PEDIATRIC CLINICAL TRIALS PROGRAM FOR AIDS

Release Date:  September 13, 2000

RFA:  AI-00-015
 
National Institute of Allergy and Infectious Diseases
 (http://www.niaid.nih.gov/)

Letter of Intent Receipt Date:  November 15, 2000    
Application Receipt Date:       March 21, 2001

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 conduct Pediatric HIV/AIDS clinical research.  The 
purpose of this RFA is to solicit applications from institutions interested in 
establishing cooperative clinical trials groups to plan and direct pediatric 
therapeutics and prevention research.  The awardees will have the capacity and 
expertise to conduct all phases of clinical trials involving children, 
adolescents and pregnant women with all stages of infection.  Studies will 
focus on high priority research questions on the treatment and pathogenesis of 
HIV disease and its sequelae.  The scope of activities will range from studies 
requiring in-depth laboratory support to research in long-term clinical 
outcomes.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS led national 
activity for setting priority areas. This Request for Applications, Pediatric 
Clinical Trials Programs for AIDS is related to HIV disease. Potential 
applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and not for profit 
organizations; public and private institutions, such as universities, 
colleges, hospitals, laboratories, units of State and local governments; and 
eligible agencies of the Federal government.  Foreign institutions are not 
eligible to apply as primary grantees; however, foreign institutions may 
participate as part of a domestic application.  Racial/ethnic minority 
individuals, women, and persons with disabilities are encouraged to apply as 
Principal Investigators.

An applicant proposing to form a Pediatric AIDS Clinical Trials Group (PACTG) 
will coordinate the submission of an integrated package of applications that 
includes: (i) One Coordinating and Research Operations Center (CORC) [Core 
Application]; (ii) One Statistical and Data Management Center (SDMC); and 
(iii) Clinical Site applications.  An applicant may choose to use a single 
Coordinating Center (CC) which combines the functions of a CORC and a SDMC for 
operational, statistical, and data management support.  The number of Clinical 
Site applications should be based on the scope of proposed research activities 
and on the scientific expertise to accomplish the proposed research agenda.

Potential clinical site applicants are urged to formally affiliate with a 
Group applicant, although applications will be accepted from independent 
clinical sites for possible later linkage with the Group. 

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this program 
will be 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. Details of the responsibilities, relationships, 
and governance of a study funded under cooperative agreement(s) are discussed 
under the section Terms and Conditions of Award.

The total project period for applications submitted in response to this RFA 
may not exceed five years.  At this time, the NIAID has not determined whether 
and how this solicitation will be continued beyond the present RFA.

FUNDS AVAILABLE

The estimated total funds (direct and Facilities and Administrative Cost) 
available for the first year of support for all awards made under this RFA 
will be $36 million. In FY 2002 the NIAID plans to fund one (1) Group award. 
Although this program is provided for in the financial plans of the NIAID, 
awards pursuant to this RFA are contingent upon the availability of funds for 
this purpose and the receipt of a sufficient number of applications of high 
scientific merit.  Funding beyond the first and subsequent years of the grant 
will be contingent upon satisfactory progress during the preceding years and 
the availability of funds.

RESEARCH OBJECTIVES

Background

Many major advances in the care and prevention of pediatric HIV/AIDS have 
occurred since the existing PACTG last underwent competitive renewal in 1997.  
As a consequence, research priorities have rapidly evolved and become much 
more complex.  In the United States and other developed countries, new HIV 
infections in infants exposed to HIV in utero or neonatally have fallen 
sharply with the implementation of effective means to prevent mother-to-infant 
transmission.  In contrast to the successes in preventing mother-to-infant 
transmission of HIV, new infections in high-risk adolescents continue unabated 
and at an alarming rate.  Furthermore, both HIV-infected youth and those at 
high risk for HIV infection have been difficult populations to reach and 
engage in long-term health care and research programs.  Like HIV-infected 
adults, HIV-infected children have benefited from dramatic improvements in 
control of HIV replication and slowing of disease progression resulting form 
highly active antiretroviral therapy.  However, HIV-infected children were 
heavily pre-treated prior to the advent of highly suppressive antiretroviral 
regimens and they, their families and clinicians struggle with many questions 
including: what are the optimum treatment regimens to use?;  can more 
“pediatric friendly” regimens be developed?;  what are the most appropriate 
doses to use for treatment across the spectrum of pediatric ages?;  when is 
the best time to switch regimens and what tools should be used to guide that 
decision?;  what is the long-term clinical effectiveness of regimens that are 
currently recommended?;  what is the long-term safety of the drugs currently 
used to combat HIV in children on chronic therapy?;  and finally, now that 
HIV-infected pregnant women and their babies (infected and uninfected) are 
exposed to a growing number of powerful antiretroviral drugs, what are 
appropriate antiretroviral doses during pregnancy and what is the short and 
long-term safety of infants exposed in utero and neonatally to these 
antiretrovirals?  

