
cooperative agreements, resulting in a total of 15 pediatric
ACTUs and 32 adult ACTUs.  The cooperative agreements
supporting the current 47 ACTUs end at different times, some
in June 1991, others in August 1992, and others in August
1993.  For ease of performance evaluation and redirection of
the ACTG through the recompetition process, all adult ACTUs
will be recompeted as a group in fiscal year 1992 and all
pediatric units be recompeted as a group at a later date.
This recompetition will allow the simultaneous application
for funding of existing adult ACTUs and of new sites that
might wish to join the ACTG.
 
B. Current Structure and Functions of the ACTG
 
The current structure of the ACTG is tripartite: 1) 32 adult
ACTUs and 15 pediatric ACTUs; 2) the Division of AIDS
Treatment Research Program (TRP); and 3) the Statistical and
Data Analysis Center (SDAC), and the Operations Office
(supported by two separate contracts managed by TRP).
SDAC and the Operations Office provide technical and
logistical support and advice to the investigators at the
request of the ACTG Executive Committee.
 
These three components of the ACTG system cooperatively
perform a wide range of scientific planning and coordinating
functions related to the conduct of clinical trials
including: assessment of treatment research needs,
establishment of scientific priorities among these needs,
development of new research protocols addressing these
priorities, implementation and analyses of these studies,
and the establishment of quality control programs to ensure
that accurate data are collected.
 
The scientific investigators at the ACTUs through scientific
committees and the Executive Committee, develop a scientific
agenda, set priorities for clinical trials and initiate
development of protocols.  The majority of ideas for
clinical trials are initiated by ACTU investigators.  Most
Phase III protocols are open to participation by any ACTU.
Phase I/Phase II protocols are usually conducted at a
limited number of ACTUs.  Protocols are developed by the
investigators with substantial involvement of the pertinent
TRP Medical Officer following jointly determined
priorities.
 
The components of the ACTG are described below.
 
      1. The ACTUs
 
An individual ACTU is located at a clinical research
institution and consists of the
multidisciplinary scientific investigators, medical
clinicians, data managers, and administrative staff
necessary to conduct clinical trials on investigational
therapies for HIV infection.  Access to ancillary non-ACTU
services (e.g., Institutional AIDS Ward, CRC, designated
State AIDS Center) provide useful additional resource
support.  An ACTU may have one or more subunits (sites not
located at the main ACTU that are established by formal
administrative and financial arrangements between
institutions).  Each main ACTU is responsible for the proper
functioning of its subunit(s).
 
The Principal Investigator is a physician who has the
responsibility for the guidance and leadership of the ACTU.
The Principal Investigator has the responsibility for
selecting the clinical trials in which the ACTU
participates.
 
The ACTUs conduct all phases of the clinical trials research on
new and improved treatment intervention for all aspects of
HIV infection including associated opportunistic
infections, oncological, and neurological conditions.
However, individual ACTUs vary with respect to emphasis in the
scientific area and type of clinical trials conducted at the
site.
 
      2. TRP
 
The Associate Director, TRP, supports clinical trials
research by providing scientific and technical advice;
serves as a source of expertise; facilitates protocol
development and implementation; and reviews protocols to
ensure consistency, scientific soundness, and conformance
with FDA requirements for Investigational New Drug (IND)
trials.  The Associate Director, TRP, coordinates the
activities required to develop new agents from initial human
trials to their final FDA approval.  In addition, the
Associate Director, TRP, facilitates the transfer of
effective therapies from the research setting to routine
patient care.
 
      3. SDAC and the Operations Office.  See Appendix II
      Section E. on SUPPLEMENTARY RESOURCES FUNDED UNDER
      OTHER MECHANISMS.
 
