Subject: NIH GUIDE - RFA AI-91-10 - V20(25) 06/28/91 - P1/2
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Fri, 28 Jun 91 10:28 EST

Hi Paul,
This is part 5 of 6 of this week's NIH Guide.  Please post to the
NIH Listserver as RFAAI-91-10(P1).910628.
             Thanks, Mary Broaddus
 
$$XID RFA AI9110 AI-91-10 P1O2 *****************************************
 
REQUEST FOR APPLICATIONS
 
EXPANSION OF THE PEDIATRIC AIDS CLINICAL TRIAL UNITS
 
RFA:  AI-91-10
 
P.T. 34; K.W. 0715008, 0785170, 0755015
 
National Institute of Allergy and Infectious Diseases
 
Application Receipt Date:  September 13, 1991
 
The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications from domestic institutions for the expansion of the
pediatric AIDS Clinical Trial Units.  Reissuance of this initiative in
future years is not anticipated until the end of the project period to
be funded under this competition.
 
Healthy People 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000," a
PHS-led national activity for setting priority areas.  This RFA,
Expansion of the Pediatric AIDS Clinical Trial Units, is related to the
priority area of HIV infection.  Potential applicants may obtain a copy
of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, D.C. 20402-9325 (telephone 202-783-3238).
 
I. INTRODUCTION AND RESEARCH OBJECTIVES
 
The Division of AIDS (DAIDS), NIAID, currently supports a pediatric AIDS
clinical therapeutic trials program.  This effort consists of 15
institutions that conduct clinical trials in pediatric AIDS Clinical
Trial Units (pediatric ACTUs) and 12 institutions that conduct pediatric
trials as a part of a larger research effort in adult AIDS Clinical
Trial Units (adult ACTUs).  Collectively, these pediatric ACTUs and
pediatric components of adult ACTUs comprise the pediatric AIDS clinical
trials program of the DAIDS.  The pediatric AIDS clinical trials program
operates within the framework of the larger DAIDS-supported AIDS
Clinical Trials Group (ACTG) that consists of three major components:
grant and cooperative agreement funded clinical trial institutions, the
DAIDS Treatment Research Program (TRP), and the Statistical and Data
Analysis Center (SDAC).
 
The research objectives of the pediatric clinical trials program are:
to provide an effective and efficient system to evaluate the safety and
efficacy of therapeutic interventions against HIV infection, AIDS, and
its associated conditions in children and adolescents; to ensure that
questions of the highest scientific priority will be selected, primarily
by the participating investigators with the assistance of the NIAID; to
develop new agents from initial trials in pediatric patients to their
final approval by the Food and Drug Administration (FDA); and to
facilitate transfer of effective therapies from the research setting to
routine patient care.  These goals are accomplished through the accrual
of pediatric patients into trials, analysis of the results of these
trials, and publication of their findings.  Throughout this process, the
participation of awardee clinical investigators from individual clinical
trial units with substantive programmatic involvement of the NIAID under
the cooperative agreement mechanism (see Section VI, MECHANISM OF
SUPPORT) is key to the ACTG efforts.  This participation is best
exemplified by the unique role these investigators play on the
Scientific, Resource, and Executive Committees of the ACTG.
 
For a complete description of the current structure and function of the
ACTG, see Appendix II.  Applicants are strongly encouraged to read this
Appendix before preparation of an application.
 
II.  PURPOSE
 
The purpose of this Request for Applications (RFA) is to provide support
for the expansion of the pediatric AIDS clinical trials program through
the establishment of new pediatric clinical trial units.  Pediatric
components of adult ACTUs that are currently enrolling patients,
subunits of pediatric ACTUs currently enrolling patients, and new
applicants are invited to apply.  Upon funding, each new unit will be a
free-standing pediatric unit, thus the Principal Investigator is
expected to be a pediatrician.  This RFA specifically addresses the
requirements for ancillary services including outreach for pediatric and
adolescent populations.  While the inclusion of adolescents is
encouraged, the main thrust of the RFA is on infants and children.  We
expect that applications will include obstetricians and their services
as a part of the research team.  Applications considered responsive to
this RFA must demonstrate a capability to conduct pediatric clinical
trials and provide the necessary ancillary services and outreach for
HIV-infected infants, children, adolescents and their families.  The
ancillary services are specified under "Specific Instructions - Section
2.5."  The RFA focuses on these ancillary services because of the
critical link between provision of such services and the ability to
recruit and maintain pediatric patients in clinical trials.  Because of
the increasing incidence of maternal-fetal transmission, applicants are
required to describe the capability to conduct perinatal transmission
studies or plans to develop such capability.  Needs for increased
attention to studies of primary HIV infection, opportunistic infections,
neurologic complications of HIV infection, and enrollment of
HIV-infected adolescents into clinical trials must be addressed.  Strong
emphasis will be placed on the enrollment of study participants from
populations currently underrepresented in clinical trials (e.g., infants
and children of minority women and substance abusers and disenfranchised
youth).
 
III.  OVERVIEW OF CLINICAL TRIALS COMPOSITION
 
The pediatric component of the ACTG is composed of the network of
pediatric ACTUs funded as cooperative agreements.  In addition, the
National Institute of Child Health and Human Development-sponsored sites
and the National Hemophilia Foundation are participating within the ACTG
framework.
 
Investigators and staff at pediatric ACTUs participate in the ACTG
effort by enrolling patients into ACTG pediatric protocols, by
participating in ACTG pediatric activities, by developing concept sheets
for studies to advance the scientific agenda for HIV infection and its
complications in pediatric patients, and through substantial
programmatic involvement of NIAID staff (see Section VII, TERMS OF
AWARD).
 