Tragically, the impressive advances which have occurred in prevention of 
mother-to-infant transmission and treatment of HIV-infected women and children 
in the United States and other resource-rich nations are unavailable in most 
resource poor nations where the epidemic is at its worst and continues to 
accelerate at a staggering rate.  The NIH supports a comprehensive biomedical 
and behavioral research programs to address this complex array of problem.  
This RFA focuses on the component of that program directed to the research 
needs of the developed world.  Other components such as the HIV Prevention 
Trials Network (HPTN) and new initiatives to build and support greater basic 
and clinical research capacity are aimed at the epidemic in the developing 
world.  This RFA also requires collaborations between PACTG investigators and 
HPTN and other international investigators to facilitate scientific exchange 
and optimize resource utilization.

Research Objectives and Scope

The goal of this RFA is to establish a flexible, comprehensive pediatric 
clinical trials program to address the questions of highest priority in 
treatment of pediatric and adolescent HIV/AIDS and prevention of mother-to-
infant transmission.  The focus is on the needs of the epidemic in the U.S. 
and other developed countries.  This RFA seeks to re-focus pediatric HIV 
research priorities in the following areas: expand and enhance the adolescent 
research agenda and efforts to engage youth in treatment research 
opportunities; strengthen and augment long-term follow-up studies of safety 
and clinical effectiveness; continue pediatric treatment research at 
approximately the present level of effort; evaluate the safety, pharmacology 
and activity of new regimens and strategies that may be used in HIV-infected 
pregnant women.  Relevant objectives include, but are not limited to:

o  Support the development of novel interventions, drugs or biologics, to 
treat HIV infection in children and adolescents.

o  Assess the optimal use of and timing of the introduction of therapeutic 
modalities from acute/early infection through advanced disease

o  Evaluate the durability of potent antiretroviral regimens in suppressing 
viral replication and in impacting the developing immune system.

o  Identify novel therapeutic interventions to preserve or restore immunologic 
integrity, including studies of safety, toxicity and immunogenicity of 
experimental therapeutic HIV vaccines in pediatric populations.

o  Evaluate novel interventions against opportunistic diseases.

o  Investigate therapeutic interventions to elucidate the pathogenesis of HIV 
disease.

o  Support the development of novel strategies to prevent maternal–infant 
transmission of HIV as well as collaborate with other NIH programs to prevent 
infection of adolescents.

o  In collaboration with the HIV Vaccine Trials Network (HVTN), evaluate the 
safety, toxicity and immunogenicity of candidate vaccines to prevent HIV 
infection in pediatric populations.

o  Evaluate the long-term safety of antiretroviral therapies in uninfected 
infants exposed to antiretroviral agents (ARVs)

o  Evaluate the long-term impact of antiretroviral therapies in infants, 
children and adolescents treated with ARVs with particular emphasis on lipid 
abnormalities and other metabolic toxicities.

This RFA strongly encourages collaboration with the HPTN, HVTN and other 
research organizations or sites that are engaged in international research, 
both for scientific exchange and cross enrichment, and for consideration of 
international pediatric studies that are both scientifically appropriate and 
of high priority in both domestic and international settings.

SPECIAL REQUIREMENTS

TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator as well as the 
institutional official at the time of award.

The administrative and funding instrument used for this program is 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. Consistent with this concept, the dominant role and prime 
responsibility for the activity resides with the awardees for the project as a 
whole, although specific tasks and activities in carrying out the research 
will be shared among the awardees and the NIAID Scientific Coordinator.

Cooperative agreements are subject to the administrative
requirements outlined in OMB circulars A-102 and A-110.  All pertinent HHS, 
PHS, and NIH grant regulations, policies and procedures, with particular 
emphasis on PHS regulations at 42 CFR Part 52 and HHS regulations at 45 CFR 
Part 74 and 92, are applicable. These special terms and conditions pertaining 
to the scope and nature of the interaction between the NIAID and the 
investigators will be incorporated in the Notice of Grant Award.  However, 
these terms will be in addition to, not in lieu of, the customary programmatic 
and financial negotiations that occur in the administration of cooperative 
agreements.

I.  Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research 
objectives, approaches and details of the projects within the guidelines of 
the RFA, and for performing the scientific activity.  Awardees have primary 
responsibility as described below.

A.  Coordinating and Research Operations Center (CORC) or coordinating Center 
(CC) will be responsible for:

1.  Research Agenda - The Principal Investigator (Group Chair) of the CORC or 
CC will be responsible for developing, implementing, monitoring, and updating 
the Group research agenda.

2.  Bylaws/Operating Procedures - The Group Chair will be responsible for 
ensuring that there are well-documented policies, procedures, and Bylaws to 
guide all aspects of the Group activities and operations.

3.  Executive/Steering Committee - An Executive/Steering Committee will be 
established as the main governing body of the Group.  The Committee will be 
chaired by the Group Chair and will include: the Principal Investigator of the 
SDMC and the Director of the CORC's Operations Center; and the DAIDS TRP 
Associate Director (or designee); one community representative; and at least 
one clinical site Principal Investigator.

