Full Text AI-96-001
 
PEDIATRIC AIDS CLINICAL TRIALS GROUP
 
NIH GUIDE, Volume 25, Number 4, February 16, 1996
 
RFA:  AI-96-001
 
P.T. 34

Keywords: 
  Clinical Trial 
  AIDS 
  Children (Patients) 

 
National Institute of Allergy and Infectious Diseases
 
Letter of Intent Receipt Date:  March 27, 1996
Application Receipt Date:  June 11, 1996
 
PURPOSE
 
The Division of AIDS (DAIDS) of the National Institute of Allergy and
Infectious Diseases (NIAID) announces the availability of a Request
for Applications (RFA) to establish a multisite Pediatric AIDS
Clinical Trials Group (PACTG).  The purpose of this RFA is to solicit
applications from institutions interested in participating in a
cooperative group to plan, direct, and conduct Phase I, II, and III
clinical trials.  These clinical trials will address high priority
research questions on the treatment and prevention of human
immunodeficiency virus (HIV) disease and its sequelae.  The focus
will be on:  (1) treatment of primary HIV disease, (2) interventions
designed to prevent perinatal transmission of HIV, and (3)
prophylaxis and treatment of opportunistic infections.  Modalities of
intervention may include, but are not limited to: (1) drugs or
combinations, (2) active and/or passive immune based therapies, (3)
immunomodulators, and (4) gene transfer techniques.
 
The initiative targets HIV infected and perinatally exposed infants,
HIV infected children, HIV infected pregnant women at risk of
transmitting HIV to the infant, and HIV infected adolescents, when
therapeutic research questions specific for this age group are
identified.
 
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,
Pediatric AIDS Clinical Trials Group, relates to the priority area of
pediatric HIV infection.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202/783-3238).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic institutions, public and
private organizations (for-profit and non- profit), such as
universities, colleges, hospitals, laboratories, units of State and
local government, and eligible agencies of the Federal government.
Foreign organizations are not eligible to apply.  Racial/ethnic
minorities, women, and persons with disabilities are encouraged to
apply.
 
The PACTG will consist of:  (1) ONE COORDINATING AND OPERATIONS
CENTER (CORC), (2) 18-25 PEDIATRIC AIDS CLINICAL TRIALS UNITS
(PACTUS), and (3) ONE STATISTICAL AND DATA MANAGEMENT CENTER (SDMC).
Applicants applying for more than one award must submit a separate
application for each category.
 
Each applicant for a CORC award is responsible for identifying, in
the body of the application, the SDMC with which it proposes to work
and must coordinate the preparation of the application with them.
Accordingly, each applicant for the SDMC award is expected to
identify the CORC applicant with which it plans to work and must
ensure that the applications are coordinated.
 
Each applicant for a PACTU award must identify, in a cover letter and
in the body of the application, the CORC with which it proposes to
collaborate.  PACTU applicants must be able to meet the minimum
annual recruitment standards as described in this RFA under "C.
APPLICATION PREPARATION; 2. Pediatric AIDS Clinical Trials Unit
Application; Accrual Potential."
 
Each CORC applicant should demonstrate the capability to develop and
manage a comprehensive multicenter research program comprising a
comprehensive research agenda, scientific and managerial leadership,
laboratories to support the research agenda, organizational and
governance structure, and an Operations Office.
 
Upon the formation of the PACTG, the group will annually accrue 200
or more HIV positive (HIV+) children who have not been previously
enrolled on PACTG protocols and 300 HIV+ pregnant women.  This
enrollment is exclusive of the subjects accrued to pediatric and
perinatal clinical trials funded by the National Institute of Child
Health and Human Development (NICHD).  NICHD-funded institutions
participate, at all levels, in the collaborating group of
institutions comprising the PACTG.  It is anticipated that the NICHD
sites will contribute an additional 100 HIV+ children who have not
been previously enrolled on PACTG protocols and an additional 150
HIV+ pregnant women.
 
MECHANISM OF SUPPORT
 
The administrative and funding instrument to be used for these awards
will be the cooperative agreement (U01).  The cooperative agreement
is an assistance mechanism in which substantial NIAID scientific and
programmatic involvement is anticipated during performance of the
activity.  Under the cooperative agreement, the NIAID's purpose is to
support and encourage the recipients' activities by working jointly
with the awardees in a partner role, but not to assume direction,
prime responsibility, or dominance.  Details of the responsibilities,
relationships, and governance of the studies to be funded are
described under the section entitled, SPECIAL REQUIREMENTS, "Terms
and Conditions of Award." The total project period for each award may
not exceed four years.  The anticipated award date is March 1, 1997.
 
It is anticipated that the award for the CORC will be approximately $
5,000,000 to 8,000,000 total costs per year.  The awards for the
PACTUs will be approximately $ 18,000,000 to 21,000,000 total costs
per year for 18-25 PACTUs; and the Statistical and Data Management
Center award will be approximately $ 3,000,000 to 5,000,000 total
costs per year.  Because the nature and scope of the research
proposed in response to this initiative may vary, it is anticipated
that the size of individual awards will vary.
 
This RFA is a renewal of the ongoing PACTG Program.  Reissuance of
this RFA is uncertain.  If it is determined that there is sufficient
programmatic need for continuing, the NIAID will invite applications
for competitive renewal of this program.
 
FUNDS AVAILABLE
 
The NIAID plans to fund one CORC, 18 to 25 PACTUs, and one SDMC.
Approximately $30,000,000 total costs is expected to be available for
the first year of support under this RFA.  The number of awards to be
made is dependent on the receipt of a sufficient number of
applications of high scientific merit and the availability of funds.
Funding beyond the level awarded in the first year will be contingent
upon the continued availability of funds for this purpose and the
continued progress of the PACTG.
 
RESEARCH OBJECTIVES
 
A.  Background
 
HIV disease is now the seventh leading cause of death in the United
States (U.S.) for children between one and fourteen years of age.
Approximately 6500 HIV+ women deliver children annually in the U.S.,
and currently 1000-2000 of these children will be infected with HIV.
The World Health Organization estimates that by the year 2000,
approximately 10,000,000 children worldwide will have been infected
with HIV, nearly all by perinatal transmission of the virus.
 
The HIV epidemic in children follows the epidemic in women.  It is a
major health problem in urban centers where an increasing number of
racial/ethnic minorities, women, and injection drug users are being
infected.  In addition, the epidemic is growing in rural areas where
access to appropriate health care and research protocols is extremely
difficult because of logistical problems.
 
The goal of NIAID's research on pediatric HIV disease is to identify
and support the development of improved interventions to prevent and
treat HIV infection and its sequelae in infants, children, and
adolescents. Considerable progress has been made in initial therapy
of HIV disease with antiretrovirals, prophylaxis of Pneumocystis
carinii pneumonia (PCP), and the dramatic reduction in the risk of
perinatal transmission of HIV achieved by the administration of the
ACTG Protocol 076 regimen. [Note:  This regimen is the current
standard of care, using zidovudine (ZDV) for the prevention of
perinatal transmission.]
 
Current antiretroviral regimens produce short-term improvements in
quality of life, but little improvement in survival.  The development
of resistance results in current regimens becoming ineffective.
Therapy for many common opportunistic infections requires the use of
multiple drugs, many of which are toxic or only available for
parenteral use.  Many drugs in use or under investigation for adults
are not available in a pediatric formulation, and the current
available regimen for prevention of perinatal transmission is
expensive, difficult to administer, and not completely effective.
 
The relatively small number of newly infected HIV+ children in the
U.S. imposes limitations on the design and conduct of clinical trials
in this country.  For example, a Phase III efficacy trial of
antiretroviral agents might require 800 subjects, which is about one
half the annual number of new pediatric cases projected by the
Centers for Disease Control and Prevention.  As the ACTG Protocol 076
and other preventive regimens become routinely used, this number
could fall to approximately 600 new cases per year.  Therefore,
because of this possible decrease in numbers, pediatric clinical
trials must be carefully designed and targeted to address high
priority questions with the potential for major gains in therapeutic
effect.  Similarly, it is important to design these trials to obtain
the maximum information about mechanisms of action and disease
pathogenesis.  Successful conduct of such trials requires the efforts
of a large multicenter clinical trials organization.
 
Limitations on the number of HIV+ pregnant women lead to similar
conclusions with regard to trials designed to prevent perinatal
transmission of HIV.
 
B.  Definitions
 
Advanced Technology Laboratory (ATL) - The ATLs are central
laboratories that enable the PACTG to implement state-of-the-art
assays and technologies that are essential for the completion of the
scientific agenda, as defined in the PACTG CORC Application.  In
addition to the performance of these assays for the group, these
laboratories may investigate the feasibility, validity, and
standardization of the assays and techniques.  The ATLs are not
intended to conduct basic research directed at finding new assays.
Awards for ATLs will be  made through the PACTG CORC and will provide
support for protocol related studies only.
 
Collaborating Institution - A collaborating institution of the PACTG
may be either the CORC, the Statistical and Data Management Center,
or a PACTU.
 
Cooperative Agreement - A cooperative agreement is an assistance
mechanism in which substantial NIAID programmatic involvement with
the recipient is anticipated during performance of the planned
activity.
 
Coordinating and Operations Center (CORC) - The CORC is the central
group, consisting of the Group leadership (Group Leader and
Executive/Steering Committee) and Operations Office.  This group
coordinates all aspects of the PACTG and has oversight for the ATLs.
 
Data and Safety Monitoring Board (DSMB) - The DSMB is an independent
group of experts established by NIAID and charged with the
responsibility of monitoring the progress of trials, the safety of
participants, and the efficacy of treatments being tested.  The DSMB
also makes recommendations to NIAID concerning continuation,
termination or modification of the trials based on observed
beneficial or adverse effects of any of the interventions under
study.  This panel is funded separately by NIAID.
 
