Full Text AI-92-14


NIH GUIDE, Volume 21, Number 39, October 30, 1992

RFA:  AI-92-14

P.T. 34, FF

  Clinical Trial 
  Treatment, Medical+ 

National Institute Of Allergy And Infectious Diseases

Letter of Intent Receipt Date:  November 16, 1992
Application Receipt Date:  January 21, 1993

The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications for establishing adult AIDS Clinical Trials
Units (ACTUs) at minority institutions.

o  Institutions that have more than 50 percent minority student
enrollment and award the M.D., D.D.S., D.V.M., or other doctoral
degree in the health professions.


The Division of AIDS (DAIDS) of the NIAID, administers a major
clinical trials program to evaluate therapeutic interventions for the
treatment of Human Immunodeficiency Virus disease (HIV), Acquired
Immunodeficiency Syndrome (AIDS), and associated sequelae resulting
from HIV infection.  These objectives are accomplished through the
AIDS Clinical Trials Group (ACTG) which consists of adult and
pediatric ACTUs, the Statistical and Data Analysis Center (SDAC) and
the DAIDS research programs.  Appendix I, "Structure and Function of
the ACTG", describes the cooperative model.  Applicants are
encouraged to read this section of the RFA before preparing an

The purpose of this Request for Applications (RFA) is to encourage
applications from minority institutions to establish Adult AIDS
Clinical Trials Units and become part of the AIDS Clinical Trials
Group (ACTG).  The adult ACTG currently is composed of 35
institutions.  Minority institutions are in a unique position to
access and serve minority populations, and contribute to the overall
ACTG effort to identify new therapeutic interventions for the
treatment of HIV infection and its associated sequelae.  These units
could assume a leading role to specifically focus on research
questions of particular relevance for HIV infected minorities and
underrepresented populations.

Applicants will be required to demonstrate expertise in conducting
clinical trials to evaluate interventions for the treatment of HIV
infection and for the treatment and prophylaxis of opportunistic
infections associated with immunosuppression.  Optional areas for
proposed clinical studies include oncological and neurological
complications of AIDS.  Additional areas covered by this RFA include
clinically relevant laboratory studies in virology, pharmacology,


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, AIDS
Clinical Trials Units At Minority Institutions, is related to the
priority area of HIV infection.  Potential applicants may obtain a
copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202- 783-3238).


This competition is limited to domestic universities or colleges that
possess the capabilities to conduct clinical research on HIV
infection and AIDS. Applications may not contain an international
component.  Preference will be given to institutions that have more
than 50% minority student enrollment.


Awards funded under this RFA will be supported through National
Institutes of Health Cooperative Agreements (U01). Assistance
provided through the cooperative agreement differs from the
traditional research grant in that the Government component (NIAID)
anticipates substantial programmatic involvement during the
performance of the award.  The interaction of NIAID staff with the
investigators is expected to facilitate the research.  There is no
intent, real or implied, for staff to direct an ACTUs activities or
to limit the freedom of investigators.  The nature of staff
interaction is described below.  All policies and requirements that
govern the grant program of the U.S. Public Health Service and the
National Institutes of Health apply to these cooperative agreements.

This RFA is a one-time solicitation with a specified deadline for
receipt of applications.  Reissuance of this initiative is uncertain.
If by the end of the third year of award NIAID has not announced an
intention to reissue the RFA, awardees who plan to apply for
continuing support should contact NIAID program officials for advice
on how to recompete.


Approximately $3,800,000 (total costs) will be available for the
first year of funding.  This level of support is dependent on the
receipt of a sufficient number of applications of high merit and the
availability of funds.  Approximately three to four applications will
be funded under this RFA.  Awards will be made for a project period
of four years.  The anticipated award date is September 1, 1993.
Funding beyond the first and subsequent years of the award will be
contingent upon satisfactory performance during the preceding
years, including meeting research objectives and patient accrual
targets, and the continuing availability of funds for this purpose.


Background:  Infection with HIV and progression to AIDSis an
increasing health risk for minority and underrepresented populations.
Epidemiological data indicate that minorities are disproportionately
affected by AIDS in comparison to the overall population.  According
to census figures, African Americans (12 percent), and Hispanics (8
percent) together account for approximately 20 percent of the U.S.
population.  The Centers for Disease Control has reported that as of
March 1992 African Americans and Hispanics account for 29 percent and
16 percent, respectively, of the 218,307 AIDS cases in the United
States.  Of the AIDS cases reported among adult females, 52 percent
are African Americans, 21 percent are Hispanic, and 25 percent are
white.  AIDS has become a major health problem for American citizens
with a special impact on minority men and women.

o  For purposes of this RFA, minority and underrepresented
populations are defined as individuals belonging to a particular
group, gender, or subculture that has been determined by the NIAID to
be underrepresented in AIDS clinical trials research.  These include
racial and ethnic minorities, injection drug users, and women.  In
awarding grants under this RFA, the NIAID will give priority to
minority institutions that serve patient populations that are African
American, Hispanic, Native American, and Asian/Pacific Islanders.

Research Scope:  Consistent with the objectives of the adult AIDS
clinical trials program, all applicants will be required to
demonstrate the capability to conduct efficacy trials on therapeutic
interventions for the treatment of HIV infection; and both efficacy
and prophylaxis trials on experimental interventions for
opportunistic infections.