4.  Administrative Support - The CORC will be responsible for coordinating all 
research activities at the direction of the Group Chair or designee.  These 
activities include but are not limited to: (i) protocol development and 
implementation; (ii) administrative support for the Group Chair, scientific 
leadership, committees, and meeting coordination; (iii) maintenance of Group 
administrative records and archives; and;(iv) fiscal management and oversight 
of the Group resources.

5.  Protocol Development - The Group will initiate protocol development only 
when there is sufficient commitment among the membership to expeditiously 
complete accrual, analyze, and publish the research results.  There must be 
clear procedures for designating members of protocol teams and selecting units 
for limited site studies.  The Group must develop a mechanism to monitor the 
progress of studies throughout all stages and provide status reports to DAIDS 
on a mutually agreed upon schedule.  Early notification that a study is being 
considered must be provided to DAIDS to allow for comment on the scientific 
objectives relative to other NIAID/NIH research programs.  Prior to 
implementation, all protocols must be submitted to DAIDS for approval based on 
safety, ethics, and consistency with other NIH sponsored research.  DAIDS will 
communicate all decisions, in writing, to the Group.

6.  Laboratories - The Group Chair will be responsible for establishing a 
laboratory network in support of the research agenda.  Funds will be awarded 
to the CORC for laboratory support.  The Group Chair will: (i) identify the 
number, type and resources needed; and (ii) develop and implement a mechanism 
to evaluate performance, assess resource allocation, and redistribute funds as 
necessary.

7.  Study Oversight - The Group leadership will establish procedures to: (i) 
ensure adequate protection of the rights and safety of subjects involved in 
the research; (ii) guarantee the quality and integrity of the resulting data; 
(iii) maintain accurate and timely information on each study; and (iv) provide 
interim study summaries to the NIAID Therapeutic Data and Safety Monitoring 
Board as requested.

8.  Federally Mandated Regulatory Requirements - The Group must be in 
compliance with all Federal regulations, and NIH policies applying 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.

9.  Reporting Requirements - Administrative: The Group Chair will submit 
periodic reports to DAIDS on a mutually agreed upon schedule.  The reports 
will include, for example, lists of investigators and other key personnel, all 
affiliated sites, protocol abstracts, patient accrual and demographics, and 
publication information.  Annual Report: The Group Chair will submit to DAIDS 
an annual report summarizing group activity, accomplishments, performance 
evaluations and future directions.

10.  Performance Evaluation: The Executive/Steering Committee will establish 
procedures for evaluating the performance of all Group components and provide 
DAIDS with annual reports.  Procedures will include processes for the addition 
or elimination of clinical sites or laboratories, redistribution of resources 
among components based on performance measures such as patient 
accrual/retention, data quality and scientific contribution.  The process will 
include procedures for recommending to DAIDS annual adjustments to 
institutional budgets based on performance.  

11.  Publication of Data - Timely presentation and/or publication of major 
findings is essential and requires acknowledgment of NIAID support.  Prior to 
the submission of manuscripts for publication, a copy must be provided to 
DAIDS.  The awardee retains the rights to the data consistent with current 
HHS, PHS, and NIH policies; however, DAIDS under this cooperative agreement 
will have access to all data and may periodically review it.

12.  National Meetings - The Group is expected to hold at least one national 
meeting a year in the Washington, DC metropolitan area. Responsibility for 
logistics, scientific content, and fiscal support will be with the sponsoring 
group.

13.  Conflict of Interest - The Group will develop and implement a Conflict of 
Interest (COI) Policy acceptable to the NIAID, addressing any COI that may 
occur through financial interest or other associations between members of the 
Group and the private sector.

14.  Discretionary Funds - The CORC will maintain and manage a discretionary 
fund that must be expended through procedures consistent with the Bylaws.  The 
funds may be used for either scientific or operational needs such as, but not 
limited to, the addition of new clinical or laboratory sites, funding of 
innovative pilot studies, outsourcing laboratory work or supplementing 
superior performers.

15.  Community Representation - The Group will develop and implement a plan 
for community representation in Group activities. The plan should address how 
the representatives' inclusion will make a substantive contribution to the 
overall success of the Group.

16.  Demographic Diversity  - The Group must have plans in place to ensure the 
overall demographic diversity of study participants and have plans in place 
for incorporating new, minority and women investigators into the Group's 
activities.

17.  Collaboration - The Group will have a plan that details how it will 
interact with other NIAID/NIH-sponsored HIV/AIDS clinical research groups 
including procedures to integrate and complement the scientific agendas of 
other NIH Institutes to address specific pediatric HIV priorities.

B.  Statistical and Data Management Center (SDMC)

1.  Study Design, Conduct, Analyses, and Publications  - The SDMC will be 
responsible for:  (i) statistical leadership for the Group research agenda; 
(ii) performing interim analyses of safety and efficacy; (iii) generating 
executive summaries of study results for use by the protocol team, DAIDS, and 
collaborators; (iv) conducting final analyses and participating on publication 
writing teams; (v) performing cross-protocol analyses utilizing data from 
multiple sources; (vi) producing study monitoring reports for the Group and 
DAIDS; (vii) conducting analyses and summaries for annual and interim reports 
for DAIDS-sponsored Investigational New Drug Applications; and (viii) 
developing innovative clinical trial designs and analysis methodologies 
consistent with the Group research agenda.