Under the terms of this RFA, funds will be provided to pediatric ACTUs
on the basis of research activities, provision of crucial ancillary
services and outreach required to recruit and maintain this special
population, essential personnel, equipment, patient care costs, and
supplies necessary to enroll and retain an agreed-upon number of
infants, children, and adolescents into an array of pediatric clinical
trial protocols each year of grant support.  For the first year of
funding, applicants will use the examples of existing pediatric
protocols provided in this RFA to construct budgets (Section V).  In
future years, the cost of new protocols will be estimated in advance so
that budgets will reflect the number of new pediatric patients, the
number of pediatric patients continuing on study, and the cost of the
individual pediatric protocols in which the unit will be participating.
This funding is designated as Clinical Core Funding.  The majority of
this clinical core support will be dispensed at the beginning of each
annual fiscal period.  Following a mid-period review of accrual and
other performance factors, a decision will be made by NIAID staff about
releasing the balance of the Clinical Core Funding for that budget
period.  In addition, at the time of the annual non-competing
application, budgets for Clinical Core Funding will be reviewed and may
be adjusted depending upon the complexity and costs of protocols to be
undertaken by the pediatric ACTU and the unit's performance record, in
accord with the priorities of the ACTG and NIAID.
 
In each budget period, a portion of the total ACTG pediatric budget may
be set aside and designated as Incentive Funding.  These funds will be
awarded as administrative supplements after NIAID staff review, or as
competing supplements, consistent with NIH and NIAID policies, during a
budget period and will support activities including, but not limited to,
the following:  (1) augmenting awards to pediatric ACTUs able to accrue
a greater than expected number of patients into high-priority protocols;
(2) availability in mid-period of priority protocols established by the
ACTG and the NIAID that require funding not included in the Clinical
Core Funding budget; and (3) providing limited support to institutions
whose investigators contribute a substantial amount of uncompensated
time and effort to ACTG committees or other program activities.
 
IV.  SPECIAL INSTRUCTIONS FOR PREPARING ACTU APPLICATIONS
 
Form PHS 398 (rev. 10/88) must be completed, but special attention must
be given to the following:
 
A. Page 1 of Form PHS 398
 
Complete items 1-18 as instructed.  Please note that this must be Page 1
for the entire application and that all succeeding pages must be
numbered consecutively.
 
Complete line 2 of the application face page by checking the YES box and
inserting the title and number of this RFA, "Expansion of the Pediatric
AIDS Clinical Trials Units, AI-91-10."
 
Items 7 and 8:  The requested budget must represent the TOTAL budget of
the entire application including Clinical Core Funding, funding for
continuing patients, and virology and/or pharmacology laboratory support
if included in the application.
 
Item 12:  Only domestic organizations are eligible to apply and
applicant organizations may not include an international component,
including subunits, as part of the application.
 
B. Page 2 of Form PHS 398
 
The abstract must contain a brief summary of the proposed work and
objectives for the application.
 
C. Page 4 of Form PHS 398
 
Justification for budget elements must be presented.
 
D. Page 5 of Form PHS 398
 
A summary total budget (personnel, equipment, and supplies) for all
years of requested support must be presented on page 5.  Justification
for the budget elements must be presented.
 
E. Biographical Sketches
 
Prepare biographical sketches for all professional personnel
participating in the pediatric ACTU for which support is requested using
the appropriate page from the form PHS 398 and applying the same page
limitations.  The biographical sketches, with the Principal Investigator
first and those of the other key professional personnel following in
alphabetical order, must be placed at the end of the application,
appropriately numbered and referenced in the Table of Contents.
 
The cooperative agreement application, including the narrative and
itemized budget with justification, must be assembled and paginated as
one complete application.
 
V. PEDIATRIC CLINICAL TRIALS UNIT
 
The structure and functions of the ACTG (ACTUs, TRP, and SDAC) will be
retained, as described in Appendix II.  However, the major changes will
be the linkage between ACTU performance and funding and the required
provision of ancillary services (including outreach) for recruitment and
retention of pediatric patients on clinical trials.  Following are those
elements of change that specifically apply to the pediatric ACTUs.
 
PROCEDURES FOR COSTING PEDIATRIC PROTOCOLS
 
Pediatric protocols will be developed following the same procedures
outlined in Appendix I (i.e., proposed studies summarized as concept
sheets that are reviewed, approved, and prioritized by the appropriate
ACTG Scientific Core Committee and the ACTG Executive Committee whose
membership includes the Associate Director, TRP; approved concept sheets
are then developed into protocols).
 
Pediatric protocol development will be modified in that the total per
capita cost of each patient accrued to the study for its duration will
be determined for a new protocol before initiation of the study.  Thus,
consideration of cost effectiveness and appropriate utilization of
available resources will be a part of the NIAID approval process for new
pediatric protocols.
 
For the first year, applicants will provide budgets based on costs
determined for the two sample pediatric protocols provided in the RFA.
For future budgets, as new costed protocols are introduced, costs for a
new study will be determined by relating the new study to one of the two
sample protocols to which it is most closely related and for which the
applicant has previously submitted a cost estimate.  In instances where
a subunit's costs structure differs from that of the parent unit,
protocols must be costed for the subunit.
 
REVISION OF THE PEDIATRIC ACTU ADMINISTRATIVE FRAMEWORK
 
Clinical Core Funding
 
Clinical Core Funding consists of those resources required to maintain
an infrastructure and ancillary services sufficient to accrue a
projected minimum number of new pediatric patients each year.  Clinical
Core Funding will include costs for provision of ancillary services and
outreach, research and research support, personnel, supplies/equipment,
patient care, laboratory support for protocol-mandated
immunophenotyping, and costs for virology and/or pharmacology tests if
these are to be performed at another site.
 