Optional areas for which an applicant may choose to demonstrate
capabilities include: (1) Phase I/II evaluation of interventions to
establish safety, tolerance and pharmacokinetic behavior; (2)
evaluation of interventions for the treatment of malignancies
associated with immunosuppression; and (3) evaluation of therapeutic
interventions for the neurological complications of HIV infection.
Additionally, all applicants will have the option to apply for
laboratory funding in support of the clinical trials.


o  Terms of Award

The current structure of the ACTG is tripartite:  (1) adult and
pediatric ACTUs, (2) the Division of AIDS, and (3) data and
operations supports contracts (e.g., the Statistical and Data
Analysis Center (SDAC) and the Operations Office).

These three components comprise the ACTG system and cooperatively
perform a wide range of scientific planning and coordinating
functions related to the conduct of clinical trials.  Included among
those functions are: assessment of treatment research needs,
establishment of scientific priorities, development of new research
protocols, implementation and analyses of these studies, and the
establishment of quality control programs to ensure that the data are
of the highest quality.

The scientific investigators at the ACTUs, through scientific
committees and the Executive Committee, with assistance from TROP and
CRP, develop a scientific agenda, set priorities for clinical trials,
and initiate the 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.

o  Awardee Rights and Responsibilities

The ACTU investigators will be responsible for the overall conduct of
the research including developing concept sheets for studies,
protocol development, accrual to protocols, production of high
quality data, and the timely dissemination of the research results.
All awardees must be capable of enrolling a minimum of 60 to a
maximum of 150 new patients annually for four years after award.  The
Principal Investigator of each ACTU is responsible for the proper
functioning of the main unit and any subunits, including all
scientific and administrative aspects.

ACTU performance in each budget period will determine the base budget
award, release of increments of the base budget, and the amount of
incentive funding (See Fiscal Managemnent) awarded during that budget
period.  The Principal Investigator will submit interim progress
reports, due at the end of five months after the beginning of each
budget period.  This report will include a summary of expenditures
and obligations to date and give the investigator the opportunity to
comment on any circumstances at the ACTU that may compromise their
ability to achieve their objectives.  The level of support in future
award years will be contingent upon 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

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 the NIAID).

Investigators may form a clinical trials unit through consortium
arrangements with other institutions or health care agencies. The
goals of such arrangements are:  (1) to contribute substantially to
the capability of the awardee institution for recruiting and
retaining patients on clinical trials; (2) to provide increased
access to special patient populations (e.g., minorities and substance
abusers, and adolescents); and (3) to provide special clinical or
scientific expertise not available at the Main Unit.  These
collaborating institutions would be designated as Subunits, although
ultimate financial and scientific responsibility would reside with
the Main Unit.

o  NIAID Rights, Responsibilities, and Authorities

NIAID Treatment Research Program (TRP)

Substantial programmatic assistance is provided by the TROP and the
CRP to ensure that ACTG clinical trials address questions of the
highest scientific priority.  The two programs support clinical
trials research by providing scientific, technical, and
administrative advice; facilitating protocol development and
implementation; andreviewing protocols to ensure consistency,
scientific soundness, and conformance with FDA requirements for
Investigational New Drug (IND) trials.  TROP and CRP coordinate the
activities required to develop new agents from initial human trials
to their final FDA approval.  In addition, these programs facilitate
the transfer of effective therapies from the research setting to
routine patient care.

Fiscal Management

Clinical base funding consists of those resources required to
maintain an infrastructure and ancillary services sufficient to
accrue a projected minimum number of new patients each year.
Clinical base funding includes costs support for protocol-mandated
assays, ancillary services, and administrative costs.

Clinical base funding is based on the projected number of new
patients to be accrued each year.  Each ACTU prepares a clinical base
budget sufficient to accrue a minimum  number of patients per year.
The budgets are constructed using the costs of individual ACTG
protocols to which patients may be enrolled and the number of
patients projected to be accrued to those protocols.

Clinical base funding to ACTUs will be administered in the following
manner:  the majority of clinical base funding will be released at
the beginning of the budget year.  At mid-period, the performance of
the unit will be assessed by NIAID staff, using accrual, quality of
data, 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,
poor data quality), 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.

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:

o  funding of NIAID/ACTG designated high priority protocols not
anticipated at the beginning of the budget period

o  increasing focus on a scientific area during a budget year for
which resource needs exceed the funding of the individual ACTUs;

o  funding 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 chairing an ACTG
scientific committee).

Incentive funding will be awarded either as administrative
supplements after review by TROP and DEA staff, or as competing

NIAID Staff Assistance

The NIH will assist the AIDS Clinical Trials investigators through
the NIAID staff.  The NIAID scientific and program staff will provide
assistance to recipients of cooperative agreements by advising and
coordinating ACTG activities. 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, as designated, will be responsible for the following

o  The Associate Director, TROP, and the Associate Director, CRP,
will assist the ACTG Executive Committee in establishing the
scientific priorities of the ACTG.

o  The Chief, Medical Branch, CRP, will assist in protocol
development and assist the Chief, Clinical Research Management
Branch, TROP, with review of protocols and advise on appropriate
utilization of resources.

o  The Chief, Clinical Research Management Branch, TROP, will assist
in promoting the timely implementation and completion of clinical
trials designated as priority studies by the ACTG Executive Committee
and the NIAID, and provide technical advice and assistance.

o  The Associate Director, TROP, 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 areas).

o  The Associate Director, TROP, will coordinate activities among
other areas of NIH-sponsored research and assist in dissemination of
results of clinical trials to the scientific and medical communities.

o  The Chief, Operations and Data Management Branch, TROP, will
assist in providing operational and data management support.