2.  Data Management – The Statistical and Data Management Center will: (i) 
provide central registration and randomization for all study subjects; (ii) 
develop case report forms and standardized criteria for clinical endpoint 
verification; (iii) design and implement systems for the efficient tracking 
and transfer of clinical and laboratory data (including quality assurance and 
specimen tracking) to the central database; (iv) provide data management 
training to the clinical sites, laboratories, and the DAIDS Clinical Site 
Monitoring Contractor; (v) provide CRF notebooks to collaborators; (vi) 
provide for central storage, security, processing and retrieval of study 
results; and (vii) prepare selected public access databases.

3.  Collaborations - When collaborating with other clinical study groups, 
procedures of conduct will be determined by the Associate Director, 
Therapeutics Research Program (TRP) and the leadership of each participating 
Group.  Generally, the procedures of the lead Group will be followed.

4.  Management  - The SDMC must have a management plan and agree to abide by 
the Bylaws of the Group.

C. Coordinating Center 

The Terms of Award for the CORC and SDMC presented above will be merged into a 
single set of Terms for applicants choosing to use a Coordinating Center.

D.   Clinical Sites

1.  Clinical Site Responsibilities - Clinical Sites must agree to accept and 
abide by the Group’s Bylaws, the research priorities, and the performance 
standards. DAIDS-sponsored clinical research cannot be initiated at any 
performance site until a Site Establishment Plan is approved by DAIDS.

2.  Laboratory - Clinical site laboratory capabilities will be determined by 
the Group leadership.  The responsibilities of clinical site laboratories 
include: (i) processing and logging of clinical specimens; (ii) shipping of 
specimens to designated laboratories or repositories; (iii) performance of 
standard testing and other protocol mandated testing as designated by the 
Group Chair; (iv) participating in QA programs required by the Group.

3.  Investigational Drug Management - Investigators performing clinical 
studies sponsored by the NIAID must comply with all Federal regulations for 
investigational agents, and with DAIDS Standard Operating Procedures, and 
Pharmacy Guidelines and Procedures. 

4.  Quality Management - Clinical sites must establish a quality management 
plan to assess the accuracy and completeness of all research records, and 
operating procedures.  

5.  Site Monitoring  - Clinical sites shall cooperate with the DAIDS Clinical 
Site Monitoring Contractor, and other federally supported site monitoring 
staff who will inspect records to ensure compliance with all federal 
regulations, NIH policies on patient safety, quality management and data 
completeness and accuracy.

6.  Participation of New Investigators, Women and Minorities  - Clinical sites 
will establish procedures, and opportunities to ensure the participation of 
new investigators, especially women and racial/ethnic minorities, in all 
aspects of the research effort. 

7.  Community Advisory Boards (CAB) - All sites must establish a CAB 
representative of the HIV infected community in the catchment area.  The site 
should have plans that demonstrate how the CAB will be included in the 
activities to substantively contribute to the success of the unit.  Funds 
requested in the application must be made available to the CAB for 
reimbursement of reasonable expenses including representation at the annual 
Group meeting(s).  

II.  NIAID Responsibilities

NIAID staff assistance will be provided by the Associate Director, 
Therapeutics Research Program, who will serve as NIAID's Scientific 
Coordinator.  The NIAID Scientific Coordinator will have substantial 
scientific/programmatic involvement during the conduct of this activity 
through technical assistance, advice and coordination above and beyond normal 
program stewardship for grants, as described below.

The role of DAIDS staff described in these Terms is to assist and facilitate.  
Communication will be primarily with the Group Chair and the scientific 
leadership.  However, DAIDS will interact with the Principal Investigators of 
any affiliated institution as needed.  The following are specific 
responsibilities of DAIDS staff and the NIAID's role as an IND sponsor as 
defined in 21 CFR Part 312.

1.  Scientific Role in NIAID Sponsored Clinical Research - The Associate 
Director, TRP or designee will serve as a source of information and work 
closely with the Executive/Steering Committee to ensure that the research 
efforts are consistent with the NIAID priorities for HIV clinical research, 
and complement those of other NIAID and NIH programs.  The DAIDS will serve as 
the liaison between pharmaceutical companies, the FDA, and the Group.

2.  DAIDS Role in Protocol Development - In order for a clinical study to be 
initiated, the protocol must be approved by the chair of the DAIDS Clinical 
Science Review Committee (CSRC). The CSRC will evaluate the proposal relative 
to: (i) the NIAID priorities for HIV clinical research; (ii) subject safety; 
(iii) compliance with Federal regulations; (iv) study oversight and 
monitoring; and (v) feasibility of timely completion.  The Associate Director, 
TRP will return comments and recommendations to the Group within 30 days after 
review.  A DAIDS pharmacist will participate on the protocol team, consult on 
the pharmaceutical aspects of protocol development and will interact with 
pharmaceutical companies to ensure product availability.  If a protocol is 
disapproved, DAIDS will not provide study agents or permit expenditure of 
NIAID funds.