      4. ACTG Interaction
 
National meetings of the entire ACTG are held three times a
year.  The primary purpose of these meetings is to bring the
ACTG together to review the work of the scientific and
resource committees.  This includes a review of the
scientific agendas set forth by the scientific and resource
committees of the group, scientific plenary sessions
covering topics at the leading edge of HIV therapeutics,
updates on protocols, and workshops dealing with the conduct
of ACTG studies or operations.  Invited guests from the FDA,
the NIH, and pharmaceutical industry also participate in
these meetings as do representatives from the Community
Constituency Group (that includes HIV infected persons) and
other interested parties.  The ACTG has a committee
structure consisting of scientific committees, resource
committees, and the Executive Committee.
 
The structure and functioning of the committees and the
development of protocols are described below.
 
            a. Committees
 
Scientific Committees
 
There are nine ACTG Scientific Committees:  Primary
Infection, Opportunistic Infection, Oncology,
Pharmacology/Pharmacokinetics, Neurology, Pediatrics,
Immunology, Virology, and Women's Health.
 
The scientific committees form the scientific nucleus of the
ACTG.  Each committee has a chair, vice chair, and a core
committee, that are ACTU investigators. In addition ACTU
investigators with relevant expertise and interest in the
committee's research area represent the ACTUs. Each
committee also has a single representative from SDAC, the DAIDS, and
HIV-infected persons and their advocates.  The ACTU
investigators constitute a large majority representation on
all ACTG committees.
 
The role of each Scientific Committee, and the Executive
Committee, is to cooperatively develop a research agenda and
establish research priorities in a particular scientific
area and continually reassess those priorities in light of
new ideas and research opportunities.  The committees also evaluate the
conduct and status of active studies in light of current
national priorities for AIDS clinical research.
 
In addition to providing general expertise, the Scientific
Committees (Immunology, Virology, and Pharmacology) also
have responsibility for developing and recommending
laboratory quality assurance policies in the areas of flow
cytometry, viral assays, marker evaluation, and
pharmacological assays.  The committees meet during each
ACTG meeting.  In addition, committees meet and/or are in
contact at times other than ACTG meetings.
 
Resource Committees
 
Resource Committees were formed to provide technical
expertise and practical advice to the ACTG.  There are three
ACTG Resource Committees: Site and Data Management Committee
(SDMC), Patient Care Committee, and the Community
Constituency Group.  With the exception of the advisory
Community Constituency Group (see below), a majority of the
membership of the SDMC and Patient Care Committee are ACTU
investigators or ACTU professional staff.  The Chief,
Operations and Data Management Branch, represents TRP on the
SDMC and the Chief, Clinical Research Management Branch,
represents TRP on the Patient Care Committee.  The Community
Constituency Group is comprised solely of HIV infected
persons and patient advocates and is strictly advisory to
the ACTG Executive Committee.
 
The Executive Committee
 
The Executive Committee develops general ACTG policies
concerning committee structure and membership, committee
operations, publications, access to data, interim data
monitoring, agendas for group meetings, competing protocols,
the evaluation of ACTU performance, and ACTG meetings.  In
addition, the Executive Committee establishes scientific
priorities for the ACTG and assures equal access to trials
for all patient populations.  The majority of the twelve
member Executive Committee are representatives from the
ACTUs.  The Executive Committee also includes the Associate
Director, TRP, two representatives from the Community
Constituency Group (including HIV infected individuals), and
one representative from the SDAC.

            b. Protocol Development
 
Ideas for individual studies may be introduced from any
source, although most come from ACTU investigators.
Proposed studies are summarized in the form of a "concept
sheet," which includes the study's rationale, objectives,
design, eligibility criteria, treatment regimen, and sample
size estimates.
 
The concept sheets are reviewed by TRP (Medical Officer and
Clinical Trials Review Committee).  The appropriate
Scientific Core Committee and the Executive Committee
review, approve, and prioritize concept sheets.  Approved
concept sheets are developed into protocols by a team
composed of a protocol chair (an ACTU investigator); TRP
representatives (Medical Officer, and a Regulatory Affairs
representative); one SDAC statistician; one Operations
Office representative; and an ACTU investigator
immunologist, virologist or pharmacologist, as required.
The final draft of the protocol is forwarded to the Food and
Drug Administration (FDA).  After FDA approval and
notification from the pharmaceutical company that the
investigational agent is available in sufficient quantity,
the protocol is opened for enrollment.
 