Clinical Core funding will be based on the projected number of new
pediatric patients to be accrued each year.  For pediatric subunits or
pediatric components of existing adult ACTUs that do not currently have
pediatric support, the budget must include funds for continuing
pediatric patients accrued prior to this RFA and who are still being
actively followed as part of an ACTG protocol.  Each applicant must
prepare a Clinical Core budget sufficient to accrue a minimum of 25 to a
maximum of 50 new pediatric patients per year.  The budgets will be
constructed using the cost of individual ACTG protocols to which
pediatric patients may be enrolled and the number of pediatric patients
expected to be accrued to that protocol (see Section V) for additional
details on the costing of protocols and direction on the construction of
the budget).  Clinical Core Funding for each new pediatric patient must
include the total cost of follow-up for the entire duration of the
patient's time on study.
 
Clinical Core Funding to pediatric ACTUs will be administered in the
following manner:  the majority of Clinical Core 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
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 pediatric ACTU
performance (e.g., failure to meet accrual goals, failure to institute
ancillary and outreach services), 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.
 
Incentive Funding
 
A portion of the total ACTG pediatric budget may be set aside each year
for Incentive Funding.  These funds will be used to support activities
such as:
 
a. funding for personnel or patient care costs for pediatric ACTUs that
are able to EXCEED the target accrual goal to ACTG and NIAID-designated
high-priority protocols; upon approval by the NIAID, a pediatric ACTU
may apply for Incentive Funding;
b. initiating a high-priority protocol or to focus on a scientific area
during a budget year for which resource needs exceed the clinical base
funding of individual ACTUs;
c. funding for awardee institutions to supplement costs incurred as a
result of substantial uncompensated participation by investigators in
ACTG activities (e.g., travel or other program work, such as a chair of
an ACTG scientific committee).
 
Incentive Funding will be awarded either as administrative supplements,
after review by TRP and DEA staff, or as competing supplements.  The
criteria for these awards include performance and special needs as
described under c, Incentive Funding.
 
PEDIATRIC CLINICAL TRIALS UNIT - INSTRUCTIONS FOR FORM PHS 398 (revised
10/88)
 
THE FOLLOWING INSTRUCTIONS REPLACE THOSE GIVEN IN FORM PHS 398 (REVISED
10/88); OTHERWISE INSTRUCTIONS IN THE FORM MUST BE FOLLOWED:
 
SPECIFIC INSTRUCTIONS - SECTION 1
 
Form Page 4
 
Construction of a Detailed Budget:
 
Appendix III contains guidelines for developing Core Budgets for
pediatric units.  Core Budgets must support obstetrical and perinatal
services as well as the ancillary services, including outreach,
necessary to recruit and retain pediatric patients onto ACTG protocols.
 
Appendix IV contains descriptions of two current ACTG pediatric
protocols of different complexity and scope, from a small phase I study
to a large phase III efficacy study.  These two protocols represent the
range of costs of ACTG pediatric protocols, from uncomplicated
outpatient studies to complicated labor-intensive inpatient studies.
Using the form "COST OF CLINICAL TRIALS" (Appendix IV), applicants must
calculate and list the institutional direct cost per patient for the two
protocols.
 
The Clinical Core Funding budget will be constructed by projecting the
total number of patients expected to be accrued to one or both of the
protocols (or any existing ACTG pediatric protocol of similar phase,
complexity, scope, and resource requirements).  As examples of the scope
of pediatric studies performed by the ACTG, Appendix V contains a
listing of ACTG pediatric protocols by title that are currently open to
enrollment.  The Clinical Core budget total provided in applications
from pediatric subunits or pediatric components of existing adult ACTUs
that do not currently have pediatric support must include support for
continuing patients.  The budgets for continuing pediatric patients must
be presented on a separate form PHS 398 budget page.
 
Pediatric clinical trial units may be formed 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 providing the necessary
ancillary support services, including outreach, and for recruiting and
retaining pediatric patients on clinical trials; (2) to contribute to
the performance of the awardee institution (the Main Unit) by providing
access to patient populations (e.g., infants and children of minority
women and substance abusing women, and disenfranchised youth), not well
represented at the Main Unit.  These collaborating institutions would be
designated as Subunits, although ultimate financial and scientific
responsibility would reside with the Main Unit.  (Appendix VI contains
Guidelines for Establishment of Subunits).
 
Additionally, the clinical core budget must include costs required to:
 
a. collect, log, process, store, and ship clinical specimens to
designated ACTG-certified virology and pharmacology core laboratories as
required by ACTG pediatric protocols; and
 
b. maintain ACTG specimen inventories and storage facilities and
cooperate in all ACTG batch-testing efforts by shipping specimens to
designated ACTG-certified virology and pharmacology core laboratories as
required by ACTG pediatric protocols.
 
Efficient use of funds for clinical trials will be a major determinant
of award levels.
 
SPECIFIC INSTRUCTIONS - SECTION 2
 
IN PLACE OF ITEMS A-D OF THE RESEARCH PLAN, APPLICANTS FOR PEDIATRIC
ACTU AWARDS MUST DEMONSTRATE THE FOLLOWING MINIMUM REQUIREMENTS:
 
1.  PROFICIENCY IN PEDIATRIC THERAPEUTIC CLINICAL TRIALS (2-3 pages)
 
The applicant must describe the extent and scope of previous pediatric
clinical trials experience, especially experience involving HIV
infection and its complications in infants and children.  Information
needed for the evaluation of proficiency must include the following:
 
a. Applicants not previously associated with the ACTG:
 
1) describe clinical trials experience in terms of kinds of studies;
provide a breakdown and numbers of infants, children and adolescents,
patients, including disease state and demographic features;
2) describe how data management was performed and the data quality
assurance program in effect;
3)    list all related publications;
4) describe the level of scientific participation in the study (e.g.,
protocol design, oversight, analysis of data, and/or presentation and
publication of results).
 
b. Applicants who are Pediatric Subunits, Components of Existing ACTUs,
or NICHD-funded units:  (where applicable, NIAID will provide to the
Review Committee copies of ACTU Institutional Evaluation Reports and
accrual statistics)
 
1) describe in detail scientific contribution to the ACTG, including
chairing or participating on committees, protocol chairs, concept sheet
submissions, laboratory effort, and serving on working groups;
2) provide the total accrual of the parent ACTU and state what
proportion was contributed by the subunit (e.g., component);
3) list the ACTG protocols in which the pediatric subunit (e.g.,
component) participated, including the number and demographic features
of patients accrued;
4) describe the system of data management used (i.e., data entry at the
subunit or transfer of case report forms or other data to parent unit)
and the quality assurance program in place at the subunit;
5) relate any extenuating circumstances or other situations that might
have affected the subunit's performance as reflected in the evaluations;
6) describe previous efforts to develop consortium arrangements with
health care facilities/services that serve the target populations (e.g.,
infants and children of minority women and substance abusing women, and
disenfranchised youth) not well represented at the ACTG unit.
 