3.  DAIDS Involvement in IND Applications - The DAIDS will have the option to 
cross-file or independently file an INDA for study agents evaluated in Group 
studies.  The Chief, Regulatory Affairs Branch (RAB) will advise the 
investigators on specific regulatory requirements for INDA sponsorship.

4.  Clinical Trials Agreements (CTA) - When a pharmaceutical collaborator 
provides a study agent to DAIDS, a CTA will be negotiated describing 
respective responsibilities and rights.  The agreement will include, but is 
not limited to, INDA sponsorship, safety and data monitoring, and access to 
data.  The Group Chair generally will be consulted on the terms prior to the 
execution of the CTA.  Pharmaceutical collaborators generally request that 
patentable inventions discovered through the studies are brought to their 
attention, and the company has rights of first refusal provided that the 
collaborator has rights to the background patent.  Investigators will be 
required to agree to these terms.

5.  DAIDS Role During Study Conduct - A DAIDS Medical Officer will monitor the 
safety and efficacy of the intervention(s) for ongoing studies, and will be 
provided with interim and final reports.  When a collaborating institution or 
research group sponsors a protocol, their medical representatives will conduct 
monitoring activities.

6.  DAIDS Role in Protocol Closure - The Associate Director, TRP will monitor 
the progress of the studies by reviewing reports submitted to DAIDS through a 
Data and Safety Monitoring Board, and through regular meetings with the Group 
Leadership.  DAIDS may find it necessary to terminate an ongoing study for any 
of the following reasons:  (i) risk to subject safety; (ii) the scientific 
question is no longer relevant or the objectives will not be met; or (iii) 
slow accrual.

7.  Access to Data - The Associate Director, TRP or designated DAIDS 
contractor will have access to all data generated under this cooperative 
agreement, and may review the data as recorded on the case report forms or in 
the central database.  Data must be available for external checking against 
the original source documentation as required by federal regulations.  The 
awardees will retain the primary rights to the data consistent with HHS, PHS, 
and NIH policies.  The DAIDS has an external Clinical Site Monitoring Contract 
to evaluate Good Clinical Research Practice, regulatory compliance, accurate 
protocol implementation, internal quality management, and test product 
accountability.  The monitoring contractor will visit performance sites 
quarterly or as needed to review selected protocols, provide training on 
protocol conduct, review internal QM plans, audit pharmacies, and document 
error resolution.  The DAIDS may provide public access to selected data sets 
generated with the use of public funds within a reasonable time after the 
primary analysis and publication.

8.  Laboratory Quality Assessment - The DAIDS will provide through its 
contract resources support for laboratory quality assessment.  Management of 
the contracts will reside with DAIDS.  Scientific and technical oversight of 
these contracts will be provided by DAIDS in collaboration with Group 
investigators, and the Chief, Drug Development and Clinical Sciences Branch.

9.  Adverse Event Reporting - In order to provide for consistent adverse 
experience reporting across clinical trials groups, DAIDS has established 
policies and procedures delineated in the Serious AE Reporting Manual.  
Groups, in collaboration with DAIDS, will have the responsibility for ongoing 
maintenance of the modified ICD-9 system for classifying and coding the types 
of adverse experiences reported.

10.  DAIDS as a Resource for Performance Evaluation  - The performance of all 
Group components will be reviewed annually by the Associate Director, TRP 
using the comprehensive annual progress report, and site monitoring reports.  
The Chief, Clinical Research Management Branch, and the Chief of the Drug 
Discovery and Clinical Sciences Branch, TRP will assist the Group in 
developing evaluation instruments.  Substandard data, insufficient subject 
accrual or retention, inadequate progress in fulfilling the research agenda, 
non-compliance with federal regulations or these Terms of Award may result in 
a reduction in budget, withholding of support, or termination of award.  If 
the Group Chair proposes to redirect resources among affiliated member awards, 
DAIDS concurrence is required.

III.  Collaborative Responsibilities  

Group Governance - The Group Chair will establish an Executive/Steering 
Committee as the central decision making body for the Group.  The Committee 
will include the DAIDS TRP Associate Director (or designee) as a voting 
member.  A Chairperson, other than the DAIDS Official, will be elected by the 
Group membership as defined in the Bylaws.

IV.  ARBITRATION

Any disagreement that may arise on scientific or programmatic matters (within 
the scope of the award) between award recipients and the NIAID may be brought 
to arbitration.  An arbitration panel will be composed of three members: one 
selected by the Steering Committee or by the individual awardee in the event 
of an individual disagreement; a second member selected by the NIAID; and the 
third member with expertise in the relevant area who is selected by the two 
other members. Together they will review any scientific or programmatic issue 
that is significantly restricting progress.  While the decisions of the 
Arbitration Panel are binding, these special arbitration procedures will in no 
way affect the awardee's right to appeal an adverse action in accordance with 
PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR 
Part 16.

STUDY POPULATIONS

The study population is limited to HIV infected infants, children, 
adolescents, and pregnant women.