Once a protocol has been activated, the protocol chair is
responsible for the overall conduct of the study, for its
ongoing performance and is expected to take the lead in
dissemination of study results, including publications.
Safety and toxicity studies (Phase I/Phase II trials)
usually involve the participation of a limited number of
ACTUs; whereas, large-scaled Phase III efficacy studies
involve multiple ACTUs.  Because most ACTG clinical trials
are conducted under an IND held by the DAIDS/NIAID,
regulatory requirements mandate review and approval of
protocols by the NIAID Clinical Trials Review Committee
(composed of DAIDS staff), prior to their initiation.
 
C. Major Strengths and Accomplishments of the ACTG
 
The ACTG has established the capability to conduct all phases of
clinical trials, including large-scale, multicenter trials,
within the framework of investigator-initiated research
involving scientists from many disciplines.  Over 170 ACTG
protocols have been conducted and more than 14,000 persons
have been enrolled in ACTG clinical trials.  Considerable
advances have been made in antiretroviral drug therapy
(including the extension of life-prolonging therapy to early
stages of the disease), and in the area of prophylaxis of
opportunistic infections.  Noteworthy ACTG protocols
include:
 
o Protocol 002, a study of 574 persons with AIDS,
which showed that a dose of zidovudine (AZT) lower than the
earlier approved dose was equally beneficial in the
treatment of AIDS;
 
o Protocol 016, a double-blind, placebo-controlled
study of 713 patients with AIDS-related complex which
demonstrated a beneficial effect of AZT; and
 
o Protocol 019, a double-blind, placebo-controlled
study of 3,207 persons with asymptomatic HIV infection, which
revealed a beneficial effect of AZT.  This latter study,
especially, has had enormous implications for the thousands
of asymptomatic persons who are HIV-infected.
 
HIV associated malignancies are becoming an increasing
problem as the epidemic matures.  Patients are living longer
with improved therapy of the primary infection and
opportunistic infections, thus increasing the likelihood
that a given patient will develop an HIV-related malignancy.
In addition, it is becoming apparent that treatment of non-
Hodgkin's lymphoma (NHL) in HIV-infected patients can
improve survival in some cases.  New modes of therapy for
Kaposi's sarcoma, such as angiogenesis inhibitors, are nearing
readiness for human trials and will require large scale
clinical trials in order to evaluate their effectiveness.
In addition, the number of women with HIV infection is
increasing.  These patients are at increased risk for
cervical neoplasia associated with human papilloma virus.
 
The ACTG Oncology Committee has carried out a program of
phase I, II, and III trials of agents and regimens for
therapy of Kaposi's sarcoma and non-Hodgkin's lymphoma
(NHL).  A large phase III trial comparing two regimens for
NHL started late in 1990.  A large phase II trial which
includes chemotherapy induction and maintenance with an
antiretroviral combined with interferon is in development.
Several phase I trials are ongoing and in development.
There is also a single trial in development for Hodgkin's
disease.
 
Neurologic complications are an important component of the
spectrum of HIV infection.  Studies on the identification,
treatment, and possible prophylaxis of these complications
is an important ACTG objective.
 
In addition, the ACTG is currently collaborating with more
than 10 pharmaceutical firms with antiretroviral drugs in
development.
 
The recompeted ACTG system will retain the exemplary
features of the current system (including primary emphasis
on high quality multidisciplinary investigator-initiated
research in all phases of clinical trials) and incorporate
the changes required to meet the challenges imposed by the
evolution of the AIDS epidemic.  Increased emphasis will be
placed on linking funding to performance, coupled with the
flexibility to allocate resources as clinical trials
research priorities require.
 