Division of AIDS (DAIDS) - The Division within the NIAID that has the
primary responsibility for basic and clinical research on HIV/AIDS.
 
Executive/Steering Committee - The Executive/Steering Committee,
established and chaired by the Group Leader, represents the main
governing body of the PACTG.  This committee will be responsible for
the conduct and overall activities of the PACTG. (Refer to "SPECIAL
REQUIREMENTS; B. Awardee Rights and Responsibilities" in the RFA.)
 
Group Leader -  The Group Leader is responsible for the leadership
and coordination of all PACTG activities both scientifically and
administratively, and serves as the Principal Investigator for the
CORC award.  The Group Leader may also be associated with a PACTU.
 
NICHD Site - NICHD sites are funded by the National Institute of
Child Health and Human Development to conduct AIDS clinical trials
research in children and pregnant women.  These institutions
participate, at all levels, in the collaborating group of
institutions comprising the PACTG.  The NICHD sites and investigators
are selected, funded, monitored, and evaluated by NICHD or its
contractor.
 
Operations Office - The Operations Office is a unit within the CORC
that will take responsibility for coordinating PACTG administrative
activities.
 
Participant Subunit -  A subunit is an institution supported under
the fiscal and managerial umbrella of a PACTU. Subunits may be
established to support the scientific agenda and/or accrual goals.
All subunits are subject to the same policies and procedures mandated
by Federal regulations, DAIDS and NIAID policies, and the bylaws of
the PACTG.
 
Pediatric AIDS Clinical Trials Group (PACTG) - The PACTG is a
collaborative network of institutions comprised of the CORC, PACTUs,
and the SDMC. This group conducts all phases of clinical trials and
laboratory studies. The PACTG consists of experienced investigators
in multiple disciplines (e.g., pediatrics, infectious diseases,
virology, immunology, clinical pharmacology, neurology,
neuropsychology, obstetrics and gynecology, and biostatistics).
Clinical investigators and sites supported by the NICHD will
participate in the PACTG under an agreement between NICHD and NIAID.
 
Pediatric AIDS Clinical Trials Unit (PACTU) - A PACTU is a clinical
site that is a member of the collaborating group of institutions
comprising the PACTG.  A PACTU may be organized as a main clinical
site or a main site and several subunits under the leadership of one
Principal Investigator.
 
Statistical and Data Management Center (SDMC) - The SDMC is the
component of the PACTG that is responsible to the Group leadership
for the statistical aspects of study design and analysis and
management of the PACTG database.
 
Therapeutics Research Program (TRP) - The TRP is a program within the
DAIDS that is responsible for the scientific, administrative, and
operational management of clinical therapeutic research programs
funded by the Division.
 
C.  Research Goals and Scope
 
The primary goals of the PACTG are to evaluate in Phase I, II, and
III clinical trials: 1) innovative interventions for the prevention
of perinatal transmission of HIV, and 2) innovative therapeutic
strategies and interventions for HIV infection and its complications
in infants and children.  The structure for the group, as defined in
this RFA, is intended to strengthen coordination between the PACTG
research agenda and understanding in the basic sciences in order to
increase understanding of the pathogenesis and complications of
pediatric HIV disease and perinatal transmission.  This structure
will also allow the PACTG to exploit the most recent developments in
the biology of HIV and its transmission, and to develop more
effective treatments and interventions while enhancing knowledge of
the pathogenesis of HIV disease, its complications, and its
transmission.
 
The NIAID HIV/AIDS Research Agenda comprehensively documents the
Institute's major scientific programs, priorities, and plans in the
following scientific areas: pathogenesis, epidemiology and natural
history, therapeutics research and development, vaccine research and
development, and pediatric disease.  The agenda forms the basis for
NIAID's scientific planning, program management and evaluation, and
communications about the scope and nature of NIAID's efforts in HIV
research.
 
The PACTG will play a crucial role in helping to fulfill the goals
and priorities delineated in the Pediatric Section of the NIAID's
HIV/AIDS Research Agenda. For this reason, it is important that the
PACTG identify (by gender and minority status for individuals who
choose to be identified) its leadership, advisory boards, and
committees.
 
The PACTG will focus on those parts of the Pediatric Section related
to the treatment and prevention of pediatric HIV and its
complications.  Copies of the Pediatric Section of the NIAID HIV/AIDS
Research Agenda are available from program staff listed under
INQUIRIES.
 
The Group Leadership will identify the highest priority research
questions from the major therapeutic areas, and develop a
comprehensive clinical trials agenda consistent with the NIAID
HIV/AIDS Pediatric Research Agenda.  The PACTG will be responsible
for developing a prioritized plan to address the research questions
in the NIAID HIV/AIDS Research Agenda.  Specific areas of the NIAID
HIV/AIDS Research Agenda are summarized below:
 
Prevention of Perinatal Transmission of HIV -  Nearly all new cases
of pediatric HIV infection are due to perinatal transmission.  The
ZDV regimen developed by the PACTG in ACTG Protocol 076 has
demonstrated that perinatal transmission of HIV can be significantly
reduced. Additional ongoing trials are investigating the use of HIV
hyperimmune globulin (HIVIG) and other agents.  Because the ZDV
regimen from ACTG Protocol 076 is complex, costly, and likely to be
ineffective in patients with resistant HIV, there is a need to
develop shorter, more effective, and less expensive regimens.
Insights into the mechanisms and biology of perinatal transmission of
HIV are emerging from ongoing natural history studies and will be
developed as ACTG Protocol 076 comes to a close. These insights
should permit the rational design of new regimens.  These regimens
may involve more effective combinations of antiretroviral agents,
passive and/or active immunotherapy, and obstetrical interventions or
combinations of the above.  Specific goals should include the
following:
 
1.  Development of new antiretroviral agents, or combinations of
agents, and other modalities for prevention of perinatal transmission
(including all necessary Phase I and Phase II trials) in pregnant
women and infants for the rational design of efficacy regimens.
Recognizing the international nature of the problem, and the limited
capacity in the U.S. for the conduct of multiple efficacy trials, the
PACTG might undertake research in Phase I and II trials to initially
evaluate regimens which could undergo further evaluation in overseas
trials funded through other mechanisms by NIAID or other domestic and
foreign agencies.
 
2.  Design and conduct efficacy trials of promising regimens for the
prevention of perinatal transmission with the goal of improving upon
currently available treatments by simplifying them or increasing
efficacy.  Increased efficacy, low cost, low potential toxicity, and
the potential for worldwide use are desirable characteristics of new
regimens.
 
3.  Design clinical intervention trials in perinatal transmission to
provide as much information as possible regarding the biology of
transmission as well as the reasons for success or failure of the
intervention being studied.
 
4.  When appropriate, conduct long-term follow-up studies of infants
born to mothers who participated in perinatal transmission trials to
evaluate potential long term adverse consequences of the therapies.
Similarly, conduct appropriate studies in women who participated in
perinatal transmission trials to evaluate consequences of the
therapies.
 
5.  Determine, if possible, clinical and laboratory markers useful
for deciding what regimen, if any, is appropriate for pregnant women
who are HIV+.  This will require careful thought when designing
future efficacy trials.
 
Primary Therapy of HIV Disease in Pediatrics - Considerable progress
has been made in the development of antiretroviral drugs for the
primary therapy of HIV disease in children.  ZDV, ddI, ddC, and d4T
have all been extensively evaluated in children.  Combinations of
agents designed to improve efficacy and impair development of
resistance are underway.  As new agents become available, it is vital
that necessary information becomes available to allow for the safe
and rational use of these agents in children as rapidly as possible.
New information regarding the pathogenesis of HIV disease suggests
that significant events which ultimately damage the immune system
occur within the first weeks after the initial infection.  Since the
time of acquisition of infection can be well defined in some children
who acquire HIV by perinatal transmission, the opportunity exists to
evaluate effective antiretroviral therapy beginning at or before the
time of infection.  The PACTG should focus on:
 
1.  Initiation of clinical trials of new agents or combinations in
therapeutic regimens for children, in parallel with research for
adults, if possible.  Emphasize rapid implementation of Phase I/II
trials designed to establish tolerable doses, pharmacokinetics and
preliminary anti-viral activity of new agents, combination therapy,
and novel approaches (e.g., gene transfer methods).
 
2.  Development and initiation of protocols to study the effect of
interventions given immediately after delivery in order to answer
questions about treatment during acute infection.  Such trials should
be designed to relate treatment to the pathogenesis of the disease.
 
3.  Production of the necessary information for labeling of new
agents for children using minimal information required by FDA rules.
 
4.  The conduct of Phase III efficacy trials when the possibility
exists to make improvements over currently available therapy, or when
pediatric specific disease questions cannot be answered in adult
populations.
 
5.  Utilization of data from completed trials, such as ACTG Protocol
152, to study the impact of the development of resistance to
antiretroviral agents retrospectively.  When practical assays are
available, design prospective studies to evaluate whether change in
therapy, triggered by resistance or other markers, results in
clinical benefit.
 
6.  The development of protocols suitable for subjects for whom
standard regimens are no longer effective.
 
Prevention and Treatment of Opportunistic Infections - The incidence
of various opportunistic infections in children differs from that in
adults.  Serious bacterial infections play an important role.  While
toxoplasmosis is seen less frequently than other infections, PCP and
Cytomegalovirus (CMV) occur as primary disease rather than latent
infection.  Some important illnesses (e.g., measles) may occur before
primary immunization has taken place and cause significant mortality
in children with symptomatic HIV infection.  In general, agents used
to treat opportunistic infections in adults are effective in
children, but suitable formulations and knowledge of the
pharmacokinetics are lacking. Therefore research related to
opportunistic infections should focus on:
 
1.  Evaluation of pharmacokinetic and pharmacodynamic properties of
agents known to be effective so that rational use in pediatric
subjects is possible.
 