2.  ADMINISTRATIVE AND ORGANIZATIONAL STRUCTURE FOR CONDUCT OF PEDIATRIC
CLINICAL STUDIES (6-12 pages)
 
The applicant must detail the essential features necessary for
performance of pediatric clinical studies, including organizational
structure, qualifications of key personnel, and facilities.  The
narrative must specifically address the following:
 
a. Organization - structure of pediatric clinical trials unit and its
administrative relationship with the parent institution; describe
whether the pediatric clinical trials unit is an integral part of the
patient care activities of the institution or is constituted as a
separate research unit.  The applicant must describe how studies of
acute illness requiring inpatient care will be conducted, in addition to
the plan for outpatient studies.  The relationship with obstetrical and
other units caring for HIV-infected women must be described.
 
b. Facilities - a description of space available for performing both
outpatient and inpatient pediatric clinical studies at the main
pediatric ACTU and any subunits must be included; describe the patient
care area where pediatric study subjects would receive care (e.g.,
primary, obstetrical, and perinatal) and ancillary services (e.g.,
outreach counseling, child care, and transportation) if different from
the clinical trials unit.  The availability of a General Clinical
Research Center (GCRC) for the clinical trials must be noted (see
Section V, 11, Linkages).
 
c. Personnel - describe key personnel listed on budget page 4.
Describe, in detail, the personnel for delivery of ancillary services
(e.g., outreach workers, paraprofessionals [sites may want to use
ex-drug abusers, and ex-prostitutes], additional social workers and
psychologists/counselors).  In addition to the personnel listed on this
page, describe the type, number, and qualifications of any other
personnel who might assist in the conduct of the studies, e.g.,
physicians or other health care personnel in training,
institution-supported administrative or health care personnel, State-or
municipal-supported personnel, community volunteers, or others.
Culturally sensitive individuals representative of the target
population(s) must be represented among staff for delivery of ancillary
services.
 
d. Programmatic Reporting - Provide examples of progress reports
submitted for other clinical trials activities.
 
The following are requirements for submitting interim progress reports.
Reports will be required at the end of five months following the budget
period start date on the notice of award.  Each report will consist of:
a cover page (include grant number, period of performance, name and
address of the awardee, and date of submission); a brief description of
the work performed during the reporting period; problems and their
resolution; and a brief narrative explaining any differences between
planned and actual progress.
 
3.  SCIENTIFIC TYPES OF STUDIES (5-7 pages)
 
Studies of treatment and prophylaxis of perinatal transmission, primary
HIV infection, and opportunistic infections will continue as
high-priority areas and ALL applicant institutions must participate in
such studies.  Sites that have suitable expertise and appropriate
patients for any of the above areas, including neurodevelopmental
expertise, must include in the Clinical Core budget support for
necessary personnel.  It is important that most pediatric antiviral
trials currently under consideration in the ACTG include extensive
neuropsychological testing.  In this section the applicant must address
the following:
 
a. Describe the plan for participation in high-priority areas:
 
1) perinatal transmission
2) primary HIV infection
3) opportunistic infections
4) neurologic complications of HIV infection
5) HIV-associated malignancies
 
b. Qualifications of key personnel necessary for each area of emphasis
(in addition to personnel described in 2.c. above and on budget page 4)
c. Special scientific expertise, facilities, or other unique features
the proposed site might offer to the ACTG effort in reference to the
designated scientific areas of emphasis.
 
4.  TYPES OF PROTOCOLS (2-3 pages)
 
ACTG pediatric protocols vary both in terms of type (i.e., phase I, II,
or III) and in complexity.  It is the expectation of the NIAID that each
ACTU will accrue mainly pediatric patients across the range of phase I,
II, and III studies.  This section must estimate how the projected total
accrual of pediatric patients in the first year will be distributed
among the types of clinical trials (i.e., phase I, II, and III).
 
5.  ANCILLARY SERVICES/ACCRUAL AND RETENTION PLAN (7-9 pages, plus
supporting letters)
 
Applicants must delineate in a clear, concise plan the delivery of
ancillary services, outreach, and health care.  The plan must address
the following issues:
 
a. Provide evidence of commitment to the provision of ancillary services
(e.g., language interpretation, child care, patient transportation
to/from the research center, support groups, and counseling) and
outreach to pediatric patients and their families in their own
communities and/or at community health care facilities serving these
populations.  This may involve the establishment of subunits or other
contractual arrangements in order to facilitate delivery of these
multidisciplinary services at the community level and at the same time
enhance recruitment and retention of pediatric patients onto clinical
trials.  Letters of agreement in support of these linkages, as well as
definitive plans to operationalize the linkages, must be provided.
 
b. Demonstrate a capability of working with the economically deprived in
order to address issues regarding foster care, informed consent in
guardianship situations, entitlement needs, and family dynamics.
Because the majority of pediatric HIV infection is perinatally acquired
and occurs in low socioeconomic settings, this experience is necessary.
 
c. Demonstrate a capability in working with the community and community
organization programs serving the target population.  Evidence of this
could be the presentation of a plan developed jointly between the
applicant and a community based organization.
 