The NIAID will serve as the sponsor for Investigational New Drug
(IND) applications required for conducting studies of agents under
evaluation by the ACTG, provide updated information on the safety and
efficacy of investigational new agents supplied to ACTUs under an IND
Application sponsored by the NIAID (Note:  NIAID will not provide
investigational agents or guarantee expenditure of NIAID funds for a
study after requesting termination of the study);

o  The Chief, Pharmaceutical and Regulatory Affairs Branch, TROP,
will conduct 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, Part 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).

o  The Chief, Clinical Research Management Branch, TROP, will conduct
on-site visits to review progress of the research, and issues
concerning administrative, technical, and fiscal management.

For activities described herein that require approval by NIAID staff
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), the
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.  In the event
that the NIAID is the holder of the IND, any action taken by NIAID
under its responsibility for the safety of the trial should not be
subject to arbitration.  The 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.

o  Cooperative Rights and Responsibilites of NIAID and the Awardee

Committees of the ACTG

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, core member, and additional
members with relevant expertise and interest in the committee's
research area.  Each committee also has representatives from TROP and
CRP, SDAC, and HIV-infected persons and their advocates.  Each
standing committee has at least 10-15 members from awardee
institutions and one to two members representing the NIAID.

The role of each Scientific Committee, together with TROP and CRP,
and the Executive Committee, is to develop a research agenda and
establish research priorities in a particular scientific area and
continually reassess those priorities relative to new research
opportunities; and to evaluate the conduct and status of active

In addition to providing general expertise, the Immunology, Virology,
and Pharmacology Committees 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 were formed to provide technical expertise and
practical advice to the ACTG.  There are three ACTG Resource
Committees: Site and Data Management, Patient Care, and the Community
Constituency Group.

The Executive Committee, in consultation with TROP and CRP, develops
general ACTG policies concerning committee structure and membership,
committee operations, publications, access to data, interim data
monitoring, and agendas for the group meetings.  In addition, the
Executive Committee, with assistance from TROP and scientific
committees, and establishes scientific priorities for the ACTG.  The
majority of the members of the Executive Committee are ACTU
investigators.  Representatives from TROP and CRP, persons from the
Community Constituency Group (including HIV infected individuals),
and the SDAC also sit on the Executive Committee.

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, sample size estimates, and cost impact

The concept sheets are reviewed by TROP and CRP staff members
comprising a Clinical Trials Review Committee (CTRC).  The
appropriate Scientific Core Committees 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); TROP and CRP representatives; an SDAC
statistician; an Operations Office representative; and immunologist,
virologist, pharmacologist, as required. 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
CTRC prior to their initiation.  After FDA approval of the final
protocol it is opened for enrollment.  Once a protocol has been
activated, the protocol chair is responsible for its ongoing
performance and is expected to take the lead in dissemination of
study results, including publication of results.

Access to Data, Ownership of Data, and Publication Policies

In addition to the reporting requirements currently in existence for
awardees of traditional NIH research project grants, the following

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, TROP.  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 NIAID 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 the NIAID
for the preparation of internal reports on ACTG activities and to
fulfill regulatory requirements. However, the awardees will retain
rights to the data (see below).  Publication of findings is the
responsibility of the investigators in accordance with the
publication policies established jointly by the ACTG investigators
and the Associate Director, TROP.  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.

ACTG member institutions will generate clinical trials 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, with the assistance of the Associate Director,
TROP, 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 entire 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,
TROP.  The Associate Director, TROP, and the Associate Director, CRP,
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.  As required for safety monitoring of clinical
protocols, the Associate Director, TROP, and the Associate Director,
CRP, will have access to the data.

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, TROP, 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 the award may result in
withholding of funds by the NIAID.



NIH policy is that applicants for NIH 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 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, together with a rationale
for its choice.  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 the Research
Plan and summarized in Item 5, Human Subjects.

Applicants 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 U.S.
racial/ethnic minority populations (i.e., Native Americans, including
American Indians or Alaskan Natives, Asian/Pacific Islanders, African
Americans, Hispanics/Latinos).  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

The usual NIH policies concerning research on human subjects applies
to ACTUs and subunits.  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.

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 and minorities in the 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


Prospective applicants are asked to submit, by November 16, 1992, a
letter of intent including the components for which an application
will be submitted, the name and institution of the Principal
Investigator.  Names of prospective co-investigators 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 and
to promote early interactions between applicants and NIAID staff.
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 should be sent to Dr. Frederick
Batzold (see INQUIRIES below.).


Structure And Composition Of The Application

All applications are to be submitted on the form PHS 398(rev. (9/91).