2.  Development of a suitable alternative to trimethoprim/sulfa for
prophylaxis of PCP in children.
 
3.  Evaluation of the safety, tolerance, and interactions of oral
agents for the treatment and prevention of Mycobacterium avium
intracellulare (MAI) and CMV infections in children.
 
4.  Evaluation of the pharmacokinetics of agents effective against
multi-drug resistant (MDR) tuberculosis when they become available.
 
5.  Evaluation of the immunogenicity and effectiveness of childhood
vaccines in HIV infected children when the results of the studies are
likely to have a significant impact on the care and well being of
children.
 
6.  Evaluation of new agents, as they become available, for
pharmacokinetics and safety in children for the treatment of enteric
pathogens.
 
Immune Based Therapy -  The pathogenesis of HIV involves destruction
of components of the host immune system.  In addition, there is ample
evidence that immune mechanisms can play a role in controlling HIV.
Thus, evaluations of immune based therapies may increase our
understanding of the pathogenesis of HIV disease, and may prove
useful in the treatment and prevention of pediatric HIV disease.
PACTG activities should focus on:
 
1.  Evaluation of active and passive immunization in children, using
HIVIG, monoclonal antibodies, and vaccines.  These modalities may
play a role both in treatment of HIV and in the prevention of
perinatal transmission.
 
2.  Evaluation of the ability of cytokines to modulate favorably the
course of HIV disease in children.
 
3.  Support of innovative cell transfer studies, particularly the use
of cord blood for immune reconstitution and as a substrate for gene
therapy.
 
Adolescents -  Adolescents are an increasingly important population
affected by HIV.  Not only are an increasing number of new HIV
infections in adolescents occurring through sexual contact or
injection drug use, but some perinatally infected children are living
into their teens.  The PACTG should support research directed at
specific questions related to the pharmacokinetic, pharmacodynamics,
and interactions of drugs which might be expected to differ in the
adolescent population.  In general, the PACTG should include
adolescents in therapeutic protocols when their inclusion would
enhance the ability to answer the scientific questions addressed in
the protocols.  Often, treatment protocols designed for adults are
more appropriate for subjects in their teens and the group is
encouraged to refer adolescents to other trials or make arrangements
to have appropriate trials available at their sites.
 
Nutrition and other Supportive Care -  Nutrition and other supportive
care play an important role in the overall health of children with
HIV.  The PACTG should address scientific questions relating to
nutrition and supportive care through clinical trials.
 
Long Term Follow-up -  As treatments improve over the years, an
increasing number of children will be living longer while receiving
various combinations of antiretroviral agents and other drugs or
treatments.  It is expected that some of these regimens may have long
term toxicities which would influence decisions about their use.  The
PACTG should develop and maintain a long term follow-up protocol that
will monitor subjects over an extended period of time for the purpose
of identifying such problems.
 
Other -  The above items are not meant to be limiting.  The PACTG may
propose clinical trials outside those mentioned provided they address
important scientific questions which may provide information that
will improve treatment or prevention of pediatric HIV disease and its
complications.
 
SPECIAL REQUIREMENTS
 
A.  Terms and Conditions of Award
 
The following terms and conditions will be incorporated into the
award statement and provided to each Principal Investigator as well
as the institutional officials at the time of award. These terms are
in addition to, not in lieu of, otherwise applicable Office of
Management and Budget (OMB) administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Part 74 and 92, and other HHS,
PHS, and NIH Grants Administration policy statements.
 
The administrative and funding instrument used for this program is
the cooperative agreement (U01), an "assistance" mechanism (rather
than an "acquisition" mechanism), in which substantial NIH scientific
and/or programmatic involvement with the awardee is anticipated
during the performance of the activity.  Under the cooperative
agreement, the NIH purpose is to support and/or stimulate the
recipient's activity by involvement in and otherwise working jointly
with the award recipient in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity.
 
Consistent with the cooperative agreement concept, the dominant role
and prime responsibility for the planned activity resides with the
awardees for the PACTG.  Specific tasks and activities in carrying
out the activity will be shared among the awardees, DAIDS staff and
its contractors.
 
The cooperative agreement funding mechanism will require
collaboration between: the DAIDS Associate Director of the TRP, the
Group Leader of the PACTG, and the Principal Investigator of the
SDMC.  The DAIDS will assist in coordinating the activities of the
PACTG as defined below and will facilitate the exchange of
information.
 
B.  Awardee Rights and Responsibilities
 
Awardees will have primary responsibility for defining the details
for the project within the guidelines of the RFA, performing the
scientific activity, and agreeing to accept close coordination,
cooperation, and participation of NIAID staff in those aspects
described below.
 
1.  Responsibilities of the Coordinating and Operations Center (CORC)
 
a.  Research Agenda -  The Principal Investigator (Group Leader) of
the CORC, in collaboration with other investigators constituting the
key scientific and managerial leadership, will be responsible for
developing, implementing, monitoring, and updating the PACTG
scientific clinical trials research agenda consistent with the
research goals and priorities of the NIAID's HIV/AIDS Research
Agenda, Pediatric HIV Disease Section.  These research goals will be
reviewed on a mutually agreed upon schedule with DAIDS staff.
 
b.  Bylaws/Operating Procedures -  The Group Leader will be
responsible for ensuring that there are well-documented and clearly
defined policies, operating procedures, and bylaws guiding all
aspects of PACTG activities.
 
c.  Executive/Steering Committee -  An Executive/Steering Committee
will be established by the PACTG as the main governing body of the
group.  The committee will be chaired by the Group Leader.  The
composition must include the Principal Investigator of the SDMC and
at least one member from each of the following: DAIDS staff, the
community, NICHD staff, PACTG sites, and NICHD sites.
 
d.  Protocol Development -  The PACTG will initiate development of
each protocol only when there is sufficient commitment among the
Principal Investigators and other scientific leaders within the group
to proceed expeditiously to write the protocol, complete accrual, and
analyze and publish the study results. Early notification that the
PACTG is considering a trial must be provided to the DAIDS to allow
for comment on scientific rationale, feasibility, costs, and
compatibility with overall NIAID research priorities and activities.
The PACTG must have clear procedures for designating members of
protocol teams and selecting sites for limited-site trials.  The
PACTG must develop a mechanism to monitor progress, from study
initiation through publication, and provide status reports to the
DAIDS, on each study, in a format and on a schedule mutually agreed
upon.
 
e.  Protocol Submission -  Prior to implementation of a clinical
trial, the PACTG leadership must submit a final draft protocol to
DAIDS for review and approval  based on consistency with the NIAID
HIV/ AIDS Research Agenda and overlap with other NIAID clinical trial
programs.  DAIDS will communicate all decisions, in writing, to the
PACTG; it will be the PACTG's responsibility to disseminate this
information to investigators and others as appropriate.
 
f.  Administrative Support - The Operations Office, within the CORC,
will be responsible for coordinating, administering, and supporting
all research activities at the direction of the Group Leader or
designee.  These activities include, but are not limited to: (i)
protocol development and distribution; (ii) administrative support
for the Group Leader and scientific leadership of the PACTG and all
committees; (iii) coordination of protocol specific training; (iv)
assembly, review, and submission of regulatory documents to the
Pharmaceutical and Regulatory Affairs Branch (PRAB) for registration
of sites to conduct clinical trials; (v) maintenance of group
administrative records and archives; (vi) coordination of efforts
with DAIDS regarding one annual national group meeting to be held in
the Washington D.C. metropolitan area in collaboration with the Adult
ACTG; and (vii) preparation of administrative and scientific reports
(in conjunction with the group's SDMC.)
 
g.  Advanced Technology Laboratories (ATLs) -  The Group Leader, in
consultation with the Executive/Steering Committee of the PACTG, will
be responsible for identifying and justifying ATLs with expertise in
virology, immunology, and pharmacology which are required to support
the PACTG research agenda.  Using funds awarded to the CORC, the
Executive/Steering Committee will: (i) identify and justify the
number of suitable ATLs; (ii) propose a plan for the competitive
selection of the ATLs; (iii) determine appropriate distribution of
resources; (iv) develop and justify a mechanism to monitor laboratory
performance; and (v) propose a plan to  periodically assess
allocation of funds.
 
h.  Laboratory Quality Assurance and Data Management -  All virology,
immunology, and pharmacology laboratories supported through the PACTG
must adhere to technical and analytic guidelines set forth by the
scientific leadership of the PACTG.  All laboratories must
participate in quality assurance programs supported by DAIDS and
overseen jointly with the PACTG.  In addition, all PACTG-supported
laboratories must utilize a common laboratory data management system
for specimen tracking and data transmission as designated by DAIDS.
 
i.  Study Oversight Responsibility -  The PACTG leadership must
establish procedures to: (i) assure adequate protection of the rights
and safety of subjects involved in its clinical investigations; (ii)
guarantee the quality and integrity of resulting data; and (iii)
maintain accurate and timely information on the progress of each
study.  This oversight must include compliance with all Federal
regulations and NIH policies and procedures.
 
j.  Federally Mandated Regulatory Requirements -  The PACTG must be
in compliance with all Federal regulations and NIH policies which
apply to the conduct of research involving human subjects.  These
include, but are not limited to, Title 21 CFR 50, 56, 312, and Title
45 CFR 46. The PACTG must be able to demonstrate that: (i) each
institution conducting PACTG trials has a current, approved Assurance
Number on file with the NIH Office for Protection from Research Risks
(OPRR); (ii) each protocol and informed consent is approved by the
responsible Institutional Review Board (IRB) prior to subject entry;
(iii) each investigator has supplied a completed (including
curriculum vitae) FDA 1572 to DAIDS for each protocol conducted at
each site; and (iv) each subject (or legal representative) gives
written informed consent prior to entry on study.  The PACTG must
assure timely reporting of all serious and unexpected toxicities and
adverse experiences to DAIDS in accordance with DAIDS established
policy and procedures delineated in the "ACTG Adverse Experience
Reporting Manual."
 
k.  Reporting Requirements - The PACTG will submit to the DAIDS
requisite information in order to meet administrative, oversight, and
regulatory needs.
 