D. Community Program for Clinical Research on AIDS (CPCRA)
 
The NIAID National program of community-based clinical
research on the treatment of HIV infection and its
complications is also sponsored by TRP. The purpose of the
CPCRA is to develop the capability to conduct scientifically
sound research in community settings in order to expand HIV-
related research opportunities and broaden the base of
persons involved in NIAID-sponsored projects.  These
projects, supported by contracts, extend research
opportunities to clinicians in primary care settings by
providing administrative and technical support. CPCRA sites
are especially effective in targeting HIV-infected persons
from minority populations, women at risk for HIV infection,
and persons who are drug users.
 
Eighteen contracts were awarded in October 1989. The
recipients of these contracts are primary care providers in
a wide diversity of clinical settings across the country and
currently care for 30,000 persons with HIV infection. The
co-existence of an ACTU and a CPCRA site in the same Standard
Metropolitan Statistical Area (SMSA) results in providing
the HIV-infected person with the full range of NIAID-
sponsored clinical trials. NIAID requires that CPCRA sties
establish formal communication links with ACTUs in the same
SMSA. Adult ACTUs will be required to likewise establish a
communication with a CPCRA site in the same SMSA as part of
the application in response to this RFA.
 
E.  Supplementary Resources Funded Through Other Mechanisms
 
      1. Statistical and Data Analysis Center (SDAC)
 
The purpose of the SDAC contract is to provide extensive
biostatistical expertise and data management coordination to
the ACTG.  The award was made to the Harvard School of
Public Health in September 1989.
 
At the request of the Executive Committee, the SDAC assits
the ACTUs in the statistical analysis and data management of
data emanating from all the participating ACTUs conducting
studies.  These responsibilities include:  statistical
design and proposed analyses of an ACTG clinical trial;
the development of forms for clinical trials data
collection; the routing of such data to the central data
management centers; and a complex series of quality
control measures designed to ensure the accuracy and
timeliness of the submitted information.  A senior SDAC
statistician serves as advisor to and members of ACTG
scientific committees and the Executive Committee.
 
      2. The Operations Office
 
A new five-year contract for the Operations Office was awarded
to Social and Scientific Systems (SSS) on March 1, 1991.
Activities required under the new contract include:
provision of services necessary to establish and maintain a
system for the receipt and review of concepts for new
clinical trials; development of systems and procedures
required to coordinate all activities related to the
implementation/conduct and completion of ACTG studies;
provision of technical and administrative support for
meetings of protocol teams, ACTG committees; provision of
scientific information specialists support for the medical
branch of TRP; development and implementation of a
microcomputer-based management information system to track
the progress of clinical trials from concept stage through
protocol implementation and completion; and development and
maintenance of an ACTG Standard Operating Procedures (SOP)
manual documenting all standard SOPs approved by the
Executive Committee with respect to ACTG activities.  At the
request of the ACTG Committees (Executive and Scientific),
the Operations Office assists in the functions described
above to facilitate protocol development, protocol
implementation and logistical information management for the
clinical trials at the ACTUs.
 
      3. Monitoring
 
            a. Clinical Site Monitoring
 
In July 1990, a contract was awarded by the TRP to
Pharmaceutical Products Development, Inc. (PPD) in
Wilmington, NC to provide site monitoring for ACTUs and
CPCRA sites.  This contractor, at the request of the ACTG
Executive Committtee, conducts routine site-monitoring
visits, special mail and on-site audits to assess the
quality of the data collected at each ACTU and conformance
to FDA and DAIDS policies and procedures.
 
All ACTUs are responsible for the quality of the research
records at their unit and are expected to provide complete
and accurate research records.   Although ACTUs differ in
the way they ensure that research records are accurate and
complete, each ACTU is expected to institute an internal
quality assurance program supervised by a clinician.
External review of the QA at each ACTU is to be provided by PPD
periodic on-site monitor visits (approximately four per
year).
 
            b. Laboratory Quality Assurance
 
All ACTU flow cytometry, virology, and pharmacology
laboratories are required to participate in quality
assurance programs established by the ACTU EXecutive
Committee.  All ACTU hematology laboratories are required to
furnish documentation demonstrating their ongoing
participation and certification by an external hematology
proficiency testing program, such as that administered by
the College of American Pathologists (CAP).  This
documentation shall be collected as part of the site
registration process.
 