The application should be assembled and paginated as one complete

A separate narrative and itemized budget with justification must be
prepared for each component for which support is requested.  Detailed
instructions for the preparation of budgets are given in Item II B:
"Budget Requirements, pp.15 to 17.

Part  A   Adult Clinical Trials Unit  (REQUIRED)

Part  B   Laboratory Support
o  Virology  (REQUIRED)
o  Pharmacology  (OPTIONAL)

Part  C  Developmental Research (ALL OPTIONAL)
o  Virology
o  Pharmacology
o  Immunology
o  Other (Clinically Relevant Areas)





Applicants are required to describe their proficiency in conducting
clinical trials and proposed plans for research in the areas of
antiretroviral interventions and the treatment/prophylaxis of
opportunistic infections.  Optional areas for which past experience
and proposed plans may be submitted include the evaluation of
interventions for AIDS related malignancies and neurological
complications of HIV infection.


Describe previous experience in conducting clinical trials,
particularly HIV research.  Include the types of studies (Phase
I/II/III), the size of the studies, the source of study participants,
and the demographic features of the population.

Describe prior participation in the design and development of
clinical trials protocols.

Applicants that were funded under the Minority Infrastructure
initiative (RFA AI-90-04) should describe their accomplishments in
establishing a clinical trial infrastructure.


A list of currently open ACTG protocols for adult patients is given
in Appendix III.

Describe the plan for participation in types of studies (Phase
I/II/III) and kinds of studies (antiretroviral interventions,
treatment and prophylaxis of opportunistic infections).  Estimate the
total number of patients to be accrued in the first year and a
projection as to the types and kinds of studies in which the ACTU
plans to participate.

Provide the same information that is requested in B.1. if optional
studies in oncology and neurology are proposed.

Describe the experience and responsibilities of key staff necessary
for each area of emphasis.

Describe the special scientific expertise, patient populations, and
other unique features that the proposed site would bring to the ACTG


Describe the administrative and organizational features that will be
implemented to support the proposed studies.  The following areas
should be addressed.

The proposed administrative structure of the clinical trials unit.

The administrative relationship of the clinical trials unit to
patient care clinics that serve the proposed population for the ACTG
research studies.  Indicate whether or notthe clinical trials unit
will be a integrated with the primary care activities.

The qualifications, experience and responsibilities of key
administrative personnel including the nurse coordinator and
co-investigators.  Include other personnel that may be available to
the ACTU through institutional or other agreements.


Describe the facilities available for both inpatient and outpatient
studies at the main ACTU and any subunits.

Describe the location(s), relative to the ACTU, where the study
participants receive their primary care and whether any common space
will be used for both purposes.


Provide a clear, concise plan for outreach and recruitment of
clinical trials participants.  This plan must document the capability
to enroll a Minimum Of 60 New Patients To A Maximum Of 150 On An
Annual Basis into ACTG protocols.  The plan should address the

The primary source of study participants such as primary care
clinics, consultative services, HIV testing sites, referral from
community-based clinics/physicians or other sources.

The demographic features of the patient population in the catchment
area including the number of AIDS cases, HIV seroprevalence, gender,
race/ethnicity, and risk transmission categories.

Data on prior success in accruing patients to clinical studies or
data from clinic records from which an estimate can be made of the
number of patients that may be available for ACTG studies.

If referral sources are to be utilized, describe the policies and
procedures for communication and the arrangements that will be
implemented for continued primary care of study participants.


Provide a plan for the delivery of ancillary services. The resources
should include language interpretation, as applicable, child care,
patient transportation, and other services necessary for the
recruitment and retention of patients.  Describe the types of
personnel, and their responsibilities that are being requested or
will be provided through other sources.  Culturally sensitive
individuals representative of the patient population must be

Linkages are intended to foster the provision of multidisciplinary
services and support in a collaborative environment with the patient
community.  The listing of support linkages given below are either
REQUIRED or strongly ENCOURAGED, as indicated.  Letters of agreement
in support of these linkages and definitive plans to implement the
arrangements should be included.  A list of government funded
projects with which linkages are encouraged or required is given in
Appendix IV.

o  Community Advisory Board (CAB) [REQUIRED].

A Community Advisory Board must be established at each ACTU. The
purpose of this interaction is to inform the patient community about
the availability of ACTU studies and provide input about study design
and other factors that might affect patient acceptance of, or
compliance with, ACTG protocols. Describe the proposed composition of
the CAB and functions to be performed for the ACTU.  Inclusion of
women and minorities on the CAB is required and should reflect the
demographics of the HIV infected population in the catchment area.

o  Community Program for Clinical Research on AIDS (CPCRA) [REQUIRED]

Establish a formal communication linkage with NIAID funded CPCRA
sites located in the same SMSA.  The purpose of this relationship
will be to make certain that the most appropriate clinical trials
programs are available to patients in the catchment areas and that
there is no competition for study participants.  A letter of
agreement should be included that has been co-signed by the CPCRA
Principal Investigator.  The letter should describe procedures for
screening, recruitment, and assignment of patients to protocols and
whether any staff or facilities will be shared by the two programs.

o  General Clinical Research Center (GCRC) [ENCOURAGED] Institutions
that have a GCRC funded by the National Center for Research Resources
may identify the GCRC as a resource for conducting studies.  A letter
of agreement from the GCRC should be included if this resource is to
be utilized.