Administrative - To facilitate DAIDS compliance with reporting
obligations, the PACTG Group Leader, working through the Operations
Office and SDMC, will submit various administrative information to
DAIDS.  Types of information will include address lists of
investigators and other key contacts, protocol abstracts, tracking
data, participating sites, accrual and demographic data, and
publication information.  Some information will be required weekly,
some less often.  Submission by electronic means, wherever possible,
is preferred.
 
Performance  -  The PACTG Executive/Steering Committee will establish
procedures for regularly evaluating performance of the PACTUs,
Operations Office, and the SDMC.  Procedures will include a process
for the addition, reduction, expansion, or removal of PACTUs and
subunits based on scientific contributions/protocol participation;
observance of protocol requirements; data management/quality; and
subject accrual and retention.  This mechanism will include a
procedure for recommending to DAIDS an adjustment of institutional
funds based on the level of contribution and performance.
 
The PACTG Group Leader will submit to the DAIDS an annual progress
report summarizing the data on protocol performance by the PACTG as a
whole and by each participating clinical unit.
 
These reports will include at a minimum: (i) subject accrual and
retention rates; (ii) subject demographics; (iii) timeliness and
completeness of all data, including adverse events; (iv) timeliness
of IRB approvals of new protocol versions; (v) completeness and
quality of laboratory data; and (vi) scientific contributions,
including publications.  These data should be compiled across all
studies and by protocol, as appropriate.
 
Regulatory - Reporting requirements will be in agreement with Federal
regulations and NIAID procedures for clinical trials.  Prior to the
date specified, the PACTG Group Leader will submit to the DAIDS data
summary reports that are required of Investigational New Drug (IND)
sponsors to by the Food and Drug Administration (FDA).
 
The PACTG will submit to DAIDS a narrative summary of the data
contained in these reports and future plans for each study one month
in advance of each IND report's due date.  A system for providing
such information in a timely manner must be implemented by the PACTG.
 
l.  Publication of Data -  Prompt and timely presentation and
publication in the scientific literature of major findings is
essential.  Publications or oral presentations of work performed
under this cooperative agreement will require acknowledgement of
NIAID support and NICHD support when NICHD-funded sites participated.
Prior to the submission of manuscripts for publication, the PACTG
will provide a preprint to the DAIDS.  Although the awardee will
retain custody and primary rights to the data consistent with current
HHS, PHS and NIH policies, DAIDS will have access to all data
generated under this cooperative agreement and may periodically
review it.
 
m.  Interaction with DAIDS  -  The PACTG Group Leader will meet with
the Associate Director, TRP on a mutually agreed upon schedule.  The
purpose of the meetings will be as follows: to discuss research
progress, establish priorities, and plan future activities; and to
meet with investigators representing other NIAID clinical trials
programs to ensure coordination of research agendas.  Additional
meetings between DAIDS and the PACTG Group Leader may be held as
needed.
 
n.  National Meetings - It is expected that the PACTG will hold two
national meetings per year, at least one of which will be held in
conjunction with the Adult ACTG in the Washington, D.C. metropolitan
area.  Portions of these meetings are open to the public.  Upon award
of this cooperative agreement, responsibility for both logistical
support and scientific content of meetings, for other than the one
combined national meeting in the Washington, D.C. area, will transfer
to the PACTG Operations Office.  DAIDS will continue to provide
logistical support (e.g., contracting with local hotels and vendors,
providing on-site registration, and audio visual support) through a
contractor, for the combined ACTG group meetings. The PACTG will be
responsible for developing and coordinating the scientific agenda for
its portion of the joint meeting.
 
o.  Conflict of Interest - The PACTG will develop, establish, monitor
and enforce a Conflict of Interest (COI) Policy, acceptable to NIAID,
addressing and resolving any conflict of interest issues that may
arise through financial ties between members of the PACTG and the
private sector.  A report on the PACTG's activities regarding COI
issues will be part of the biannual review.
 
p.  Discretionary Fund  - The Operations Office will maintain and
manage a Discretionary Fund.  These funds will be expended only upon
approval by the Executive/Steering committee.  The Executive/Steering
Committee will develop criteria and review procedures for allocating
discretionary funds, based on scientific and  administrative needs
and priorities of the group.  Appropriate uses may include innovative
pilot studies; supplementing budgets of collaborating institutions
which are undertaking resource intensive studies; facilitating the
initiation of large efficacy studies; accommodating non-routine
protocol mandated requirements on an as needed basis; and supporting
additional clinical or laboratory sites needed by the group.
 
q.  Inclusion of NICHD Sites -  Under an agreement between NICHD and
NIAID, clinical sites funded by NICHD participate fully in the
activities of the PACTG.  The CORC and the SDMC must accommodate the
continued participation of the NICHD sites in the PACTG.  The NICHD
funds a network of sites and a data coordinating center that collects
data from the NICHD sites and electronically transmits those data to
the PACTG SDMC.  NIAID and NICHD program staff will assist in this
requirement.  NICHD investigators will be expected to conduct
research and contribute to the pediatric effort according to
standards set for NIAID units; however, the NICHD or its contractor
will evaluate NICHD site performance.
 
r.  Participation of New Investigators, Women, and Minorities -  The
CORC will establish and implement strategies to ensure the
participation of new investigators, especially women and
racial/ethnic minorities, in all levels of the PACTG research effort.
 
2.  Responsibilities of Pediatric AIDS Clinical Trials Units (PACTUs)
 
a.  Clinical Studies -  Each PACTU must agree to conduct clinical
trials according to the priorities and performance goals established
by the PACTG and according to the PACTG bylaws.  PACTUs must have the
capability to recruit and retain yearly a minimum of 10 new (never
before enrolled on a PACTG trial) HIV-infected children (including
adolescents); and if planning to participate in perinatal
transmission trials, PACTUs must recruit and retain yearly a minimum
of 15 additional HIV+ pregnant women.  Each PACTU will identify,
enroll, and retain HIV infected infants, children and pregnant women
who are representative of the catchment area.  PACTUs must agree to
include members of the community in the planning and dissemination of
information about clinical trials.
 
b.  Routine Laboratory Assays - The CORC will identify the virology,
immunology, and pharmacology capabilities, if any, that will be
carried out at the PACTUs.  Each PACTU must have the capability to
perform on site or obtain (via collaboration or purchase) protocol-
specific  laboratory services, as required by the CORC.  Use of
existing DAIDS-certified laboratories in the same community, whenever
possible, is strongly encouraged.  Laboratories performing protocol-
mandated tests will be required to participate in DAIDS laboratory
quality assurance programs.
 
c.  Quality Assurance: Investigational Drug Management -Investigators
performing trials under NIAID cooperative agreements must comply with
the requirements listed in the DAIDS Standard Operating Procedures
and Pharmacy Guidelines and Instructions for ACTG. Investigators must
follow all Federal regulations for investigational agents.  [Note:
The pharmacy manual provides guidance on storage, dispensing, and
accountability of investigational agents.]
 
As part of site registration, each clinical unit must complete a
DAIDS pharmacy plan that must be approved for compliance with FDA and
DAIDS requirements.  Upon approval by PRAB, each site may participate
in DAIDS sponsored trials.  Sites must also register for each
protocol sponsored under a NIAID IND by submitting appropriate
regulatory documents to the PRAB, DAIDS.  These documents will be
verified complete and accurate by the PACTG.  Once a site is
registered by PRAB for a protocol, drug will be supplied by the NIAID
Clinical Research Products Management Center, and subjects can be
enrolled.
 
d.  Quality Assurance: Internal Data Quality Control -  Each PACTU
must establish an internal quality assurance program to assess the
quality of its research records. The plan must be approved by and
consistent with the quality control policies developed by the PACTG.
These policies should include, but are not limited to, quality
control measures for collection, reporting and recording of data.
Each PACTU's internal audit plan should apply to the main unit as
well as any subunits.
 
e.  Quality Assurance: External Data Quality Control - Each PACTU
must cooperate with NIAID Clinical Site Monitoring contractor and
other appropriate Federally supported site monitoring staff who may
inspect records to assure site compliance with all Federal
regulations and NIH policies with respect to subjects' safety, data
completeness and accuracy.
 
f.  Participation of New Investigators, Women, and Minorities - Each
PACTU will establish procedures to ensure the participation of new
investigators, especially women and racial/ethnic minorities, in all
aspects of the PACTG research effort.
 
3.  Statistical and Data Management Center Responsibilities
 
a.  Study Design, Conduct, Analysis and Publication  - The
statistical staff will be responsible for the following:  (i)
providing statistical scientific leadership for the PACTG and
collaborating institutions and organizations; (ii) collaborating at
all stages of protocol development and implementation; (iii)
performing timely interim analyses of safety and efficacy results for
review by protocol teams and/or the DAIDS DSMB; (iv) performing final
analyses for publication, participating in the writing of scientific
papers and publishing study results in conjunction with other
protocol team members; (v) producing timely study monitoring reports,
deliverable to the Group Leader and the Associate Director, TRP; (vi)
conducting secondary analyses of PACTG data to improve the planning,
design, conduct and interpretation of PACTG trials; and (vii)
preparing summary tables and data analyses for use in IND annual and
interim submissions to the NIAID, FDA, and the DSMB.
 
b.  Data Management -  The data management staff will: (i) provide
central registration and randomization of subjects on all studies;
(ii) develop case report forms; (iii) develop standardized criteria
for verification of clinical endpoints; (iv) design and implement a
system to provide for the efficient transfer of study results from
clinical sites to a central database, using either a centralized or
distributed data entry approach; (v) in conjunction with the
Laboratory Data Management System contractor and the NIAID AIDS
Specimen Repository, facilitate the tracking and identification of
laboratory specimens and the merger of laboratory test results with
subject clinical data; (vi) provide for centralized storage,
security, processing, and retrieval of study results; (vii) provide
limited online access for PACTUs to their own blinded data in the
central database; (viii) prepare selected, significant public access
datasets, with adequate documentation, deliverable to a location
designated by DAIDS; (ix) provide for an electronic mail system,
capable of exchanging messages through the Internet, to facilitate
communication among PACTUs, other PACTG components, and DAIDS; (x)
provide data management training of the clinical unit staff and DAIDS
Clinical Site Monitoring contractor in the areas of form completion
and use of the e-mail system and clinical methodology; and (xi)
develop reports detailing site performance in data management,
deliverable to the Group Leader and the Associate Director, TRP.  The
data management staff must function in accordance with policies and
bylaws of the PACTG.
 
c.  Collaboration - When collaborating with any other clinical trial
groups, the PACTG will agree to follow procedures of conduct as
determined by the Associate Director, TRP in consultation with the
leadership of each clinical trials group.  Normally, one group will
be given the lead responsibility by DAIDS and its procedures and
policies will be followed by all other collaborators.
 