d. Provide evidence of commitment to the provision of personnel for
delivery of ancillary services (e.g., additional social workers,
psychologists/counselors, paraprofessionals [e.g., ex-drug users], and
outreach workers).  Culturally sensitive individuals representative of
the target population(s) must be included among personnel.
 
e. Document the capability to access the projected number of pediatric
patients into ACTG studies.  Each applicant must project a minimum
number of patients to be accrued in the first year, a number that
defines the size of the budget.  Accrual of a minimum of 25 pediatric
patients/year to ACTG studies is necessary to qualify as a prospective
clinical trials unit (see Section V for information on accrual goals).
Each applicant must consider the following issues:
 
1) primary source of study subjects (i.e., inpatient or outpatient units
providing primary care, consultative services, HIV-testing sites,
referrals from community-based physicians or agencies, or other);
2) if referral, describe policies and procedures for communication,
provision of ancillary service, outreach and non-protocol related care,
follow-up by research staff or primary care provider, and transfer of
care back to primary care provider upon completion of study;
3) the amount of primary care provided by the research staff;
4) for new applicants, past records of clinical trials or data from
inpatient or clinic records showing number of patients under care (or
projected) and an estimation of percentage suitable for ACTG studies.
 
f. Describe the demographic features of pediatric patients in the
catchment area, including number of AIDS cases, HIV seroprevalence data,
sex, race/ethnicity, and risk transmission categories.  If available,
include a categorization of HIV status (asymptomatic, symptomatic, and
AIDS) for pediatric patients currently being seen or anticipated.
 
6.  PLAN FOR OBSTETRICAL AND PERINATAL RESEARCH (2-3 pages, plus
supporting letters)
 
Applicants must delineate a plan for the delivery of obstetrical and
perinatal care, in the context of clinical trials for the prevention of
perinatal transmission that necessarily involves the mother.  The plan
must address the following issues:
 
a. Describe the nature, organization, and relationship of the pediatric
unit and clinical sites providing obstetrical and perinatal care to
mothers and infants who will participate in studies of perinatal
transmission.
 
b. Describe the clinical trials research capability of each obstetrician
planning to participate in studies of perinatal transmission.  Include a
curriculum vitae and a list of publications for each individual.
 
c. Letters providing evidence of institutional commitment must be
included.
 
7.  PLAN FOR RECRUITMENT OF CHILDREN OF MINORITY WOMEN AND DRUG ABUSERS
(2-3 pages, plus supporting letters)
 
a. Consider the establishment of subunits or other formal arrangements
at patient care sites and drug treatment centers (see LINKAGES, Section
V, 11) that provide care or treatment for large numbers of HIV-infected
women, minorities, and their children (see Appendix V for Guidelines for
Establishment of Subunits).  Letters of agreement in support of subunit
or other formal arrangements must be included.
 
b. Describe a plan for outreach to pregnant females or mother target
populations.  If applicable, letters of agreement must be provided.
 
c. Describe a plan for the inclusion of infants and children of minority
women and substance abusers, disenfranchised youth, and persons with
hemophilia (or justification for not including adequate numbers of these
populations) in clinical studies.  These populations are currently
underrepresented in NIAID clinical trials.  This plan MUST project
inclusion of minorities (especially mothers/infants) in numbers that are
consistent with the demographic features of HIV infection among the
populations in the applicant catchment area (see Section V, Specific
Instructions - Section 2).
 
d. Describe the strategy and procedures for interaction with community
health care providers or agencies that have led, or is likely to lead,
to referral of HIV-infected women and minorities for clinical studies.
The number and type of staff who are culturally sensitive to the needs
of these populations and their children must be mentioned.  Letters of
agreement to support these interactions must be provided.
 
8.  DATA MANAGEMENT PLAN (3-5 pages)
 
a. Describe the plan for managing the clinical trials data from both
inpatient and outpatient studies, i.e., collection, entry, maintenance,
monitoring, storage, and transmission.
 
The plan for data storage must take into account that Federal
Regulations require the retention of research records for
investigational drugs for two years after a marketing application is
approved for the drug.  If an application for the drug is not approved,
the records must be retained for two years following discontinuation of
shipment and delivery of the drug and after the FDA has been notified.
 
The plan must include establishing procedures for:
 
1) staff education and training on the requirements of specific
protocols;
2) completion of the forms required for patient study visits (the time
from patient visit to data entry must be noted);
3) transcription of laboratory data from lab slips to data forms in
preparation for data entry;
4) data entry into the ACTG PC-based distributed data entry system in a
timely fashion;
5) design and maintenance of a filing system for patient charts and
completed data forms and ensuring the security of these files;
6) provision of adequate resources with respect to both staff and PC
hardware and software to accomplish these responsibilities.
 
The Data Manager should have a basic knowledge of PC hardware, software,
and DOS.
 
b. Describe a plan for establishing on-site quality assurance procedures
to assess the accuracy and completeness of all research records,
compliance with Federal Regulations regarding clinical trials (e.g.,
Institutional Review Board approval and informed consent process).
Assignment of dedicated personnel (e.g., 0.5 FTE research nurse or 0.5
FTE data manager with supervision by a research nurse) is strongly
encouraged.
 
c. The computer equipment that will be required for a clinical trials
unit is listed in Appendix VII.  Required equipment may be requested as
part of the application.
 
9.  PHARMACY PLAN (3-5 pages, plus supporting letters)
 
Each application must include a pharmacy plan that addresses the
development and maintenance of the investigational drug control system.
The pharmacy plan must include the guidelines set out in the ACTG
Pharmacy Manual (available upon request from the NIAID Operations
Office, contact Kim Adams at (301) 230-3150) and FDA regulations
involving the use of investigational drugs:
 
a. technical procedures for control of drug ordering
b. procedures for dispensing
c. procedures for accountability
d. drug storage
 
The plan must contain separate sections describing the details
applicable to each clinical trials site included in the application.
Letter(s) of agreement in support of the plan(s) from pharmacy personnel
at the participating institutions must be included.
 