o  HRSA AIDS Demonstration Projects  [ENCOURAGED]

If a HRSA project is in the same SMSA, it is strongly encouraged that
a working relationship be established as evidenced by a letter of

o  National Institute on Drug Abuse (NIDA) Treatment and Research

In order to increase the number of HIV infected drug users or former
users in ACTG protocols, applicants are encouraged to establish
agreements with NIDA Centers located in the community from which
patients will be accrued.

o  Describe any other linkages that will be established in support of
the ACTU including, but not limited to: community based
organizations, designated state AIDS centers, and the NCI lymphoma


A list of required computer equipment is found in Appendix V and may
be requested in the application.

o  Describe a plan for managing the clinical trials data. The plan
should take into account that Federal Regulations require the
retention of research records for investigational drugs for two years
after a marketing application is approved.  Additionally, if a drug
is disapproved or all studies are terminated the record must be
retained for two years following the discontinuation of shipment and

o  The data management plan should describe:

the expertise and duties of the data manager relative to data
management, oversight and supervision

procedures for staff training on the protocol requirements

procedures for the transcription of data to the primary research
record and the time to data entry into the data base

the design, maintenance, and security of the filing and storage of
patient charts and records

the quality assurance procedures that will be implemented at the ACTU
to ensure the accuracy and completeness of all research records and
compliance with Federal Regulations regarding clinical trials in
human subjects


Applications must provide a pharmacy plan that addresses the
development and implementation of investigational drug control
systems for the ACTU and any subunits where investigational drug will
be dispensed.

o  The plan must conform with the guidelines of the ACTG Pharmacy
Manual (available upon request from the ACTG Operations Office, (301)
230-3150) and FDA regulations on the use of investigational drugs.
The plan must address the following:

experience of the key staff in managing investigational studies

procedures for dispensing

procedures for drug accountability and record keeping

drug storage

provide documentation of the commitment of pharmacy staff and their
duties and responsibilities.

adequate staff number of must be identified to ensure time for
patient education activities.


All ACTUs must have the capability for performing flow cytometric
immunophenotyping either on site or through an agreement with another
ACTG certified laboratory.  The laboratory must have the capability
to perform two- and three-color flow cytometric immunophenotyping on
whole blood samples using a laser-based instrument on a minimum
annual number of 500 samples.  Minimum required immunophenotypes
include:  CD4, CD8, CD3, CD19, CD45, and CD14.  Other phenotypes that
may be required include: CD25, CD38, CD45RA, CD45RO, DR, CD56, AND

The use of existing ACTG-certified laboratories is strongly
encouraged when possible.  Laboratories conducting ACTG analyses
shall be required to adhere to the methodological guidelines set
forth by the DAIDS Flow Cytometry Advisory Committee and to
participate in the DAIDS immunophenotyping quality assessment

o  Describe the available instrumentation and the analytical
methodologies used for the enumeration of the immunophenotypes.

o  Describe the qualification and experience of key personnel.

o  Describe the internal quality control/quality assurance programs,
including references ranges, for the laboratory.  Provide the
specifics of any QC/QA or proficiency testing programs in which the
laboratory has participated.


A major goal of the ACTG is to maintain the capability to address all
aspects of clinical drug evaluation.  ACTG virology and pharmacology
laboratories will evaluate clinical specimens as required by the ACTG
protocols and develop new methodologies in support of these
protocols. The number of comprehensive virology and pharmacology
laboratories will be sufficient to meet the demands of the ACTG;
however, the present need is less than the number of ACTUs.  These
laboratories may be required to accept specimens for analysis from
other ACTUs on a fee-for-service basis.


Applicants must submit a plan describing the capability to perform
and/or obtain virology laboratory services as required by ACTG
protocols.  In order to meet the protocol mandated virology
requirements, each applicant will have three options

Option 1:  As a comprehensive virology laboratory, perform all
protocol mandated determinations (e.g., p-24 antigen, PBMC
quantitative HIV culture, resistance assays, DNA/RNA PCR) on site,
and implement new methods/assays as needed.

Option 2:  Perform only HIV p-24 antigen assays and HIV PBMC cultures
on site and have another ACTU laboratory perform the other protocol
required virological assays on a fee-for- service basis.

Option 3:  Arrange for all virological assays to be performed by
another ACTU laboratory on a fee-for-service basis.

All ACTUs performing virologic assays must:  (1) use Dataworks TM
software for data transmission, (2) adhere to ACTG consensus
protocols, and (3) participate in the DAIDS virology QA programs.

The following information should be provided when applying for

Option 1:

o  prior experience in the development and application of virologic
assays relevant to HIV disease

o  experience in, and procedures for, culturing HIV from clinical
samples (PBMC and plasma) and for HIV p-24 determinations

o  procedures for antiviral drug resistance assays

o  procedures for performing HIV DNA/RNA PCR

o  intra- or interlaboratory QC/QA procedures

o  procedures for the storage and inventory of specimens

o  estimated number of assays/year to be performed and the total

Option 2:  Elements 2, 5, 6, and 7 from Option 1.