In addition, the SDMC will receive and record adverse experience
reports from the PACTG and collaborating institutions and report
these events to DAIDS; the SDMC will be required to provide
registration and randomization of subjects for, and accept data from,
any organization funded by NIAID and NICHD to participate in PACTG
trials. For planning purposes, NICHD will contribute approximately 30
percent of the group activity.  Oversight of the performance of NIAID
and NICHD funded institutions will be the responsibility of the
respective institutions.
 
d.  Participation of Women and Minorities - The SDMC will establish
procedures to ensure the participation of women and racial/ethnic
minorities in all levels of the PACTG research effort.
 
4.  NIAID Staff Responsibilities
 
The NIAID will have substantial scientific/programmatic involvement
during the conduct of this activity, through technical assistance,
advice, and coordination. Through its own funding mechanism, NICHD
staff will share in these responsibilities.
 
The role of the DAIDS staff, as described throughout these terms of
cooperation, is to assist and facilitate, not to direct the research
activities.  Communication and interaction will occur primarily with
the Group Leader and the scientific leadership of the PACTG. DAIDS
will interact directly with the Principal Investigators of any
collaborating institutions and the SDMC as needed. Following are
specific responsibilities of DAIDS staff in terms of investigational
drug research and the Division's role as a drug sponsor as defined in
21 CFR Part 312.  This project is a part of NIAID's larger program of
therapeutics research.
 
a.  Scientific Role of DAIDS in NIAID-Supported Clinical Research -
The Associate Director, TRP and/or designated staff will work closely
with the PACTG Executive/Steering Committee to assure that the
research efforts of the PACTG are consistent with the NIAID agenda
for pediatric HIV-related clinical research and are complementary to
those of the other clinical trials mechanisms supported by DAIDS.
DAIDS will serve as a resource, and will disseminate information
regarding promising new agents, therapeutic strategies, or
developments.  DAIDS staff will advise the clinical investigators, as
requested or needed, of results from other trials (e.g., adverse
experiences and early study terminations) that could influence the
design, development, or conduct of clinical trials and will serve as
the liaison between the pharmaceutical company representatives, the
FDA and the PACTG investigators.
 
b.  DAIDS Role in Protocol Review and Development - In order for a
clinical trial to be initiated by the PACTG, the study proposal must
be mutually approved by the PACTG and the DAIDS Clinical Science
Review Committee (CSRC), chaired by the Assistant Director, TRP,
DAIDS.  The NICHD scientific program staff also participate on the
CSRC deliberations concerning PACTG trials.  Once notified that a
trial is under serious consideration within the PACTG, DAIDS will
evaluate the priority of the proposed trial in relation to: (i) the
NIAID HIV/AIDS Therapeutic Research Agenda and other NIAID trials;
(ii) the likelihood of timely completion; (iii) subject safety; (iv)
compliance with Federal regulatory requirements; (v) plans for
interim monitoring of results; and (vi) resource requirements. TRP
staff will estimate the costs associated with the protocol.  The
Assistant Director, TRP will return comments and recommendations in
writing to the PACTG within 30 days.  In addition, DAIDS pharmacists
will participate on PACTG protocol teams, consulting on available
dosage forms and placebos.  They also will interact with
pharmaceutical companies to ensure adequate and timely supply of
products.
 
In the event a protocol is disapproved, the Assistant Director, TRP
will work with the PACTG Executive/Steering Committee to resolve
specific concerns and ensure consistency between the research
interests, abilities and priorities of the PACTG and NIAID.
Nonetheless, DAIDS will not provide investigational materials or
permit expenditure of NIAID funds for a protocol that has not been
approved.  Disagreements arising pursuant to protocol approval may be
submitted to an arbitration panel for resolution.  A panel composed
of one PACTG designee, one DAIDS designee, and a third member with
HIV/AIDS clinical trials expertise chosen by the other two members
will be formed to review the DAIDS decision and recommend an
appropriate course of action to the Director, DAIDS.  These special
arbitration procedures in no way affect the awardee's right to appeal
an adverse determination in accordance with PHS regulations at 42 CFR
Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.  For
protocols under a DAIDS IND, DAIDS will be responsible for filing the
protocol to the IND.
 
c.  DAIDS Role During Protocol Conduct - For ongoing clinical trials,
a DAIDS Medical Officer will monitor the safety and efficacy of the
treatment being evaluated.  NICHD may also assign a medical officer
to protocol teams. Therefore, interim and final reports on efficacy
and toxicity for all sponsored clinical trials will be routinely
provided to the DAIDS Medical Officer.  In addition, for protocols in
which the DAIDS is the IND sponsor, DAIDS will assign medical
monitors.  In instances where a collaborating institute or
organization is the sponsor of a protocol, their medical officer and
medical monitor will assume the lead.
 
d.  DAIDS Role in Protocol Closure - The Associate Director, TRP
and/or designated staff will monitor the progress of PACTG trials by
reviewing reports periodically submitted to DAIDS, through the Data
and Safety Monitoring Board which consists of experts from several
disciplines, and through regular meetings with PACTG leadership.
DAIDS may deem it necessary to deny access to further investigational
drug supplies and deny the expenditure of additional NIAID funds if
any of the following reasons apply:  (i) risk of subject safety; (ii)
scientific question no longer relevant; (iii) slow accrual, or (iv)
study will not answer question. Appeal of such a decision by the ACTG
would proceed in the same manner as an appeal regarding the
disapproval of a protocol prior to opening.
 
e.  Access to Data - The Chief, Coordinating Centers Branch (CCB)
and/or designated monitoring contractor staff will have access to all
data generated under the cooperative agreements to be funded through
this RFA and may periodically review the data as recorded on case
report forms and/or maintained in the central database.  Data must be
available for external checking against original source documents as
required by NIAID policy and Federal regulations relative to the
responsibility of DAIDS as an IND sponsor.  The awardees will retain
custody and primary rights to the data consistent with current HHS,
PHS, and NIH policies, including a policy to provide public access to
selected, significant data sets generated with the use of public
funds, within a reasonable period of time after primary analysis and
publication by the PACTG.
 
The DAIDS has established an external DAIDS Clinical Site Monitoring
Contract to document good clinical research practices, including
regulatory compliance, proper protocol implementation, and test agent
accountability.  The Clinical Site Monitoring contractor will visit
PACTUs on a quarterly basis (approximately five days per visit) to
review specific priority protocols, train in specific protocols,
review internal quality assurance plans, audit pharmacies, and
document error resolution.
 
f.  Clinical Trials Agreements - It is expected that for most
clinical trials, a pharmaceutical company collaborator will provide
investigational agents for the trials.  In order for the PACTG, DAIDS
and the company to understand their respective responsibilities and
rights, a Clinical Trials Agreement (CTA) will be negotiated and
signed by DAIDS and the company.  Important terms of the agreement
include IND sponsorship, safety and data monitoring, and access to
trial data.  Concurrence with the PACTG Group Leader normally will be
obtained prior to execution of the final agreement.  In general,
terms in the CTA covering data access and sharing will conform to
policies developed jointly by the group leadership and DAIDS.
 
Company collaborators generally request that patentable inventions
made by PACTU staff during the conduct of clinical trials be brought
to the company's attention and that the company be given rights of
first refusal to these inventions, provided that the company owns the
background patents to such inventions. PACTUs will be required to
agree to these requests through a mechanism established by NIAID.
 
g.  Laboratory Quality Assurance and Data Management - The DAIDS will
provide the PACTG with contractual support for virology, immunology,
and pharmacology laboratory quality assurance services.
Administrative and fiduciary aspects of contract management will be
the responsibility of DAIDS. Responsibility for the scientific and
technical oversight for these quality assurance programs shall reside
within the DAIDS Drug Development and Clinical Sciences Branch
(DDCSB) and will be carried out in conjunction with advisory groups
comprised of ACTG and other investigators working in a cooperative
manner.
 
The DAIDS will provide the PACTG with contractual support for the
management of virology, immunology, and pharmacology laboratory data.
Given the complex nature of these data, the large volume to be
collected and the highly technical aspects of its collection, this
activity will be supported by its own project, distinct from, but
coordinated with, the group's data management system/facility.
Similar to the quality assurance programs, the oversight and
responsibility for the laboratory data management system shall reside
within the DAIDS CCB, in conjunction with an advisory group comprised
of ACTG and other investigators working in a cooperative manner.
 
h.  DAIDS Involvement in Investigational New Drug Applications - The
DAIDS will have the option to cross file or independently file an IND
on investigational drugs evaluated in the PACTG clinical trials.  The
Chief, PRAB will advise investigators of specific requirements and
changes in requirements concerning IND sponsorship that the FDA may
mandate.  Investigators performing trials under cooperative
agreements will be expected, in cooperation with the DAIDS, to comply
with all FDA regulations associated with investigational drug
studies.
 
i.  DAIDS Review of PACTG Compliance with Federally Mandated
Regulatory Requirements - The Chief, PRAB will advise the PACTG
regarding mechanisms to meet FDA regulations for DAIDS-sponsored
studies involving investigational agents, and OPRR regulations.
 
