ACUTE INFECTION AND EARLY DISEASE RESEARCH PROGRAM

Release Date:  February 22, 2001

RFA:  RFA-AI-01-008

National Institute of Allergy and Infectious Diseases
 (http://www.niaid.nih.gov/)

Letter of Intent Receipt Date:  August 16, 2001
Application Receipt Date:       October 10, 2001

PURPOSE

The Division of AIDS (DAIDS), National Institute of Allergy and 
Infectious Diseases (NIAID), solicits applications for the competitive 
continuation of a program to study the pathogenesis of acute/early HIV 
infection in adult humans, and to develop and evaluate the impact of 
therapeutic interventions at this early stage of HIV disease.

This program was initiated under PAR-96-060, Acute Infection and Early 
Disease Research Network. There are seven current cooperative agreement 
(U01) awardees, six clinical units and a coordinating center.

The goal of this initiative is to maintain a program of five to seven 
HIV Acute Infection and Early Disease Research Units and one Statistical 
and Coordinating Center, through cooperative agreements (U01).  Each 
awarded unit will perform innovative, integrated, investigator-initiated 
pathogenesis and clinical research on acute and early HIV infection and 
will place emphasis on performing collaborative multi-unit research 
projects as part of the Acute Infection and Early Disease Research 
Program (AIEDRP).  The multi-unit structure is required in order to 
enroll sufficient numbers of these difficult-to-identify acutely HIV-
infected subjects for study.

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 (RFA), Acute Infection and Early Disease Research Program, 
is related to one or more of the focus areas. 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 non-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 are encouraged to participate as part of a domestic 
application.  Racial/ethnic minority individuals, women, and persons 
with disabilities are encouraged to apply as Principal Investigators.

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.  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.  Details of the responsibilities, relationships, and 
governance of a study funded under cooperative agreement(s) are 
discussed later in this document 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 
(F&A) costs) available for the first year of support for all awards 
(competitive renewal and new) made under this RFA will be $11.7 million.  
In Fiscal Year 2002, the NIAID plans to fund approximately 5-7 units and 
1 Statistical and Coordinating Center.  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 availability of funds.

RESEARCH OBJECTIVES

BACKGROUND

In the US, the incidence of HIV is approximately 40,000 cases per year, 
and the worldwide incidence is estimated to be 5.4 million cases per 
year.  While there is accumulating data that HIV infection can be 
effectively blocked with appropriate perinatal therapy and post-exposure 
prophylaxis, once HIV infection is established in the human host a 
predetermined chain of events is set into motion. Acute HIV infection is 
associated with extremely high levels of viremia, rapid seeding of viral 
reservoirs, and significant perturbations of cytokine production and 
host immune defenses. Yet, the clinical presentation of acute HIV 
infection can range from an asymptomatic infection to a non-specific 
mononucleosis-like syndrome.  

An enhanced understanding of acute HIV infection is critical to 
furthering our knowledge of HIV pathogenesis and natural history. 
Elucidation of factors important in transmission may be useful for 
identifying new mechanisms to prevent the spread and establishment of 
HIV infection. Study of viral reservoirs established early during acute 
infection and the viral dynamics in these reservoirs may also help 
suggest new interventions to eliminate the spread of HIV and new 
therapeutic mechanisms and targets by which to suppress viral 
replication. Study of the immune system responses from the acute through 
the early stages HIV infection may lead to significant improvements in 
our ability to slow the rate of HIV disease progression and prolong 
survival. Antiviral and/or immunological interventions during 
acute/early infection may have dramatic impact upon disease progression 
and survival.  For example, early treatment with antiretroviral therapy 
does much to preserve immune system function.  Following patients 
throughout the course of HIV infection, beginning at the time of acute 
infection, may provide additional insight into the natural history of 
the disease.  Identifying the prevalence of HIV resistance in acutely 
infected patients may provide additional insight into the epidemiology 
of HIV.

The epidemiology of acute HIV infection has complicated the HIV research 
community’s ability to access this population that is one of the most 
difficult to identify, enroll, and follow.  Therefore, it is important 
to identify investigators and sites that can access this population and, 
in turn, utilize it to perform state-of-the-art clinical and basic 
science HIV research.