      4.  NIAID Clinical Research Products Repository (CRPR)
 
DAIDS has established a CRPR, through a contract with ERC
Bioservices Corporation, for the storage and distribution of
drugs used in clinical investigations sponsored by DAIDS.
This contract is managed by the Pharmaceutical and
Regulatory Affairs Branch (PRAB) of TRP.  At the request of
the ACTU Principal Investigators, the contractor performs the
following:  receiving drugs from a variety of sources and
storing them at their required conditions; shipping and
distributing drugs upon the receipt of an appropriate order
form from a site pharmacist for an authorized investigator;
managing the inventory by performing physical inventories
and monitoring usage rates of drugs; disposing of returned
drugs as required by local, State, and Federal regulations;
and establishing a computerized management information
system to maintain drug inventories and distributions
records.
 
      5. AIDS Clinical Trials Information Service (ACTIS)
 
The ACTIS is a central resource providing information on NIH-
and industry-sponsored clinical trials for individuals
infected with HIV.  This is a free service for users and is
jointly sponsored by the NIAID, National Library of Medicine
(NLM) and FDA in collaboration with and through an inter-
agency agreement with the CDC through their contractor Aspen
Systems Corporation.  The DAIDS, through the Operations
Office, provides a weekly update to ACTIS including
information about all DAIDS-sponsored protocols including
copies of new protocols, weekly accrual lists, information
regarding protocol changes, and lists of participation
sites.
 
PART A
 
                        APPENDIX III
 
                 CORE BUDGET FOR ADULT ACTU
 
USE INFORMATION BELOW TO COMPLETE FORM PAGE 4 OF SECTION 1
OF PHS 398
 
NIAID GUIDELINES BASED ON PROJECTED ACCRUAL OF NEW PATIENTS

 
                              NEW PATIENTS
                              60-150
__________
PERSONNEL
 
Principal Investigator         10 -  30%
 
Co-investigator(s)             70 - 100%
 
Study Coordinator              50 - 100%
 
RNs/PAs/Nurse Practitioners   200 - 400%
Clinical Assistant            100 - 200%
 
Data Manager/QA Coordinator    50 - 100%
 
Data Entry Clerk               50 - 100%
 
Pharmacist                     50 - 100%
 
Social Worker                  25 -  50%
 
Administrative Support        100 - 150%
 
Laboratory Technician          25 -  50%
 
__________
 
                                                      PART B
 
                        APPENDIX III

BUDGET FOR PEDIATRIC COMPONENT OF AN ADULT ACTU
 
USE THIS INFORMATION TO COMPLETE FORM PAGE 4 OF SECTION 1 OF
PHS 398

 
__________
ITEM
 
PERSONNEL                     NIAID RECOMMENDED FTE
                                # patients:  5-15

Pediatrician                   5 - 10%
 
Study Coordinator             10 - 25%
 
RNs/PAs/Nurse Practitioners   25 - 50%
 
Data Manager                  10 - 25%
 
Pharmacist                    10 - 25%
 
Social Worker                 10 - 25%
 
                         APPENDIX IV
 
     PROPOSED ADULT ACTU COST/PATIENT/PROTOCOL/UNIT TIME
 
                    FOR FIVE ACTG PROTOCOLS
 
Attach this form to page 4 of Section 1 of PHS 398.
 
THIS SECTION WILL FEATURE A NARRATIVE OF ASSUMPTIONS TO BE USED TO
CALCULATE COSTS OF THE FIVE PROTOCOLS DESCRIBED.  COPIES OF THE VERSIONS
OF THE INDIVIDUAL PROTOCOLS AND CORRESPONDING FORMS ARE AVAILABLE ON
REQUEST FROM THE OPERATIONS OFFICE.
 