For DAIDS- sponsored trials with investigational agents, the DAIDS
has established an external Clinical Site Monitoring Contract to
document good clinical research practices, including regulatory
compliance, proper protocol implementation, and test agent
accountability.
 
In order to provide for consistent reporting of adverse experiences
across clinical trials groups, DAIDS has established policies and
procedures delineated in the "ACTG Adverse Experience Reporting
Manual."  The Adult ACTG, as the largest of the groups, will have the
responsibility for ongoing maintenance of the modified ICD-9 system
for classifying and coding the types of adverse experiences reported.
However, when differences exist that are not found within the Adult
ACTG, the PACTG will provide input into coding and classification of
adverse experience reporting for pediatric populations. This will
require collaboration with staff from the DAIDS and other trials
groups.
 
j.  DAIDS as a Resource for Site Evaluation - The Chief, Clinical
Site Management Branch (CSMB) will assist the PACTG  in developing
criteria to evaluate the performance of the collaborating
institutions.  The Chief, CSMB will provide data on the cost of the
PACTG's research activities, including protocol specific costs.
 
k.  Review of Performance  - The performance of the PACTG as a whole
and that of the individual institutions will be reviewed at least
annually by the Associate Director, TRP.  The basis of the review
will be information provided in annual progress reports, evaluations
of site performance conducted by the Executive/Steering Committee,
and clinical site monitoring reports provided to DAIDS by its
contractor.  Substandard data management/quality, insufficient
subject accrual and retention, inadequate progress in executing the
research agenda, or noncompliance with the Terms and Conditions of
Award may result in a reduction in budget, withholding support,
suspension, or termination of award.  l.  DAIDS Review of Quality
Control and Study Monitoring Procedures - The Chief, PRAB will
periodically conduct a review of the PACTG sites for the reliability
of and compliance with clinical and regulatory systems, and will
advise on the same.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
1003-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations) which have
been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.  A copy is also available through the NIH Grant Line
(data line 301- 402-2221).  Investigators may obtain copies from
these sources or from Dr. Tina Johnson (see "INQUIRIES") who may also
provide relevant information concerning the policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by March 27, 1996, a
letter of intent that includes a descriptive title of the proposed
application (Pediatric ACTG CORC, Pediatric ACTU, or Pediatric ACTG
Statistical and Data Management Center); the name, address, and
telephone number of the Principal Investigator; the number and title
of this RFA; a list of the key investigators and their
institution(s); and for PACTU and SDMC applicants, the identity of
the CORC with which the applicant plans to affiliate, if known.
 
The letter of intent is requested to provide an indication of the
scope and number of applications that will be received and to promote
early interaction among potential applicants and between the
applicants and NIAID staff.  Letters of intent from potential
applicants for PACTG CORC awards will be used by DAIDS program staff
to refer unaffiliated potential applicants for PACTUs to potential
PACTG CORCs.  The letter of intent does not commit the sender to
submit an application, nor is it a requirement for submission of an
application.  The letter of intent is to be sent to Dr. Peter
Jackson. (See "INQUIRIES".)
 
APPLICATION PROCEDURES
 
Applications must be submitted on the standard research grant
application form PHS 398 (rev. 5/95).  Applications kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/435-0714, email:  girg@drgpo.drg.nih.gov.
 
The RFA label in the form PHS 398 must be affixed to the bottom of
the face page.  Failure to use this label could result in delayed
processing of the application.  For purposes of identification and
processing, item 2 on the face page of the application must be marked
"YES" and the RFA number and the words "Pediatric ACTG - COORDINATING
AND OPERATIONS CENTER" or "Pediatric ACTG - ACTU or "Pediatric ACTG -
STATISTICAL AND DATA MANAGEMENT CENTER," as appropriate, must be
typed in.  If applying for more than one type of award, each
application must be submitted separately.
Submit a signed, typewritten original of the application, including
the Checklist, and three signed exact photocopies.  Each application
for the CORC, Statistical and Data Management Center, and each PACTU
must be submitted separately to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application
and all five copies of appendices must also be sent to:
 
Peter Jackson, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C10 MSC 7610
Bethesda, MD  20892-7610
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-8426
FAX:  (301) 402-2638
Email:  pj8v@nih.gov
 
The deadline for the receipt of applications is June 11, 1996.
Applications received after this date will be considered non-
responsive to this RFA and will be returned without review.
 
Special Instructions for the Preparation of Cooperative Agreement
Applications
 
A.  Identification of Potential Applicants and Formation of the PACTG
 
It is the responsibility of potential applicants for the PACTG CORC
award, Pediatric ACTU awards, and Statistical and Data Management
Center award as components of a PACTG to identify themselves to each
other and to establish affiliations.  In addition to the standard
communication channels among investigators, the NIAID will facilitate
the formation of the PACTG by:  (1) providing the identity of
potential CORC applicants to unaffiliated potential ACTU applicants,
and the names of unaffiliated potential ACTU applicants to potential
PACTG CORC applicants based on the letters of intent; and (2) holding
a pre-application meeting on March 20, 1996.
 
B.  Pre-Application Meeting - March 20, 1996
 
The purpose of this meeting, to be held in the Bethesda, MD area, is
to provide potential applicants with:  (1) additional information
about the structures and functions of DAIDS clinical research
programs; (2) the opportunity to ask questions and obtain
clarifications; and (3) the opportunity to establish affiliations.
At the Pre-Application Meeting, all CORC applicants will be asked to
submit a scientific agenda and laboratory requirements  to DAIDS.
This
information will be distributed to all potential applicants for a
PACTU to assist them in their response.  Subsequent to submission of
this information, CORC applicants will transmit any changes to the
scientific agenda to DAIDS. DAIDS will distribute the changes to all
potential applicants. For further information contact Dr. Tina
Johnson. (See "INQUIRIES.")  Potential applicants that request the
RFA but are unable to attend the pre-application meeting will be sent
a summary of the discussion and copies of any materials that are
distributed.
 
C.  Application Preparation
 
All applications must be submitted on the form PHS 398 (rev. 5/95).
Successful applications for each PACTG component (CORC, SDMC, and
PACTUs) will be awarded as separate cooperative agreements to the
sponsoring institutions and will include the Terms and Conditions of
Award specified in this RFA.
 
Each individual application must contain a detailed budget for the
first 12-month period and a budget for the entire proposed project
period for direct costs.
 
On page 11 of the PHS 398 application brochure, in the section
entitled PERSONNEL, it is imperative that all applicants list ALL
individuals and their institutions participating in the scientific
execution of the project in the specified format, including those
with no requested salary support.  All applicants must ensure that
the list is complete using as many continuation pages as necessary.
 
Biographical sketches and other Support pages should be placed at the
end of each individual application with the Principal Investigator
first, followed by other key personnel in alphabetical order;
biographical sketches are limited to two pages each.  A key feature
of this RFA is that it requires a CORC application to be submitted by
a Group Leader/Principal Investigator of the PACTG CORC.  All
pediatric ACTUs seeking membership in a collaborative group must
submit a separate application identifying the CORC to which they are
seeking membership.  The Statistical and Data Management Center
application must be submitted separately, and must also identify the
CORC with which it will affiliate.  The use of tables (e.g., accrual
and protocol type), diagrams, and organization and flow charts is
strongly encouraged throughout the preparation of all applications.
 
In summary, applications in response to this RFA must include, but
are not limited to, the minimum requirements:
 
1.  Pediatric Coordinating and Operations Center (CORC) Application
 
The CORC application is not subject to the page limitations as stated
in the form PHS 398.  However, the entire Research Plan must be
limited to 100 pages.  When preparing your application, use the
topics listed below as a guide for writing the research plan in lieu
of items a-d listed on pages 16-17 of the PHS 398 application
brochure.  However, the "Gender and Minority Inclusion for Research
Involving Human Subjects" and (e) "Human Subjects" must be included
in the Research Plan.
 
Research Plan and Scientific Agenda- The application should discuss
the process by which the Group Leader will identify the scientific
leadership required to produce a comprehensive research agenda on
behalf of a PACTG, the research agenda, and identification of the
scientific and managerial leadership required for the Group to
effectively and efficiently carry out its research plan.  The
research plan must clearly identify the priority areas.  The
applicant must demonstrate, in the preparation of the research plan,
linkage with the SDMC application.  For established committees (e.g.,
Executive /Steering Committee) include a gender and minority status
for individuals who choose to be self identified.
 
Operations and Management - The application should provide well-
documented, clearly defined policies, operating procedures (e.g.,
protocol development, review, initiation, conduct and closure, data
collection, and publication etc.), and bylaws (e.g., delineating the
requirements and expectations of collaborating institutions,
membership criteria and process for new site consideration by the
PACTG, standards of performance, and procedures for removing
institutions due to poor performance) guiding all aspects of PACTG
activities.
 
In addition to a discussion of the support needed for the Operations
Office, each CORC application should include a plan and a budget,
developed by the Group Leader, for administrative/managerial support.
The CORC applicant and the SDMC applicant must show evidence of
ongoing cooperation in the preparation of their applications.
 
Operations Office Procedures - The application must describe the
steps that the Group Leader will take to ensure internal and external
communication between the Operations Office and the CORC, the PACTUs,
and collaborating institutions (e.g., SDMC and DAIDS).
 
Outreach - The application must describe the mechanisms and
procedures that will be put in place for monitoring outreach and
accrual efforts at the individual PACTUs.
 