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 subpopulations 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 policy results from the NIH Revitalization Act of 1993 (Section 
492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines For Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at: 
(http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm).  The 
revisions relate to NIH-defined Phase III clinical trials and require:  a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and which is available at the following 
URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 
Investigators may obtain copies from these sources or from Frederick Batzold 
listed in INQUIRIES below who may also provide additional relevant information 
concerning the policy.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit by November 15, 2000 a letter of 
intent that includes a descriptive title of the overall proposed research; the 
name, address and telephone number of the Principal Investigator; and the 
number and title of this RFA.  Although the letter of intent is not required, 
is not binding, does not commit the sender to submit an application, and does 
not enter into the review of subsequent applications, the information that it 
contains allows NIAID staff to estimate the potential review workload and to 
avoid conflict of interest in the review.  

The letter of intent is to be sent to Dr. Peter R. Jackson at the address 
listed under INQUIRIES. 

APPLICATION PROCEDURES

Pre-Application Meeting

There will be a one-day meeting in the Washington, DC metropolitan area to 
provide potential applicants with background information and to answer 
questions from potential applicants.  For details about the meeting, please 
contact Dr. Frederick Batzold at the address listed under INQUIRIES or go to 
the URL listed below.  Information about this meeting and a detailed summary 
that will include NIAID responses to all questions raised by attendees at the 
meeting, will be available upon request as well as being available via an 
NIAID Internet site at URL: 
http://www.niaid.nih.gov/daids/pediatrictrialsrfa.htm

Applications

Applicants are strongly encouraged to call NIAID program staff with any 
questions regarding the responsiveness of their proposed project to the goals 
of this RFA.  

Applications are to be submitted on the grant application for PHS 398 (4/98).  
These forms are available at most institutional offices of sponsored research; 
from the Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, 
telephone 301/435-0714, email: GrantsInfo@nih.gov; and on the internet at 
http://grants.nih.gov/grants/forms.htm.

For purposes of identification and processing, item 2a on the face page of the 
application must be marked "YES" and the RFA number AI-00-015 and the words 
"Pediatric Clinical Trials Program for AIDS" must be entered on the face page.

Applications must be received by March 21, 2001.  Applications not received on 
the receipt date or not conforming to the instructions contained in PHS 398 
(4/98) Application Kit (as modified in, and superseded by, the special 
instructions below, for the purposes of this RFA), will be judged non-
responsive and will be returned to the applicant. 

The RFA label and line 2 of the application should both indicate the RFA 
number.  The RFA label must be affixed to the bottom of the face page.  
Failure to use this label could result in delayed processing of the 
application such that it may not reach the review committee in time for 
review.

The sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

If the application submitted in response to this RFA is substantially similar 
to a grant application already submitted to the NIH for review, but that has 
not yet been reviewed, the applicant will be asked to withdraw either the 
pending application or the new one.  Simultaneous submission of identical 
applications will not be allowed, nor will essentially identical applications 
be reviewed by different review committees.  Therefore, an application that is 
essentially identical to one that has already been reviewed cannot be 
submitted in response to this RFA.  This does not preclude the submission of 
substantial revisions of applications already reviewed, but such applications 
must include an introduction addressing the previous critique.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for Express Mail or Courier Service)

At the time of submission, two additional exact copies of the grant 
application and five sets of any appendix material must be sent to Dr. Peter 
Jackson list under “Inquiries”.

Applicants from institutions that have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources may wish to 
identify the GCRC as a resource for conducting the proposed research.  If so, 
a letter of agreement from either the GCRC Program Director or Principal 
Investigator should be included with the application.

SPECIAL INSTRUCTIONS

APPLICATION PACKAGE

A Principal Investigator who proposes to form a Group and assume the role as 
Group Chair is responsible for coordinating the preparation of a package that 
will include the following applications: One (1) Coordinating and Research 
Operations Center; One (1) Statistical and Data Management Center; and One (1) 
proposal for each individual Clinical Site [The number of clinical sites 
should be based on the scope of the research agenda].

If the Group Chair chooses to use a Coordinating Center for both operational 
and statistical and data management support, a single application should be 
submitted for both components.

For all applications:

A complete PHS Form 398 (4/98) must be submitted.

On Page 2 (Key Personnel) all professional personnel and their institutional 
affiliations for the project must be listed including those with no requested 
salary support.

Each Biographical Sketch (limited to 3 pages) and the Other Support page 
should be positioned at the end of the application with the Principal 
Investigator first followed by other key personnel in alphabetical order.

The use of tables, diagrams, organizational and flow charts is strongly 
encouraged.

Key information submitted in the appendix should be clearly referenced in the 
Research Plan Section.  Information submitted as appendices should be limited 
to essential materials in support of the application; summaries or examples of 
information are encouraged.  Letters of support that do not formally commit to 
contributions to the program should not be included.

A.  Core Application [Coordinating and Operations Research Center (CORC)]

The Research Plan (Items a-d) is not subject to the page limitations in the 
PHS Form 398.  This section of the application should not exceed 300 Pages.  
Appendices should be limited to 150 pages excluding reprints of publications 
and Annual Reports.