In FY97, six units were awarded grants to establish the AIEDRP.  A 
seventh unit was funded in FY98.  Much of the work in the early years of 
the AIEDRP has focused on the development of an infrastructure, the 
establishment of common data requirements, and the development of 
clinical and pathogenesis trials.  Shortly after the formation of the 
AIEDRP, the investigators established a statistical center to develop 
and maintain a common database for the AIEDRP.  Continuation of the 
AIEDRP is needed to extend the research begun through the multiple 
projects and to expand on the collaborative studies that may validate 
results that may with potential relevance for a broader patient 
population.

Additional information about the current AIEDRP may be found at the 
group"s Web site (http://www.aiedrp.org/).

RESEARCH SCOPE AND OBJECTIVES

This initiative will support innovative, integrated pathogenesis and 
clinical research of acute and early HIV infection in human subjects age 
13 years and older.  For the purpose of this RFA, working definitions of 
acute and early HIV infection are as follows:

Acute HIV Infection:

o Detectable plasma HIV RNA or detectable HIV p24 antigen with a 
negative ELISA, or detectable ELISA with a negative or indeterminate 
Western blot (indeterminate Western blot as defined by the Centers for 
Disease Control and Prevention (CDC))

Early HIV Infection:

o A positive ELISA with a positive detuned assay,

(Detuned assay is defined as a less sensitive HIV EIA, such as the 
Abbott Laboratories, 3A11-LS EIA assay)

or 

o A positive ELISA and Western blot with a documented negative 
serologic test within the past 12 months 

The initiative will support single-unit and multi-unit clinical research 
on HIV pathogenesis, therapeutic interventions, and factors that 
influence response to interventions.  In addition, the initiative will 
support a central Scientific Planning Committee and a Statistical and 
Coordinating Center to direct and support multicenter collaborative 
research studies.

Initial observations on pathogenesis and treatment are often conducted 
in small pilot studies.  In order to validate the preliminary results of 
these novel studies, a larger number of subjects will be needed.  The 
investigators of the AIEDRP are expected to collaborate extensively with 
other AIEDRP investigators in order to achieve this goal.  Furthermore, 
in order to understand the long-term safety and efficacy of early 
therapeutic interventions, the AIEDRP must maintain long-term follow-up 
of individuals diagnosed with acute and early HIV infection.

Each unit will be comprised of basic and clinical scientists, and will 
include one or more sites, coordinated under the direction of a 
Principal Investigator, and each unit will be part of the AIEDRP.  The 
structure of the AIEDRP and funding are not linked to a specific 
experiment or clinical trial.  Thus, this mechanism has the potential 
for considerable flexibility in resource allocation that will facilitate 
the rapid testing of hypotheses about the pathogenesis of HIV infection 
and of early-phase clinical interventions.

AIEDRP Units

In order to address the scientific needs of the initiative, each unit 
should:

o Identify, accrue and retain acute/early HIV positive individuals for 
pathogenesis studies and clinical trials.  This requires strong linkages 
with, and intense screening from, unique referral sources such as 
sexually transmitted diseases (STD) clinics, emergency rooms, blood 
banks, and primary care centers, as well as close collaboration with 
centers and investigators studying existing natural history cohorts.  
The projected enrollment of each AIEDRP unit should be at least 30 to 50 
patients per year. Of the total number of subjects, approximately 10 
subjects per year should be acutely infected.  Applications may include 
studies on ways to improve detection and recruitment of newly infected 
individuals. 

o Conduct independent and collaborative (both through the AIEDRP and 
with non-AIEDRP investigators) studies of the in vivo pathogenesis of 
early HIV disease. 

o Evaluate and optimize therapeutic interventions in small, focused 
clinical studies and in larger collaborative studies involving two or 
more units, perform extensive virologic and immunologic evaluations that 
will provide new insights into the pathogenesis of acute/early HIV 
infection and the potential effectiveness of therapeutic approaches.  
The identification and use of existing resources (such as the Adult and 
Pediatric AIDS Clinical Trials Networks (AACTG and PACTG), HIV 
Prevention Trials Network (HPTN), Adolescent Medicine Trials Network 
(ATN), and the Centers for AIDS Research (CFAR)) should be extensive.  
The banking and storage of specimens for later analyses and for use in 
collaboration with investigators outside the AIEDRP is encouraged.

o Participate actively in AIEDRP activities, through regular 
participation in, and contributions to, the Scientific Planning 
Committee, and by participation in multi-unit evaluation (Phase I/II and 
Phase II clinical studies) of novel therapeutic interventions and large 
controlled pathogenesis-related studies in acute infection and/or early 
HIV disease.

o Contribute data to a common database for cross-study analyses and 
long-term follow-up.