Plan and Budget for ATLs - A narrative and budget request for
establishing central ATLs must be included in this application.
Potential ATLs must not be mentioned by institution or site name in
any application materials or supporting documents.  The total budget
request and planned distribution among virology, immunology, and
pharmacology should be based on the scope of activities proposed
directly in support of the PACTG research agenda.
 
Discretionary Funding - The Group Leader may also request a
discretionary budget in this application that will be used to:  fund
innovative pilot studies, supplement the budgets of collaborating
institutions undertaking resource intensive studies, facilitate the
initiation of large efficacy studies, accommodate non-routine
protocol mandated requirements on an as needed basis, and support any
additional clinical or laboratory sites needed by the group.  The
Discretionary Funds may not exceed $1,500,000 total costs per year.
The application must describe how the funds will be used, what review
procedures will guide the Executive/Steering Committee for
distributing the funds, and what criteria will be used for
distribution of funds.
 
Plan for Enrolling Women Completing Perinatal Protocols Into Adult
Studies - The application must describe a plan for facilitating and
monitoring the referral of post-perinatal study subjects into adult
protocols.
 
Budget -  As a part of the proposed detailed overall first year
budget and summary budgets for future years, the applicant must show
evidence of collaboration with SDMC personnel on the preparation of
the SDMC workscope and budget.  Additionally, the applicant should
identify the annual budgets for the following four categories of
activities:  (a) administrative support for the Group Leader (b) the
Operations Office; and, within the Operations Office, (i) the
Advanced Technology Laboratories (ii) the Discretionary Funds and
(iii) support for the scientific leadership.
 
2.  Pediatric AIDS Clinical Trials Unit Application
 
Each application requesting support as a PACTU is subject to the page
limitations (25 pages) for the Research Plan.  When preparing your
application, use the topics listed below as a guide for writing the
research plan in lieu of items a-d listed on pages 16-17 of the PHS
398 application brochure.  However, the "Gender and Minority
Inclusion for Research Involving Human Subjects" and (e) "Human
Subjects" must be included in the Research Plan.  Appendices should
be limited to no more than 30 pages.  Applications exceeding the page
limitation will be returned to the applicant.
 
Principal Investigator and Coordinating and Operations Center (CORC)
Affiliate - The application for the PACTU must name a Principal
Investigator who would be responsible for clinical research.  A PACTU
applicant may propose association with more than one CORC by
submitting a separate cover letter and a separate application for
each affiliate.
 
Ability to Contribute to the Scientific Agenda - Each PACTU applicant
must demonstrate an ability to enroll adequate numbers of subjects
and contribute to the scientific agendas of all CORC applicants with
whom it proposes to affiliate.
 
Demonstrated Clinical Trials Capabilities and Expertise -Each PACTU
application must describe the following:  (a) expertise of key staff
and nature of proposed scientific contributions, consistent with the
PACTG research agenda described in the CORC application; (b) evidence
of past accomplishments relative to multi-center pediatric/perinatal
clinical trials (especially in infectious diseases), including a
break-down of accrual by protocol and by year [Note: performance data
of incumbent applicants for FY 95 and 96 will be provided to
reviewers.]; (c) organizational structure and responsibilities of key
personnel; (d) procedures and mechanisms for facilitating the
referral and enrollment of women from perinatal trials into adult
studies; (e) procedures for the protection of human subjects; (f)
internal quality assurance programs for regulatory compliance and
data management; and (g) plans to ensure the participation of new
investigators, women, and racial/ethnic minorities at all levels of
the scientific and managerial activities of the PACTU.
 
Ability to Provide Protocol Mandated Laboratory Capability -The CORC
will mandate to its affiliated sites what laboratory needs each site
should be prepared to provide.
 
Accrual Potential - As a measure of patient accrual potential into
the PACTG, each applicant must provide evidence of the ability to
enroll yearly a minimum of 10 new (never before enrolled on a PACTG
trial) HIV-infected children (including adolescents), and if planning
to participate in perinatal transmission trials, a minimum of an
additional 15 HIV+ pregnant women in such studies. Applicants
employing the standard of care regimen (ACTG Protocol 076) should
consider its impact on accrual and take this matter into account when
projecting potential accrual goals.
 
In addition, each PACTU applicant must provide evidence of the
ability to enroll subjects, other than those described above, in
trials (e.g., Phase I, OIs, etc) designed to support fully the
Pediatric scientific agenda.  Thus, the total accrual of HIV infected
children at a PACTU will be significantly greater than the accrual of
new subjects.
 
Plan for Enrolling Women Completing Perinatal Protocols Into Adult
Studies - The application must describe a plan for facilitating the
referral of post-perinatal study subjects into adult protocols.
 
Outreach - The application must demonstrate: a) evidence of the
ability to outreach to the community and means of assessing success;
b) evidence of effective community linkages and plans for involving
community representatives in research activities (e.g., Community
Advisory Board); and c) an ability to ensure the appropriate
inclusion  and retention of under-represented populations from within
the applicant's catchment area and the populations most affected by
HIV and AIDS as evidenced by a breakdown of available subjects by
protocol type (e.g., perinatal, OIs, etc).  Applicants must make a
good faith effort to demonstrate linkage with local Title IV Ryan
White sites in order to facilitate their participation in AIDS
clinical trials research.
 
Budget - Budget requests from each PACTU applicant must include all
activities that will be undertaken at the unit, such as: recruitment
and retention of new subjects, routine laboratory testing, costs
associated with the follow-up of subjects continuing on PACTG
protocols at incumbent applicant institutions, and purchase and
maintenance of any hardware and software required.  Budget requests
from incumbent institutions will be reviewed based on the following
information that will be provided to reviewers: site performance over
the past two years, annual subject accrual and retention, and types
of protocols.  Budget justifications must be based on the projected
types of studies to be conducted, number of subjects to be accrued,
and the number and type of personnel required relative to the above
projections. Incumbent applicants proposing to increase accrual
significantly over previously documented accrual  levels must provide
a compelling justification for this increase and explain how it will
be accomplished.
 
Historically, the protocol specific mean direct costs per subject per
year for PACTG Phase I, Phase I/II, Phase II, and Phase III studies
at main units and subunits have been approximately $5,719; $8,787;
$10,695; and $5,203 respectively.  The mean annual protocol specific
costs include: personnel time directed toward patient care (e.g.,
physicians, nurses, and pharmacists), laboratory costs, and  clinical
procedures.  The mean costs do not include resources devoted to
subject recruitment, screening and ancillary services, data
management, quality assurance, program administration or supplies.
 
3.  Statistical and Data Management Center Application
 
The SDMC application is not subject to the page limitations as stated
in the form PHS 398.  However, the Research Plan must be limited to
100 pages.  When preparing your application, use the topics listed
below as a guide for writing the research plan in lieu of items a-d
listed on pages 16-17 of the PHS 398 application brochure.  However,
the "Gender and Minority Inclusion for Research Involving Human
Subjects" and (e) "Human Subjects" must be included in the Research
Plan.  The workscope and activities proposed by the SDMC must be
consistent with the research agenda proposed by the CORC.  The SDMC
budget must show linkage to the research priorities in the CORC
application.
 
Principal Investigator and Coordinating and Operations Center (CORC)
Affiliate - The application must designate a Principal Investigator
who would be responsible for the SDMC.  The applicant must be
affiliated with only one CORC application, and the CORC affiliate
must be stated in a cover letter and in the application.
 
Statistical Expertise -  The application must provide documentation
of plans and standard operating procedures for protocol development,
timely interim analyses of safety and efficacy, final analyses for
publication, and procedures for supplying scientific, administrative
and regulatory reports to the Executive/Steering Committee and DAIDS.
Samples of protocols should be provided in the appendices to
demonstrate experimental design, methods of analysis, and sample size
calculations.  If the SOPs and protocols are not available, this
information should be described in detail in the text of the
application.
 
Organizational Structure/Management Plan -  The application must
include an organizational chart, procedures for communicating with
the Operations Office and other collaborating institutions,
availability of experienced biostatisticians and other key
statistical scientific leadership.  The management plan must address
areas of responsibility of key personnel.  The justification for
staffing levels for each category of staff should relate to projected
workload in terms of study size, study phase, number, and complexity
of protocols.
 
Data Management Capabilities -  Each application for a SDMC must
provide evidence of data management capabilities by describing SOPs
that address:  (a) plans for database design and administration; (b)
procedures for data collection (including from the NICHD data
coordinating center), management, analysis and quality control; (c)
plans for developing/maintaining subject registration/randomization
systems, centralized storage and retrieval of data; (d) interface
with DAIDS laboratory data management contractor for tracking
laboratory specimens and merger of laboratory data with clinical
data; (e) plans for training site personnel and DAIDS Clinical Site
Monitoring contractor; and (f) plans for providing an electronic mail
system.  The application should describe, in detail, any hardware and
software requirements and expectations to be imposed on the PACTUs
and other collaborators.
 
REVIEW CONSIDERATIONS
 
A.  Review Procedures
 
Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants and reviewed for responsiveness by the
NIAID staff.  Incomplete or non-responsive applications will be
returned to the applicant without further consideration or review.
 
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIAID in accordance with the review
criteria stated below.
 
The review of the PACTU applications will focus on each unit's
ability to contribute to the PACTG scientific agenda, as well as the
ability and expertise to conduct Pediatric AIDS clinical trials.
 
Applications will be reviewed for scientific and technical merit by a
review committee convened by the Division of Extramural Activities,
NIAID.  The second level of review will be provided by the National
Institute of Allergy and Infectious Diseases Council.
 