The Research Plan should address the following:  
1.  Comprehensive Research Agenda including the scientific priorities, key 
leadership, criteria for affiliated domestic and international clinical sites 
and laboratories. 
2.  Comprehensive Management Plan that addresses:
o  Bylaws for governance including the election of Group Leadership and 
committee membership.
o  Operational plans for the delegation of authorities, decision-making, and 
fiscal management.
o  Operational plans for the integration of NICHD participating clinical 
sites.
o  Performance evaluation plans and standards for participating institutions 
including corrective measures.
o  Outreach Plan to ensure the inclusion of women, minorities and community 
representatives in all aspect of the proposed research and Group activities.
o  Procedures for protocol development, implementation and oversight; and 
committee management.
o  Plan for collaborating with important and relevant HIV treatment or 
prevention study groups, including but not limited to the:
i.  Adult ACTG – adolescent and women’s health issues  (Required). 
ii.  HPTN – domestic adolescent agenda and coordination of domestic and 
international perinatal prevention studies (Required).
iii.  HVTN – perinatal and adolescent preventive vaccine studies 
(Required).
iv.  Adolescent Medicine Trial Network – adolescent treatment studies 
(Required).
v.  Pediatric European Network for Treatment of AIDS    (PENTA) - shared 
pediatric agenda treatment trials (Recommended).

o  Plan for other potential collaboration with international investigators.

CORC budget requests must be related to, and justified by, the scope of 
activities proposed in the research agenda.

A composite budget should be included, followed by individual budgets.  At a 
minimum the budget request should include four categories: (i) Operations 
Center, (ii) administrative support for the Group Chair, scientific committees 
and annual meetings; (iii) laboratories; and (iv) discretionary funds not to 
exceed 15% of the total cost budget request.

B.  Statistical and Data Management Center (SDMC)

The Research Plan (items a-d) is not subject to the page limitations in the 
PHS Form 398.  This section of the application should not exceed 150 Pages.  
Appendices should not exceed 150 pages excluding reprints of publications.

The Research Plan should address the following:

1.  Statistical expertise that complements the Group research agenda.
2.  Innovative approaches to clinical trials methodology.
3.  Data management expertise including: database design and procedures for 
managing both clinical and laboratory data, and plans for evaluating new 
methodologies for data transmission and systems design.
4.  Operational, procedural and overall management plans for the SDMC.

The SDMC budget request must be related to and justified by the scope of 
activities proposed in the research agenda.

C.  Coordinating Center (CC)

Applicants may choose to combine the activities of a CORC and SDMC into a 
single Coordinating Center.  The Research Plan for the CC is not subject to 
the page limitations in the PHS Form 398, item a-d.  Since a CC is composed of 
a CORC and SMDC, this section should not exceed 400 Pages. Appendices should 
not exceed 200 pages excluding reprints of publications and Annual Reports.

The CC application should address all the areas included within the CORC and 
SDMC applications described above.

D.  Clinical Sites

The Research Plan (items a-d) for each Clinical Site application is subject to 
the 25 page limitation. Appendices should not exceed 50 pages excluding 
reprints of publication.

The Research Plan Section should address the following:

1.  Clinical sites named in the Core Application should describe site 
expertise, and past accomplishments in pediatric HIV clinical research and how 
the site will contribute to the Group research agenda particularly with regard 
to recruitment and retention of HIV-infected infants, adolescents, and 
pregnant women. Independent clinical site applications should describe site 
expertise and past accomplishments in pediatric HIV clinical research and how 
the site will contribute to the research objectives in the RFA. 
2.  Operational/Management Plan including subject accrual potential, quality 
management, and regulatory compliance.
3.  Outreach Plan to assure the inclusion of women and minorities in all 
aspects of site activities.
4.  Plan for establishing and supporting a Community Advisory Board (CAB) 
representative of the catchment area.

Clinical site budget requests should be based on; (i) the scope of work 
proposed; (ii) the projected number of new subject accruals; and (iii) on-
going commitments to subjects for incumbent applicants.

Clinical site applicants named in the Core Application should use the resource 
allocation criteria developed by the Group Leadership.

Independent clinical site applicants should use the projected patient census 
as the basis for budget development.

All clinical sites must include a budget request to support CAB activities 
including representation at the annual Group meeting(s).

REVIEW CONSIDERATIONS  

GENERAL CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the NIH Center 
for Scientific Review, and by NIAID staff for responsiveness; those judged to 
be incomplete or non-responsive will be returned to the applicant without 
review.

Applications that are complete and responsive to this RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group(s) 
convened by the NIAID.  As part of the initial merit review, all applications 
will receive a written critique and undergo a process in which only those 
applications deemed to have the highest scientific merit, generally the top 
half of the applications under review, will be discussed, assigned a priority 
score, and receive a second level review by the National Advisory Councils of 
the sponsoring NIH Institutes. 

The second level of review will be provided by the National Advisory Allergy 
and Infectious Diseases Council.

REVIEW CRITERIA

The criteria to be used in the evaluation of applications in response to this 
RFA are listed below. 