Scientific Planning Committee

A Scientific Planning Committee (SPC) will be established to foster, 
coordinate, and facilitate collaborative activities within the AIEDRP.  
The composition and specific responsibilities of the AIEDRP SPC are 
noted below.

Statistical and Coordinating Center

AIEDRP units should support their own local biostatistical 
collaborators.  The central Statistical and Coordinating Center (SCC) 
will provide biostatistical collaboration for multi-unit research 
protocols and, in rare cases and at the direction of the SPC, for those 
units without such resources.  The SCC also will provide central data 
management support for core AIEDRP data and will support network 
administrative functions (operational support).

A.  With respect to biostatistical collaboration, the SCC will:

o Provide biostatistical collaboration in the design and analysis of 
clinical and basic science studies, whether single- or multi-unit, when 
requested by the unit investigators.

o Facilitate interactions among local unit biostatistical groups so 
that the entire AIEDRP may benefit from specific statistical expertise 
of any one of the local groups.

B.  A core dataset, representing fundamental clinical and laboratory 
data, will be collected in a standardized way with common data forms in 
the context of all clinical study protocols within AIEDRP.  This dataset 
will facilitate future meta-analyses of data across protocols to study 
the safety and benefit of interventions of acute and early HIV infection 
and also will form the basis for creation of a long term AIEDRP cohort.

With respect to the core dataset, the SCC will:

o Collaborate with site investigators to identify the standard data 
items comprising the core dataset and collection instruments, and 
training in their use.

o Provide central management, data editing, and quality control of the 
core dataset.

o Provide the AIEDRP investigators with summaries of the core data as 
needed for quality control, study planning, and analysis purposes.

C.  The SCC will establish an administrative support office to perform 
network administrative and operational duties.  Functions of the office 
will include, but are not limited to:

o Supporting conference calls and meetings of the SPC by coordinating 
the development of the agendas, scheduling calls and meeting sites, 
preparing conference materials, and writing and disseminating conference 
summaries, in addition, coordinating unit staff training for multi-unit 
studies.

o Maintaining files of AIEDRP materials including study protocols, 
minutes of meetings and conference calls, reports, correspondence, 
safety information, abstracts, and publications.

o Maintaining a directory of AIEDRP participants and distribution lists 
and coordinating communications.

o Preparing and distributing reports and newsletters on AIEDRP 
activities and progress.

o Conducting a visit to each AIEDRP unit early in the project period to 
provide training and orientation, and making follow-up visits to units 
requiring extra assistance during the course of the project.

o At the direction of the SPC, the administrative support office will 
coordinate the research activities of individual research projects (for 
example, large, multi-unit projects and complex single unit, multi-site 
projects), including assistance with protocol development and 
distribution, and coordinating communications with regulatory and 
pharmaceutical representatives.

SPECIAL REQUIREMENTS

Each applicant should develop a scientific agenda that includes 
proposals for collaborative studies with other AIEDRP Units.  Over the 
five-year funding period, the AIEDRP will increasingly emphasize 
collaborative studies, however, independent pilot studies may still be 
included as part of the scientific agenda.

Multi-unit research activities of the AIEDRP will be overseen by the 
AIEDRP SPC.  The AIEDRP will meet twice yearly to provide updates on the 
progress of research.  One meeting will be a large meeting to review the 
progress being made in acute infection research and to discuss potential 
areas for collaborations.  The second meeting may be a small meeting to 
focus on one or two topics that the AIEDRP investigators feel is of 
particular relevance to advance the work of the AIEDRP.  The agenda for 
these meetings will be set by the SPC.

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.

These Terms of Award are in addition to, and not in lieu of, otherwise 
applicable OMB administrative guidelines, HHS Grant Administration 
Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant 
Administration policy statements.

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.  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 
this concept, the dominant role and prime responsibility for the 
activity resides with the PIs for the project as a whole, although 
specific tasks and activities in carrying out the research will be 
shared among the PIs 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, are applicable. The 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.

1.  Monitoring Clinical Studies

When clinical studies or trials are a component of the research 
proposed, NIAID policy requires that studies are monitored commensurate 
with the degree of potential risk to study subjects and the complexity 
of the study.  Terms and Conditions of Award will be included with 
awards.  NIAID policy was announced in the NIH Guide on February 24, 
2000 and is available at:  
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-00-003.html.