Guidelines for levels of pharmacy commitment based on projected accrual
are included on the form, "PEDIATRIC ACTU CORE BUDGET," in Appendix III.
In addition, the cost of the pharmaceuticals and supplies that are not
provided by the ACTG must be included; e.g., parenteral solutions,
irrigation solutions, IV tubing, other supplies and materials, as well
as the costs associated with preparation of these medications.
 
10.  LABORATORY CAPABILITY (3-5 pages)
 
Described below are the requirements for flow cytometer, virology, and
pharmacology pediatric laboratories.  Applicants may perform these tests
in their own laboratories or purchase these services through certified
laboratories.
 
a. Immunophenotyping
 
Applicants must describe the capability of performing two-color flow
cytometry immunophenotyping using whole blood samples with analysis on a
laser-based instrument laboratory.  Laboratories must be capable of
analyzing a minimum annual number of 200 samples, including, but not
limited to, CD4, CD8, CD3, CD19, CD45, CD14, and others (e.g., CD25,
CD38, and DR,) as required in ACTG protocols.
 
Awardee laboratories will be required to participate in the ACTG quality
assurance (QA) program.
 
Whenever possible, use of existing ACTG-certified laboratories is
strongly encouraged.
 
The narrative description must contain the following:
 
1) prior laboratory experience with flow cytometry
2) description of equipment
3) qualifications of key laboratory personnel
4) description of internal QA program
5) involvement in multicenter QA efforts
 
b. Virology and Pharmacology
 
Applicants must describe the capability of performing protocol-mandated
virology (e.g., p24 antigen, and viral cultures) and pharmacology (e.g.,
AZT levels) tests.
 
Whenever possible, Use of existing ACTG-certified laboratories is
strongly encouraged.
 
Funds will not be provided to support personnel, equipment, or
facilities for the establishment of new flow cytometry, virology, and
pharmacology laboratories.  Support for existing laboratories will cover
incremental costs incurred as necessary to perform ACTG
protocol-mandated studies.
 
11.  LINKAGES (3-5 pages, plus supporting letters)
 
The following support linkages are either REQUIRED or ENCOURAGED:
 
a. Community Advisory Board (REQUIRED).  The purpose of a Community
Advisory Board (CAB) is to foster the interaction between the ACTU staff
and HIV-infected individuals in the community, in addition to community
health care providers and advocacy groups.  The goal of this interaction
is to communicate information about the pediatric ACTU, the clinical
trials, and the availability of investigational therapies and to receive
input about study design or any factor that might impact on patient
acceptance or compliance.  Describe the role and relationship of the CAB
to the research and operations of the applicant institution.  Specify
the composition of the CAB, including AIDS-related expertise of
participants, functions performed for the ACTU, and proposed meeting
schedule.  Inclusion of women and minorities is required; their
participation on the CAB should be reflective of the demographics of
HIV-infected persons in the catchment area.
 
b. General Clinical Research Center (ENCOURAGED).
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the National Center for Research Resources may
wish to identify the GCRC as a resource for conducting the proposed
research.  In such a case, a letter of agreement from either the GCRC
Program Director or the Principal Investigator must be included with the
application.
 
c. Health Resources and Service Administration (HRSA) Pediatric AIDS
Demonstration Project (REQUIRED).  An establishment of linkage with an
HRSA project to facilitate provision of comprehensive care if one is
located within the same standard metropolitan statistical area (SMSA) is
required and a letter of agreement and a plan describing the
relationship must be included.  (Appendix IX contains a listing of HRSA
AIDS Demonstration Projects).
 
d. National Institute on Drug Abuse (NIDA) Treatment and Research
Centers (ENCOURAGED) NIDA and NIAID collaborate in funding ACTG trials
in order to increase the number of HIV-infected drug users in ACTG
protocols.  Applicants are encouraged to establish linkages with NIDA
Treatment and Research Centers located in the same community.  In the
event that there is not a NIDA center in the catchment area, applicants
may establish linkage with drug treatment centers of the target
population.  (Appendix X contains a listing of the NIDA Treatment and
Research Centers).
 
e. Relationship with the National Institute of Child Health and
Development (NICHD).  Applicants from institutions that have a site
conducting clinical trials on pediatric AIDS funded by the NICHD or have
a site within the same SMSA will be required to include a letter of
agreement from the Principal Investigator of the NICHD site in which the
relationship between the two sites is described.  The following items
must be included:  screening/recruitment procedures for HIV-infected
children; whether facilities are shared; whether both sites are, or will
be, participating in ACTG protocols, and if so, how assignment to ACTG
protocols is, or will be, made.  To ensure economy of NIH-sponsored
clinical trials, applicants will not be funded by NIAID and NICHD at the
same site.
 
f. Relationship with the National Hemophilia Foundation (NHF).  As
stewards of the Federal budget, it is NIAID policy that applications
from institutions conducting clinical trials on pediatric AIDS under the
NHF contract will not be supported under this RFA.  Applicants having a
site within the same SMSA will be required to include a letter of
agreement from the Principal Investigator of the NHF site in which the
relationship between the two sites is described.  The following items
must be included:  screening/recruitment procedures for HIV-infected
children; whether facilities are shared; whether both sites are, or will
be, participating in ACTG protocols, and if so, how assignment to ACTG
protocols is, or will be, made.
 
Applicants are strongly encouraged to form other linkages including, but
not limited to:  community-based organizations that serve children at
increased risk for HIV infection, designated State AIDS Centers, NCI
lymphoma network, and community-based AIDS clinics.  A letter of
agreement for each linkage must be included with the application.
 