                 Protocol 019 (Version 5.0)
 
"Safety and Efficacy of Zidovudine for Asymptomatic HIV
Infected Individuals"
 
Phase III, multicenter, randomized double blind placebo-
controlled
 
Time Period Analyzed:  The first year on study
 
Assumptions
 
o  This protocol has no end-of-study time limit.  Study
medication continues until toxicity, AIDS or death; clinical
follow-up continues until AIDS or death; follow-up for
survival is monitored every three months until death.  This
analysis is presented at the first year of therapy; no
follow-up costs are analyzed.
 
o  Per protocol, patients whose CD4 counts drop below 500
are transferred to a phase II open-label dosing and are
followed every three months instead of every month.  For this
cost analysis, it is assumed that a patient remains on the
monthly visit schedule.
 
o  Screening charges are not included.
 
o  HIV cultures are only to be performed in subsets of
patients; this charge is not included in the analysis.
 
o The Principal Investigator (PI) time and effort are estimated at one
hour per patient per year; this is exclusive of MD time for patient
visits.
 
Required Laboratory Tests
 
Hematology:           hemoglobin, absolute neutrophil count,
                      absolute lymphocyte count, platelet
                      count, mean corpuscular volume
Chemistry:            creatinine, total bilirubin, SGPT
Urinalysis:           microscopic not required
Immunology:           absolute CD4+ count, absolute CD8+
                      count
Virology:             HIV antigen levels (p24)
Pharmacology:         AZT level
 
                 Protocol 075 (Version 3.0)
 
"Phase I Study of Combination Chemotherapy (Adriamycin,
Bleomycin, Vincristine) and Azidothymidine in the
Treatment of AIDS-Related Kaposi's Sarcoma"
 
Phase I, oncology, open label, dose escalating
 
Time Period Analyzed:  10 weeks on treatment (five cycles),
four weeks on follow-up
 
Assumptions
 
o     Patients are treated in 14-day cycles for a minimum of
      two cycles and a maximum of five cycles, depending on
      treatment response.  This analysis should assume that
      five cycles are completed.
 
o     No serious complications of therapy requiring
      additional therapy or hospitalization that would
      be charged to the research grant occur.
 
o     Cost of follow-up for survival data is not included.
 
o     The PI time and effort is estimated at 1 1/2 hours;
      this is exclusive of MD time for patient visits.
 
Required Laboratory Tests
 
Hematology:    hemoglobin, hematocrit, WBC count, WBC
               differential, mean corpuscular volume,
               reticulocyte count, platelet count
Chemistry:     electrolytes, BUN, creatinine, total
               protein, albumin, calcium, phosphorus, uric
               acid, glucose, SGOT, SGPT, alkaline
               phosphatase, bilirubin
Urinalysis:    microscopic not required
Immunology:    baseline:  two CD4+ counts; on-therapy:  one
               CD4+ count
Virology:      baseline:  HIV antibody (ELISA), two HIV
               antigen levels (p24); on-therapy:  one HIV
               antigen level (p24)
 
                 Protocol 093 (Version 5.0)
 
"A Phase II Dose-Ranging Open-Labelled Trial of Foscarnet
Salvage Therapy for AIDS Patients with Sight Threatening CMV
Retinitis Who Cannot be Treated with Ganciclovir Due to
Myelosuppression or Treatment Failure"
 
Phase II, multicenter, opportunistic infection, open-label
 
Time Period Analyzed:  two weeks induction therapy, eight weeks
maintenance therapy
 
Assumptions
 
o     This is a 10-week study; however, maintenance therapy
      may continue at the discretion of the investigator
      for a total period of therapy not to exceed one year.
      For this analysis, the cost is based on 10 weeks of
      therapy only.
 
o     Drug is administered through a central venous
      catheter; it is assumed that the cost of central
      line insertion is paid for by the third party
      carrier.  Patients are hospitalized for the first three
      days of therapy; costs of hospitalization are not
      included in this analysis.
 