Option 2/3:  Applicants having some or all of their virology
performed at another ACTG laboratory should provide the following

o  a letter of agreement from the ACTU laboratory that will be
performing the assays

o  procedures for processing and shipping samples

o  the total cost/sample/assay (e.g., labor, supplies, data analysis

o  estimated number of assays/year


ACTU pharmacology laboratories will perform protocol mandated
therapeutic drug monitoring, and develop new assays to monitor drug
levels using a variety of methodologies.  All ACTUs performing
therapeutic drug monitoring must adhere to ACTG consensus protocols
and participate in DAIDS administered QA programs.

Applicants should provide the following information:

o  prior experience in the development and application of
methodologies for therapeutic drug monitoring with specific reference
to drugs used in the treatment of HIV disease

o  capability to perform a minimum annual number of 500- 1000 drug
level assays for an agent such as a nucleoside analog

o  procedures for the storage and inventory of specimens

o  intra- or interlaboratory QC/QA procedures

o  estimated cost/sample (e.g., labor, supplies, data analysis) for
assays currently being performed


Access to clinical samples from patients with detailed medical
histories provides a unique resource to support research leading to
improved diagnosis, monitoring, and treatment of individuals with HIV
infection.  The primary objective of the developmental research is to
provide investigators with resources to answer clinically relevant
questions with emphasis on utilizing specimens generated from ACTG
protocols.  The research may be broad in scope but must be of high
clinical relevance and includes:

o  1  Developmental Virology
o  2  Developmental Pharmacology
o  3  Developmental Immunology
o  4  Other (e.g., mycology, neurology, patient compliance
Applicants for components C.1 - C.4 should follow the instructions in
the form PHS 398 (rev. 9/91) including an abstract, specific aims,
background and significance, preliminary studies, and research design
and methods.

Research projects are encouraged but not limited to the following

o  1:  Developmental Virology

o  identification and validation of virological markers
(phenotypes/genotypes) correlating with clinical disease

o  quantitation of viral burden and infectivity in body fluids and

o  development of improved methodologies to screen for antiviral drug
resistance and evaluate strategies to overcome resistance

o  characterization of drug resistant phenotypes

o  2:  Developmental Pharmacology

o  drug-drug interactions in combination therapies

o  pharmacokinetics and pharmacodynamics in diverse patient

o  improved methodologies for therapeutic drug monitoring

o  drug levels in target tissues/cells/subcellular compartments

o  effect of disease state on drug toxicity, pharmacokinetics and

o  3:  Developmental Immunology

o  characterization of immune cell phenotypes and functions

o  characterization of soluble products of immune activation

o  evaluation of the immune response to AIDS-associated opportunistic

o  4:  Other Developmental Areas

o  interaction of human host and opportunistic pathogens

o  development and validation of rapid, sensitive diagnostic methods
for opportunistic pathogens

o  resistance of opportunistic pathogens to therapeutic agents

o  issues relevant to acceptance of and compliance with ACTG
protocols by study participants



All applicants must apply for Part A, AIDS Clinical Trials Unit, and
Part B  (1) Virology Component  Part B (2) and Parts C  1-C.4 are
optional.  Awards for Parts B and/or C will be contingent on
receiving an award for Part A.  Awards for Developmental Research in
Virology (C.1) or Pharmacology (C.2) will be contingent upon
receiving an award as a comprehensive virology laboratory (Option 1)
or as a comprehensive pharmacology laboratory, respectively.

Requests for support for Parts B and C may be made through a
subcontractual agreement with another institution.


Page 1 (Face Page) of PHS 398
Complete items 1 - 18 as instructed.  This should be the first page
of the application and all succeeding pages should be numbered

Items 7 & 8:  The requested budget should be the total amount for all
components for which support is requested (Parts A, B & C).

Page 2 of PHS 398
The abstract should contain a brief description of the proposed work
and objectives.

Under "Key Personnel Engaged on the Project" List the Principal
Investigator of the ACTU and the Program Directors of each component.

Page 3 of PHS 398
Prepare a detailed Table of Contents that will allow reviewers to
readily locate specific information for each component.

Page 4 of PHS 398
The application should contain a Composite Budget for the first
twelve month budget period.  The Composite Budget should include the
subtotals for the individual detailed budgets for each component in
the application.  The subtotals for each category (personnel,
equipment supplies etc) on the Composite Budget page should be
identified by the component (Part A, B.1, C.1 etc).  Justification
for budget elements should be presented in the individual component

Page 5 of PHS 398

A summary total budget for all components applied for should be
presented for all years for which support is requested.

Note:  For more detailed instructions on the budget see "B. BUDGET

Page 6 and 7 of PHS 398

Biographical sketches and information on Other Support for all
professional personnel for all components should be placed at the end
of the application with the Principal Investigator first followed by
other key personnel in alphabetical order.