VI.  MECHANISM OF SUPPORT
 
Awards under this RFA will be made as cooperative agreements.
Assistance provided through the cooperative agreement differs from the
traditional research grant in that the Government component (NIAID)
anticipates substantial programmatic involvement during performance of
the award.  The interaction of NIAID staff with the investigators is
expected to facilitate the research.  There is no intent, real or
implied, for staff to direct a pediatric ACTU's activities or to limit
the freedom of investigators.  The nature of staff participation is
described in Section VII of this RFA under "TERMS OF AWARD:  NATURE OF
PARTICIPATION OF NIAID STAFF".  The Principal Investigator has the
responsibility for the planning, direction, and execution of the
proposed project, as well as publishing the results in a timely manner.
All policies and requirements that govern the grant program of the U.S.
Public Health Service and the National Institutes of Health apply to
these cooperative agreements.  It is anticipated that approximately six
to ten new pediatric ACTUs will be funded to supplement the current
pediatric clinical trial group.  Ongoing pediatric subunits or pediatric
components of adult ACTUs competing that are successful in competing for
these awards will cease as such.  The approximate total amount of this
RFA will be $7.6 million.  This level of support is dependent on the
receipt of a sufficient number of applications of high scientific merit
and availability of funds.  Awards will be made for a 12-month budget
period within a total project period of five years.  Continuation awards
for new budget periods within an approved project period will be made on
the basis of satisfactory performance and availability of funds.  The
anticipated award date will be February 14, 1992.  It is anticipated
that the NIAID will continue this program after the initial project
period through a competitive renewal of the cooperative agreements;
however, continuation is contingent upon available funds and NIAID
priorities.
 
Although this program is provided for in the financial plans of the
NIAID, the award of cooperative agreements pursuant to this RFA is also
contingent upon the continuing availability of funds for this purpose.
 
Interim progress reports will be required (see Specific Instructions -
Section 2 and Section X, Review Criteria) in addition to the
continuation application.  In each budget period, a report on scientific
and technical progress will be required at the end of five months
following the budget period start date on the notice of award.
Scientific and fiscal review must be completed before the funds for the
remainder of the budget period are released.  Interim funding
adjustments within the budget period may also be made.
 
VII.  TERMS OF AWARD
 
A. General Considerations
 
The ACTG investigators will be responsible for the overall conduct of
the studies performed.  The pediatric ACTU investigators will be
responsible for developing concept sheets for studies, protocol
development, the accrual of new patients, the retention of patients
enrolled on protocols, accrual to high-priority protocols, and
production of high-quality data and the publication of the research
results.  ACTU performance in each budget period will determine the core
budget award, release of increments of the core budget, and the amount
of Incentive Funding awarded during that budget period.  Accordingly,
the pediatric ACTU will submit interim progress reports, due at the end
of five months after the beginning of the budget period.  In addition,
the amount of the award made in future award years will be contingent
upon performance.  Inadequately justified performance, such as not
meeting minimum accrual goals without justification or poor quality of
data during a budget period, may result in reduction of future year
awards or interruption of support.
 
The ACTG clinical trials are assisted through four contracts that
provide technical and logistical support to the ACTUs (see Appendix
II.E.) These contracts that are administered by the TRP include:  (1) an
SDAC which is the main contract; 2) an Operations Office; 3) Clinical
Site Monitoring; and 4) a Clinical Research Products Repository.  The
SDAC, at the request of the ACTG Executive Committee, assists the ACTUs
in the statistical analysis and in the management of data resulting from
the participating ACTUs conducting studies.  Given this support, funds
for statisticians are not provided under this RFA.  The Operations
Office, at the request of the ACTG Executive Committee, assists the
investigators in the development of protocols, tracking the progress of
studies, and the development and maintenance of Standard Operating
Procedures of the ACTG.  Clinical Site Monitoring, at the request of the
Executive Committee, conducts periodic site monitoring to assess the
quality and completeness of the data collected at each ACTU.  The
Clinical Research Products Repository manages inventories of
investigational drugs and ships these drugs to the ACTU investigators at
their request.
 
The Principal Investigators and other key pediatric ACTU personnel will
attend regularly scheduled ACTG meetings in the Washington, DC area (or
at a site designated by NIAID), approximately three times per year.  In
addition, travel support will be provided for Principal Investigators to
attend special committee meetings.
 
B. Nature of Participation of NIAID Staff in the ACTG
 
The NIAID will assist the investigators as a component member of the
ACTG and will be represented by the TRP staff of the DAIDS.  The NIAID
scientific or program staff will provide assistance supporting
recipients of cooperative agreements by advice and coordination 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, as designated, will be responsible for 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, Pediatric Medical Branch, TRP, will assist in pediatric
     protocol development including assisting the Chief, Clinical
     Research Management Branch, TRP, with review of protocols 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 designed as priority studies by the ACTG Executive
     Committee and NIAID and providing 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  The Associate Director, TRP, 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, TRP, will assist
     in providing operational and data management support;
 
  o  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, 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);
 
  o  The Chief, Clinical Research Management Branch, TRP, will conduct
     on-site visits to review protocol accrual, 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, and distribution
of investigational agents from the government), NIAID will establish an
arbitration process to resolve major differences of opinion.  An
arbitration panel, composed of one pediatric 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 pediatric
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 NIAID will have access to all data generated under these cooperative
agreements 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 D. 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, 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 data base for a given
clinical trial and, therefore, will have limited scientific value.  The
investigators, with the assistance of 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, who must
follow the publication policies established by the ACTG.
 
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 pediatric
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.
 
VIII.  GENERAL REQUIREMENTS
 
Inclusion of Women and Minorities in Study Populations
 
NIH and ADAMHA (Alcohol, Drug Abuse and Mental Health Administration)
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, 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 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
U.S. 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.
 
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 clinical research applications 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.
 