A.  Core Application (Coordinating and Operations Research Center)

1.  Qualifications and experience of the Group Chair and the named Scientific 
Leadership in the design, implementation, and management of multicenter 
pediatric HIV clinical research.
Significance and innovativeness of the research agenda in addressing the 
objectives of the pediatric agenda.
2.  Quality of the management plan to set/redirect priorities, initiate 
studies, and govern Group activities.  
3.  Adequacy of past performance of existing Groups including enforcement of 
Group standards.  New Group applicants should present a plan for evaluating 
performance and ensuring compliance with the standards of the Group. 
4.  Qualifications and experience of the CORC's Operations Center Director and 
staff, and the administrative management plan.
5.  Adequacy of the criteria and standards used for inclusion of affiliated 
clinical sites and laboratories.
6.  Adequacy of (i) proposed performance standards; (ii) the process for 
performance evaluation; and (iii) resource reallocation for all Group 
components.
7.  Adequacy of the plan for the inclusion of women, minorities, and community 
representation in Group activities.

B.  Statistical and Data Management Center

1.  Qualifications and experience of the Principal Investigator and staff in 
providing statistical and data management expertise for pediatric HIV 
therapeutic multicenter clinical studies including the development of 
innovative trial designs, and analyses consistent with the Group research 
agenda.
2.  Quality of the plan for both clinical and laboratory database designs, 
data collection, cross-study analyses, database security, and site specific 
training.
3.  Quality of the plan to evaluate new data management technologies and data 
collection procedures

C. Applications proposing to use a single Coordinating Center for both 
operational and statistical/data management support will be evaluated on the 
combined criteria described above for the Core (CORC) and SDMC applications.

D.  Clinical Sites

1.  Qualifications and experience of the Principal Investigator and the staff 
in conducting pediatric HIV clinical trials, and the ability to contribute to 
the research objectives in the RFA.
2.  Quality of the site management plan for conducting research studies 
including data management, and regulatory compliance.
3.  Ability to accrue and retain a demographically diverse patient population 
representative of the catchment area consistent with accrual projections.
4.  Adequacy of the plans to involve community representatives in all aspects 
of site activities.

The initial review group(s) will also examine: (i) the appropriateness of the 
proposed project budget and duration; (ii) the adequacy of plans to include 
both genders and minorities and their subgroups where they are included; (iii) 
the provisions for the protection of human and animal subjects; and (iv) the 
safety of the research environment.

Schedule

Letter of intent receipt date:  November 15, 2000
Application receipt date:       March 21, 2001
Scientific review date:         September 2001
Advisory Council date:          January 17, 2002
Earliest award date:            March 1, 2002

AWARD CRITERIA
  
Funding decisions will be made on the basis of scientific and technical merit 
as determined by peer review, program balance, and the availability of funds.  
The earliest anticipated date of award is March 1, 2002.

INQUIRIES  
  
Written and telephone inquiries concerning this RFA are encouraged.  The 
opportunity to clarify any issues or questions from potential applicants are 
welcome.  Further information can be found at the World Wide Web site: 
http://www.niaid.nih.gov/daids/pediatrictrialsrfa.htm

Direct inquiries regarding programmatic (research scope and eligibility) 
issues to:

Dr. Frederick Batzold
Division of AIDS
National Institute of Allergy and Infectious Diseases  
Room 5154, MSC-7624
6700-B Rockledge Drive
Bethesda, MD  20892-7624
Bethesda, MD  20817 (For Express Mail or Courier Service)
Telephone:  (301) 402-0143
FAX:        (301) 480-4582
E-Mail:     fb10c@nih.gov
  
Direct inquiries regarding review issues; address the letter
of intent to; and mail two copies of the application and all
five sets of appendices to:
  
Peter Jackson, Ph.D.  
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2154, MSC-7616
6700-B Rockledge Drive  
Bethesda, MD  20892-7616
Bethesda, MD  20817 (For Express Mail or Courier Service) 
Telephone:  (301) 496-8426
FAX:        (301) 402-2638
E-Mail:      pj8v@nih.gov

Direct inquiries regarding fiscal matters to:  

Ann Devine
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2118, MSC-7614
6700-B Rockledge Drive  
Bethesda, MD  20892-7614
Bethesda, MD  20817 (For Express Mail or Courier Service) 
Telephone:  (301) 402-5601
Fax:        (301) 480-3780
E-mail:     ad22x@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic Assistance No. 
93.856(Use appropriate program number.  NIAID citations are Sec. 93.856, 
Microbiology and Infectious Diseases Research, and No. 93.855 - Immunology, 
Allergy, and Transplantation Research.) Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 
and 284) and administered under NIH grants policies and Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.

The Public Health Service strongly encourages all grant and contract 
recipients to provide a smoke-free workplace and promote the non-use of all 
tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 
1994, prohibits smoking in certain facilities (or, in some cases, any portion 
of a facility) in which regular or routine education, library, day care, 
health care or early childhood development services are provided to children.  
This is consistent with the PHS mission to protect and advance the physical 
and mental health of the American people.


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