For each individual first-year budget (A) prepared for a given
component, a corresponding four-year summary budget (B) should also
be prepared.  Page 4 of the PHS Form 398 should be used for all "A"
budgets.  Page 5 of PHS Form 398 should be used for all "B" budgets.

o  (A)  12-month budget for Part A (AIDS Clinical Trials
o  (B)  Four year summary budget for Part A

o  (A)  12-month budget for Part B.1 (Virology)
o  (B)  Four year budget for virology

o  (A)  12-month budget for each optional component applied for (B.2
Pharmacology; C.1 Developmental Virology; C.2 Developmental
Pharmacology; C.3 Developmental Immunology;  C.4 Other

o  (B)  Four year budget for each optional component

o  (A)  Composite 12-month budget: total of all (A) budgets above

o  (B)  Composite summary four year budget: total of all (B) budgets

All budgets must be placed following Page 3 of the overall
application, with the composite budgets (7. and 8. above) being
first, followed by the budgets for Part A, then Part B.1 etc.  The
12-month budget for each component must be immediately follwoed by
the applicable four-year budget. These budget pages should be
numbered consectively and appropriately referenced in the "Table of
Contents."  Each budget page must have the appropriate title
corresponding to the specific component, in the upper margin of the


That portion of the ACTU budget specifically related to the accrual
of patients and conducting protocols is designated Clinical Base
funding.  It will include the resources necessary to maintain a
clinical trials infrastructure. Clinical base funding will include:

Protocol Specific Costs: All resources necessary for the study of a
projected number of patients on to ACTG protocols for the duration of
the protocol.

Costs Not Directly Related to A Specific Protocol: Costs necessary
for the recruitment, screening and retention of patients, ancillary
services, and administrative costs.

Clinical budgets will be constructed by projecting the cost of
performing clinical trials protocols to a projected number of
patients to be accrued on an annual basis.  These costs will
represent a major portion of the Clinical Base budget and are the
protocol specific costs.


The clinical base budget will provide support for all aspects
necessary for conducting clinical studies. Specifics that may be
requested in addition to essential elements for the functioning of
the ACTU, include, but are not limited to are:

Personnel:  Specialized personnel for the recruitment and retention
of study participants, subspeciality clinical staff (e.g.,
neurologist, neuropsychologist, oncologist, gynecologist).

Equipment:  Computer equipment and software may be requested.

Supplies:  Clinical, administrative, pharmacy and those necessary for
performing flow cytometry.

Travel:  Limited to a total of 24 trips annually to ACTG sponsored
meetings.  Scientific meetings are limited to $2000/year and foreign
travel, if applicable, to $3000/year.

Patient Care:  Include the projected costs for performing clinical
laboratory tests and charges for in-patient care that will be
required by clinical trials protocols.  The amount requested should
be justified based on the number of patients the ACTU projects to
accrue annually.

Additional Information:  Appendix VI contains a list of the specific
laboratory tests that may be required by ACTG protocols.  Applicants
are required to provide the research costs for performing these tests
at their institution.  If multiple performance sites are proposed
which have signicantly different costs, the cost/test may be provided
for the individual sites.  The costs for the laboratory tests should
be attached as an APPENDIX to the application. These costs will be
used to evaluate reasonableness of the patient care costs being

Other Expenses:  Patient travel vouchers, to and from scheduled
protocol visits, child care, and other support at the ACTU to enhance
participation by individuals who otherwise may not be able to

Applicants that were funded as Minority Infrastructure Sites under
RFA 90-AI-04 should include a separate detailed budget for ACTG
protocol patients projected to be on study as of 9/93.  If an award
is made, this request may be negotiated to adjust for the actual
number of patients continuing on study at that time.


A detailed budget must be prepared for each laboratory component for
which funding is requested.  The budget for components B.1 (Option 1)
and B.2 are limited to $140,000 in direct costs/budget period
exclusive of equipment.  If applying for B.1 (Option 2 or 3), the
total direct costs are limited to $70,000/budget period.

Part B.1:  Virology

Option 1:  As a comprehensive virology laboratory, include all
personnel, equipment, supplies etc in the budget.

Option 2:  Include all personnel, equipment, supplies etc for
performing p-24 antigen and PMBC cultures as part of the ACTU.
Additionally, include the costs of processing (personnel and
supplies) and shipping the other virology samples to another ACTG
laboratory.  The total costs for the samples that will be assayed on
a fee-for-service basis should be included in the "Other Expenses"

OPTION 3:  The costs of processing (personnel, supplies) and shipping
the samples should be included.  The total costs for all the tests
performed on a fee-for-service basis should be included in the "Other
Expenses" category.

Part B.2:  Pharmacology

No special instructions.


Detailed budgets must be prepared for each Developmental Research
component for which funds are requested.  Total budget requests for
developmental research are limited to $100,000 in direct costs/budget

Application Preparation and Submission:

The research grant application form PHS 398 (Rev. 9/91) is to  be
used in applying. These forms are available at most institutional
offices and from the Office of Grants Inquiries, Division of Research
Grants, National Institutes of Health, Westwood Building, Room 449,
5333 Westbard Avenue, Bethesda, MD 20892, telephone:  (301) 496-7441.

It is important to follow the instructions for preparing the
application as described in both the PHS 398 form and in this RFA.
Failure to do so may result in an application with insufficient
information for appropriate scientific review.

For purposes of identification and processing, the RFA number and
INSTITUTIONS", respectively, should be typed on line 2a of the face
page of the application form and the "YES" box should be marked.  The
type of grant program (2b) is U01.  The RFA label available in the
PHS 398application form must be affixed to the bottom of the face
page of the application.  Failure to use this label could result in
delayed processing of the application such that it may not reach the
review committee in time for the review.