B.  Review Criteria
 
1.  Pediatric Coordinating and Operations Center (CORC) Application
 
a.  Adequacy of the proposed plans to address the research questions
in the Pediatric Section of the NIAID HIV/AIDS Research Agenda.
Adequacy of the proposed ranking of the research priorities and
justifications.
 
b.  Adequacy of the qualifications, research experience, and time
commitment of the Group Leader.  Adequacy of the qualifications and
research experience of the proposed scientific leadership, including
but not limited to previous experience with design, administration,
management, and coordination of multi-center clinical trials.
 
c.  Strength of the provided strategies to ensure for overall subject
recruitment and retention including subject enrollment into
potentially difficult areas or high priority areas of study.
Adequacy of the plans to ensure outreach to members of the HIV
infected subpopulations.
 
d.  Strength and adequacy of the plans for overall PACTG management
and operations, including the plans and mechanisms for effective
communication among group membership and committees.
 
e.  Adequacy of proposed bylaws; procedures for protocol development;
and procedures for delegation of responsibilities; plans for
performance evaluation; plans to improve performance; and procedures
to eliminate inadequate performers.  Adequacy of plans for managing
discretionary funds.
 
f.  Adequacy of plans for establishing, monitoring and enforcing a
Conflict of Interest policy.
 
g.  Adequacy of the available or proposed resources and personnel for
administering the PACTG.  Adequacy of Operations Office capabilities
in research administration, protocol development, and management of
regulatory documents.
 
h.  Adequacy of plans to assure that virology, immunology, and
pharmacology laboratories supported through the PACTG adhere to
guidelines set forth by the scientific leadership of the PACTG.
 
i.  Adequacy of the overall plan for the Advanced Technology
Laboratories (ATLs) to meet the stated research goals; and
appropriateness of the proposed plan and budget for soliciting,
reviewing, selecting, monitoring/evaluating, and terminating ATLs, in
order to accomplish the research goals and priorities.
 
j.  Adequacy of plans for effective communication and collaboration
between the NICHD-funded components and NIAID-funded components.
 
k.  Adequacy of proposed plan to accomplish mutual, ongoing
collaborations between the Operations Office and the SDMC.  Adequacy
of proposed links between the Coordinating and Operations Center
application and budget and the SDMC application and budget.
 
l.  Adequacy of plans to: (i) assure adequate protection of the
rights and safety of subjects involved in its clinical
investigations; (ii) guarantee the quality and integrity of resulting
data; and (iii) maintain accurate and timely information on the
progress of each study.  This oversight must include compliance with
all Federal regulations and NIH policies and procedures.
 
m.  Strength and adequacy of plans for inclusion of community
representation in PACTG research and organizational activities.
 
n.  Adequacy and feasibility of plans to foster participation of new
investigators, especially women and racial/ethnic minorities, in
activities at all levels of the PACTG.
 
2.  Pediatric AIDS Clinical Trials Unit Application
 
a.  Adequacy of the qualifications and availability of key personnel
to achieve the stated goals of the PACTU.
 
b.  Strength of the proposed scientific contributions of the PACTU to
the PACTG scientific agenda.  Adequacy of the plans for achieving the
proposed PACTU scientific contributions.
 
c.  Adequacy of information provided concerning the ability of the
applicants to recruit and retain yearly a minimum of 10 new (never
before enrolled on a PACTG trial) HIV-infected children (including
adolescents).  Adequacy of information provided concerning the
ability of the applicants to recruit and retain yearly a minimum of
15 additional HIV+ pregnant women, if the proposed PACTU plans to
participate in perinatal transmission trials.  Strength of evidence
that the applicants will be able to accrue additional subjects,
beyond the minimum enrollment requirement, into PACTG trials to
answer the research questions of the multifaceted pediatric
scientific agenda. [PACTU applicants employing the ACTG Protocol 076
regimen should consider its impact on accrual and take this factor
into account when projecting potential accruals.]
 
Reviewers will consider the prior HIV/AIDS research experience,
multi-center trials experience, and/or pediatric/perinatal clinical
trials research experience of the applicants and the involved
institutions.  Reviewers will also consider the applicant's specific
plans for recruitment and retention of subjects, including: ability
to accrue patients into potentially difficult or high priority
research areas; ability to achieve gender and minority representation
appropriate to the HIV infected subpopulations within the catchment
area; and ability to outreach to the HIV infected subpopulations.
 
d.  Adequacy of plans for the involvement of community
representatives in the planning and dissemination of information
about clinical trials.
 
e.  Adequacy of the plans for, and strength of the applicant's prior
experience in, collecting and promptly transmitting reliable, data,
and in developing and implementing an internal program for data
quality assurance, security and confidentiality.
 
f.  Adequacy of available facilities and resources to conduct the
proposed work.  Adequacy of proposed plans to provide or to obtain
core laboratory services as required in the Coordinating and
Operations Center application. Adequacy of the proposed drug control
procedures and plans for pharmacy support.
 
g.  Adequacy of plans for management and coordination of PACTU
activities, including communication and cooperation with other PACTG
components.
 
h.  Strength of the proposed plans and the implementation strategies
for identifying and involving new, women and minority investigators
at all levels of the proposed PACTU.
 
i.  Adequacy of plans for the protection of human subjects.
 
3.  Statistical and Data Management Center Application a.  Strength
of the qualifications, research experience and availability of the
proposed program director as well as other biostatisticians and data
systems personnel to provide statistical scientific leadership for
the design and analysis of multicenter clinical trials.
 
b.  Adequacy of the proposed linkage between the workscope of the
SDMC and the research agenda priorities proposed in the Coordinating
and Operations Center application. The adequacy of the proposed
organizational structure of the SDMC to carry out the proposed
responsibilities and the adequacy of SDMC budgetary consistency with
the  priorities presented in the Coordinating and Operations Center
application.
 
c.  Adequacy of plans for database design, security, confidentiality
and administration, and adequacy of proposed procedures and policies
for data collection, analysis and quality control.
 
d.  Adequacy of plans for developing and maintaining systems for:
patient registration/randomization; receiving, recording and
reporting of adverse events from the PACTG and collaborating
institutions; providing timely interim analyses of safety and
efficacy, and final analyses for publication; and supplying
scientific, administrative, and regulatory reports to DAIDS.
 
e.  Adequacy of the plan for interfacing and collaborating with the
DAIDS laboratory data management system contractor for tracking
laboratory specimens.  Adequacy of the plan for the merger of
laboratory data with the clinical database.
 
f.  Adequacy of plans for establishing an electronic mail system,
capable of exchanging messages through the Internet, for all
collaborating PACTG institutions and DAIDS.
 
g.  Adequacy of procedures for interacting with the Coordinating and
Operations Center's Operations Office, the NICHD, and other clinical
trials groups, as needed.
 
h.  Adequacy of the plan for training clinical (PACTU) site staff and
the DAIDS Clinical Site Monitoring contractor in: forms completion
and data management; the use of the e-mail system; and in  clinical
trials methodology.
 
NOTE:  The following section expands upon review criteria for the
Protection of Human Subjects and for Gender and Minority
Representation.  This section applies to all applications responding
to this RFA.
 
1.  Adequacy of the proposed means for protecting against adverse
effects of the research upon humans, animals or the environment,
where such are involved.
 
2.  In clinical studies, if there is inadequate representation of any
gender and/or racial/ethnic minorities in a study design AND this
affects the potential to answer the scientific question(s) addressed,
such inadequacy will be considered deficient in the study design.
The deficiency will be reflected in the priority score, unless a
convincing justification is provided by the investigator to explain
the inadequate representation.[Note:  The Group Leadership should
take overall responsibility (and state how in its Coordinating and
Operation Center application) for ensuring that the overall
representation of study population, PACTG-wide, will be appropriately
inclusive of under-represented populations.  The SDMC should address
in its application how it will ensure that the conditions of the new
Guidelines for Gender and Minority Representation are met with regard
to clinical trials design (e.g., stratifications, sample sizes,
levels of statistical significance required according to what is
previously known about gender/ethnicity effects), and how it will
conduct appropriate analyses of any data collected.  PACTU
recruitment should reflect the demographics of the catchment area
with respect to HIV- infected under-represented minorities.]
 
AWARD CRITERIA
 
The predominant criteria for funding priorities will be the
scientific and technical merit of applications in response to this
RFA.  Consideration will be given to the following factors in the
final selection of applications to be funded:  (1) inclusion of
populations currently under-represented in clinical trials; (2) cost-
effectiveness of proposed studies; and (3) the ability of the PACTG
to cover all points of the scientific agenda.
 
INQUIRIES
 
Written and telephone inquiries concerning the objectives and scope
of this RFA are strongly encouraged and may be directed to the staff
listed below.  Requests for the "NIH GUIDELINES FOR INCLUSION OF
WOMEN AND MINORITIES AS SUBJECTS IN CLINICAL RESEARCH" and the "NIAID
HIV/AIDS Research
Agenda" as well as inquiries regarding programmatic issues may be
directed to:
 
Tina Johnson, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2B31
6003 Executive Boulevard MSC 7620
Bethesda, MD  20892-7620
Telephone:  (301) 496-8214
FAX:  (301) 480-5703
Email: tj8y@nih.gov
 
Inquiries regarding review criteria and procedures:
 
Peter Jackson, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C10
6003 Executive Boulevard MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-8426
FAX:  (301) 402-2638
Email:  pj8v@nih.gov
 
Inquiries regarding fiscal issues to:
 
Carol Alderson
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B26
6003 Executive Boulevard MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 402-5937
FAX:  (301) 480-3780
Email:  ca10h@nih.gov
 
Schedule
 
Letter of Intent Receipt Date:    March 27, 1996
Pre-Application Meeting:          March 20 , 1996
Application Receipt Date:         June 11, 1996
Special Review Committee:         October 1996
NIAID Advisory Council:           January 23, 1997
Anticipated Award Date:           March 1, 1997
 
AUTHORITIES AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases Research
and 93.855 - Allergy, Immunology and Transplantation Research.
Grants are awarded under the authority of the Public Health Service
Act, Section 301 (42 USC 241) and administered under the PHS grants
policies and Federal Regulations, most specifically at 42 CFR Part 52
and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of the Executive Order 12372 or
Health Systems Agency review.
 
The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American People.
 
.

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