o     Drug administration post hospitalization is charged
      for care performed in a supervised outpatient setting
      or by home health care providers; however, in some
      instances these charges are not charged to the grant.
      Include the cost if it will be charged to the grant.
 
o     Induction therapy is administered for one hour q eight
      hours for 14 days.  The first three days are assumed to
      be during hospitalization.  The administration of
      drug in the remaining 11 days is calculated as the
      cost of treatment in a supervised outpatient setting.

o     Maintenance therapy is administered as an IV infusion
      on an outpatient basis at home or in a supervised
      outpatient setting.  This analysis should use the
      cost of a supervised home or outpatient clinic.
 
o     Screening costs are not included.
 
o     Optional tests and procedures are not included.
 
o     Costs for the subset of patients for pharmacokinetics
      are not included.
 
o     The PI time and effort is estimated at 1 1/2 hours;
      this is exclusive of MD time for patient visits.
 
Required Laboratory Tests
 
Hematology:           hemoglobin, mean corpuscular volume,
                      WBC count, WBC differential, platelet
                      count
Chemistry:            sodium, potassium, BUN, creatinine,
                      albumin, calcium, phosphorus, SGOT,
                      SGPT, total bilirubin, alkaline
                      phosphatase
Special chemistry:    free (ionized) calcium, magnesium
Urinalysis:           with microscopy rine creatinine
                      clearance
Virology:             CMV culture/immunofluorescence of
                      buffy coat, urine semi-quantitative
                      CMV culture
Immunology:           CD4+ count
Specimen handling:    serum banked for pharmacokinetics
                      studies
 
               Protocol 100 (Amended 8/23/89)
 
"Phase I Study of SC-48334 in Patients with AIDS and
Advanced AIDS-Related Complex"
 
Phase I, multicenter, open-label, dose escalating, non-
randomized
 
Time Period Analyzed: 31 days on phase I treatment, 90 days
on phase II therapy and follow-up
 
Assumptions
 
o  This is a 31-day phase I study with an optional
90-day phase II continuation of therapy.  This
cost analysis assumes 31 days on study and 90
days of phase II therapy and follow-up.
 
o  The three days of intense observation during the
initial multi-dose regimen are assumed to be
conducted in an inpatient or outpatient GCRC
with no charge to the grant for use of the GCRC
facilities or personnel.
 
o  Screening charges are not included.
 
o  No optional tests and procedures should be
included.
 
Required Laboratory Tests
 
hematology (eight tests):     hemoglobin, hematocrit,
                              platelet count, prothrombin
                              time (PT), partial
                              thromboplastin time (PTT), WBC
                              count and differential,
                              reticulocyte count,
                              haptoglobin
hematology (one test):        CBC with platelets
Chemistry (18 tests):         creatinine, uric acid, total
                              protein, albumin, SGOT,
                              SGPT, sodium, potassium, total
                              bilirubin, alkaline
                              phosphatase, LDH, calcium,
                              phosphorus, bicarbonate,
                              chloride, BUN, glucose,
                              cholesterol
Chemistry (10 tests):         creatinine, BUN, glucose,
                              sodium, potassium,
                              bicarbonate, chloride,
                              alkaline phosphatase, total
                              bilirubin, SGOT
Urinalysis:                   microscopic not required
Pregnancy test:               serum or urine
Immunology (two tests):        two CD4+ counts
immunology (one test):          one CD4+ count
virology (six tests):         baseline two each:  HIV
                              culture (blood), HIV antibody,
                              p24 antigen levels
Specimen handling:            banked serum for surrogate
                              markers
Pharm. specimens:             serum obtained for
                              pharmacokinetics studies
 
            Protocol 117 (Amendment #6, 9/28/90)
 
"A Phase II Efficacy Study Comparing 2',3'-Dideoxinosine
(ddI) and Zidovudine Therapy of Patients with HIV Infection