IX.  REVIEW PROCEDURES
 
Upon receipt, applications will be reviewed by the Division of Research
Grants staff for completeness and the NIAID staff for responsiveness.
Incomplete applications will be returned to the applicant without
further consideration.  Failure to address all minimum requirements in
the Specific Instructions, Section 2 will result in the application
being considered nonresponsive.  If the application is not responsive to
the RFA, NIH staff will return it to the applicant.
 
Those applications that are complete and responsive will be evaluated in
accordance with the criteria stated below for scientific/technical merit
by an appropriate peer review group convened by the NIAID.  Those
applications 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 review criteria to be used are
identified below.  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 scientific
merit.  The second level review will be provided by the National
Advisory Allergy and Infectious Diseases Council.
 
X. REVIEW CRITERIA
 
The following factors will be considered in the scientific and technical
review of the application:
 
  o  Adequacy of the applicant to conduct pediatric therapeutic clinical
     trials;
 
  o  Adequacy of the organizational structure, including the
     relationship between the pediatric clinical trials unit and the
     parent institution and/or describe other consortium arrangements;
 
  o  Adequacy of the physical facilities available for performing both
     outpatient and inpatient pediatric clinical studies as well as the
     description of other patient care areas where pediatric subjects
     would receive non-protocol related care and ancillary services;
 
  o  Capability to provide as requested, but no less than every five
     months, to the NIAID Program Office, information regarding the
     following:  work performed during the reporting period; problems
     encountered and their resolution; and an explanation of any
     differences between planned and actual progress.  A cover page must
     be included.
 
  o  Competence and administrative experience of the Principal
     Investigator and key staff, including past experience, in
     conducting all types and phases of clinical trials (culturally
     sensitive individuals representative of the targeted population(s)
     must be represented);
 
  o  Adequacy of a plan for participation in proposed high-priority
     areas (e.g., perinatal transmission, primary HIV infection,
     opportunistic infections, neurologic complications of HIV
     infection, and HIV-associated malignancies);
 
  o  Strength of the provisions for ancillary services at the applicant
     institution, other subunits, or through contracts;
 
  o  Capability to access the projected number of pediatric patients and
     their demographic characteristics;
 
  o  Strength of the provisions for conducting obstetrical and perinatal
     research for the prevention of transmission of HIV from mother to
     infant;
 
  o  Plan for recruitment of children of minority women and substance
     abusers, disenfranchised youth, and children with hemophilia;
 
  o  Adequacy of the data management plan;
 
  o  Adequacy of the pharmacy plan;
 
  o  Adequacy of the laboratory capability with respect to
     immunophenotyping and the description of the capability to conduct
     protocol mandated virology and pharmacology tests; and
 
  o  Status of the support linkages.
 
XI. AWARD CRITERIA
 
Scientific merit and technical proficiency based on the demonstrated and
projected capabilities described in the applications in response to this
RFA will be the predominant criteria for determining funding priorities.
However, after applications have been approved by the NIAID Advisory
Council, staff reserves the right to give consideration to the following
factors in the final selection of applications to be funded:  inclusion
of populations currently underrepresented in the pediatric ACTUs
(infants and children of minority and drug abusing women,
disenfranchised youth, and children with hemophilia) so that the ACTG
reflects the demographic features of the nationwide HIV epidemic among
pediatric populations; HIV-AIDS incidence/geographic distribution; and
cost effectiveness of conducting ACTG clinical trials.
 
XII.  METHOD OF APPLYING
 
Receipt Date
 
The deadline for receipt of applications is September 13, 1991.
Applications received after this date will be 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) must be used
in applying.  These forms are available at most institutional business
offices or from:
 
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 form PHS 398 and in this RFA.  Failure to do so
will result in an application with insufficient information for
appropriate scientific review.
 
Complete line 2 of the application face page by checking the YES box and
insert the title and number of this RFA, "Expansion of the Pediatric
AIDS Clinical Trial Units, AI-91-10."
 
Submit a signed, typewritten original of the application, and six exact,
single-sided photocopies (including the Appendices), in one package to:
 
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
o Use the mailing label contained in the application package.
 
o Submit 17 exact, single-sided photocopies of the application, in one
package directly to:
 
Dr. Allen C. 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) 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.
 
XIII.  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 Issues
 
Allen Stoolmiller, Ph.D.
Address as indicated above (Room 3A-07)
Telephone:  (301) 496-7966
 
Responsiveness to RFA
 
Tina Johnson, M.A.
NIAID/DAIDS/TRP/CRMB
6003 Executive Boulevard, Room 201W
Rockville, MD  20892
Telephone:  (301) 496-8214
 
Budget Questions
 
Ms. Jane Unsworth
Grants Management Branch
National Institute of Allergy and Infectious Diseases
Westwood Building, Room 706
Bethesda, MD  20892
Telephone:  (301) 496-7075
 
XIV. SCHEDULE
 
Application Receipt Date:     September 13, 1991
Special Review Committee      Week of October 14, 1991
NIAID Advisory Council Review:      January 23-24,1992
Anticipated Award Dates:            February 14, 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.  Cooperative
agreements 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 grants policies and Federal Regulations 42 CFR 52
and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems
Agency review.
 
                  APPENDICES
 
  I.  Structure and Functions of the ACTG
 
 II.  Guidelines for Pediatric Clinical Core Budget
 
 III. Sample ACTG Protocols and Costing Forms
 
  IV. ACTG Pediatric Protocols
 
  V.  Guidelines for Establishing Subunits
 
 VI.  Required Computer Equipment
 
VII.  CPCRA Sites
 
VIII. HRSA Demonstration Projects
 
  IX. NIDA Drug Abuse Treatment Research Units and Centers
 
                              APPENDIX I
 
             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 I
 
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
the Statistical and Data Analysis Center (SDAC) and other support
contracts.
 
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 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 target
specifically 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 initially were 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 data base management system.
 
1.  Establishment of 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, TRP; and (3) the SDAC and
other contracts (e.g., Operations Office) 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