Submit a signed, typewritten original of the application and three
exact, single-sided photocopies (including the Appendices), in one
package to:

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


Dr. Dianne Tingley
Scientific Review Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD  20892

Applicants who use express mail or courier service should substitute
Rockville, MD 20852 for the city, state, and zip code

The deadline for receipt of applications is January 21, 1993.
Applications received after this date will be returned to the
applicant without review.


A.  Review Procedures

Upon receipt, applications will be reviewed by the DRG staff for
completeness and the NIAID staff for responsiveness.  Incomplete
applications and those judged to be unresponsive to the RFA will be
returned to the applicant without further consideration.  Examples
that will result in the application being considered nonresponsive
include, but are not limited to:  (1) failure to address all required
items of the RFA, and (2) submission of optional components that are
not presented as separate narratives with separate budgets.

Those applications that are complete and responsive may be subjected
to triage by a Special Review Committee (SRC) to determine their
scientific merit relative to other applications received in response
to this RFA.  The NIH will administratively withdraw from competition
those applications judged to be noncompetitive, and notify the
applicants and the institutional business officials.  Those
applications judged to be competitive will undergo further evaluation
for scientific merit by a Special Review Committee consisting
primarily of non-Federal scientific experts.  To the extent possible,
those reviewers comprising the triage group also will participate in
this review.  The second level of review will be provided by the
National Advisory Allergy and Infectious Diseases Council.

The overall priority score for the application assigned by the
Special Review Committee will be based on the technical merit of the
required components and any optional clinical components contained in
Part A.  The technical merit of the optional laboratory components
will evaluated independently from the required components.

B.  Review Criteria

The following factors will be considered in the scientific and
technical review of:

AIDS Clinical Trials Unit, PART A:

o  Expertise and experience in conducting clinical trials research;

o  Adequacy of scientific understanding of the problem as evidenced
by the plan for proposed studies to evaluate interventions for HIV
infection, opportunistic infection, and other optional clinical
specialties (Phase I studies, oncology, neurology);

o  The qualifications and expertise of the Principal Investigator and
key personnel as evidenced by past experience in conducting clinical

o  Adequacy of the proposed administrative and organizational
structure of the ACTU;

o  Administrative experience of the Principal Investigator
and key staff in managing clinical trials programs;

o  Adequacy of the physical facilities available to the proposed
clinical trials unit, including subunits, and the
physical/administrative relationship of the proposed ACTU to primary
care clinics;

o  Quality of the outreach/recruitment plan for the accrual of

o  Quality of the plan for the recruitment of underrepresented groups
to AIDS clinical trials;

o  Strength of the ancillary services and linkages that will enhance
the functioning of the proposed ACTU;

o  Quality of the data management plan;

o  Quality of the pharmacy plan;

o  Quality of the laboratory capability for immunophenotyping.

Laboratory Support for Clinical Trials, PART B (Virology, and
Pharmacology Laboratory Support):

o  Adequacy of the scientific/technical approach;

o  Evidence of an understanding of the scope of scientific issues;

o  Ability to perform the minimum number of required assays;

o  Prior participation or experience in quality control programs;

o  Adequacy of the procedures for storage and handling of samples;

o  Qualifications, expertise, experience and time commitment of the
Laboratory Director and key personnel;

o  Adequacy of the available resources and facilities.

o  Developmental Research, PART C:

o  Originality and uniqueness of proposed research

o  Adequacy of the scientific/technical approach

o  Relevance of the research to the clinical objectives of the ACTG

o  Availability of required clinical samples

o  Qualifications, expertise, experience and time commitment of the
Project Director and key personnel

o  Adequacy of the available resources and facilities.


The predominant criterion for funding priorities will be the
scientific and technical merit of the application as judged by peer
review.  After the applications have been approved by the NIAID
Advisory Allergy and Infectious Diseases Council, staff reserves the
right to give consideration to the following additional factors in
the final selection of applications to be funded: (1) inclusion of
populations currently underrepresented in clinical trials; (2) HIV
prevalence/geographic distribution; (3) cost effectiveness of
conducting clinical trials; (4) the overall capacity of funded
institutions, in aggregrate, to carry out the research objectives of
the group.  Funding decisions for Part A will be made independent of
funding decisions for the optional laboratory components B.2, and C.1
- C.4.


Written and telephone inquiries concerning this RFA are encouraged.

Direct inquiries on programmatic issues to:

Frederick Batzold, Ph.D.
Clinical Research Management Branch
Division of Acquired Immunodeficiency Syndrome
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2A09
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-82148

Direct inquiries concerning budgetary issues to

Ms. Mary Kirker
Grant Management Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Rm. 4B22
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075

Direct inquiries regarding review requirements and issues to

Diane Tingley, Ph.D.
Scientific Review Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818


Letter of intent receipt date:  November 16, 1992
Application Receipt Date:       January 21, 1993
Special Review Committee:       March 15, 1993
NIAID Advisory Council Review:  June 23, 1993
Anticipated Award Date:         September 1, 1993


This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.856 - Microbiology and Infectious Diseases
Research and 93.855 - Allergy, Immunology and Transplantation
Research.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A, Public Law 78-410 as amended, and
administered under PHS grants policies and Federal Regulations 42 CFR
52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12371 or
Health Systems Agency Review.


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