2.  Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research 
objectives, approaches and details of the projects within the guidelines 
of RFA AI-01-008 and for performing the scientific activity. 
Specifically, awardees have primary responsibility for:

a.  research design, protocol development, implementation, participant 
recruitment and follow-up, data collection, quality control, interim 
data and safety monitoring, final data analysis, and publication of 
results.  All protocols and protocol amendments developed and conducted 
by the AIEDRP will be submitted to the NIAID Program Officer for review 
and approval by the DAIDS Clinical Science Review Committee (CSRC) as 
noted below prior to FDA submission or implementation.  A formal plan 
for monitoring the conduct of the study is to be included in each 
protocol submitted for CSRC review.

b.  establishing a Scientific Planning Committee (SPC) with the other 
Principal Investigators to facilitate information exchange, foster 
collaboration, and coordinate activities to reduce duplication.

c.  proposing concepts to the SPC for collaborative pathogenesis and 
therapeutic studies, functioning as the scientific coordinator for 
protocols (Protocol Chairperson) and assuming responsibility for 
monitoring study performance.

d.  establishing mechanisms for internal quality control and monitoring. 
Awardees are responsible for ensuring the accurate and timely assessment 
of the progress of studies, including the development of procedures to 
ensure that data collection and management are adequate for quality 
control and analysis.

e.  preparing and submitting interim progress reports, when requested, 
to the NIAID Program Officer including summary data on progress of 
multi-unit studies.  The SPC may require additional information on 
multi-unit studies from the individual awardees/sites.

f.  timely presentation and/or publication of major findings.  This is 
essential and requires acknowledgment of NIAID support. A copy of 
manuscripts for work supported by this mechanism must be provided to the 
NIAID Program Officer.  The awardee retains the rights to the data 
consistent with current HHS, PHS, and NIH policies, under this 
cooperative agreement, however, the NIAID will have access to all data 
and may periodically review it.

g.  inclusion or establishment of a Community Advisory Board (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 substantially 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 
Group meeting(s).

h.  The central Statistical and Coordinating Center (SCC) will provide 
biostatistical collaboration for multi-unit research protocols and, in 
rare cases and at the direction of the SPC, for those units without such 
resources.  The SCC also will provide central data management support 
for core AIEDRP data and will support network administrative functions 
(operational support)

3.  NIAID Responsibilities

The NIAID Program Official 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.

a.  Monitoring of study progress, which may include:

(i) periodic site visits for discussions with awardee research teams.

(ii) observation of field data collection and management techniques, 
quality control, fiscal review, and other relevant matters.

(iii) attendance at, and participation in, the SPC and other meetings.  
The NIAID retains, as an option, periodic external review of progress.

b.  Serving as a resource with respect to other ongoing NIAID activities 
that may be relevant to the AIEDRP’s research and facilitating 
compatibility to avoid study duplication.

c.  Assisting substantially in the design and coordination of research 
activities for awardees including: 

(i) providing advice on the management and technical performance of the 
investigations.

(ii) facilitating access to and use of reagents, assays, and other 
resources available through NIAID contractors and repositories.

(iii) providing technical advice and assistance with FDA regulatory 
requirements for investigational agents.

(iv) For multi-unit protocols and through participation on the SPC, a 
NIAID Representative may coordinate activities among awardees by 
assisting with: the design, development, and coordination of a common 
research or clinical protocol and statistical evaluations of data, the 
preparation of data recording forms, and the publication of results.

(v) The CSRC will review and approve single- and multi-unit clinical 
trial protocols to ensure that they are within the scope of the AIEDRP 
and are adequate with respect to patient safety, human subject 
protections, and representation of women and minorities, as required by 
Federal regulations.  The NIAID will monitor protocol progress, and may 
request that a protocol be closed to accrual for reasons including:  (1) 
accrual rate insufficient to complete study in a timely fashion, (2) 
accrual goals met early, (3) poor protocol performance, (4) patient 
safety, human subjects, and women/minority recruitment concerns, (5) 
study results that are already conclusive, and (6) emergence of new 
information that diminishes the scientific importance of the study.  The 
NIAID will not permit further expenditure of NIAID funds for a study 
after requesting closure (except for patients/subjects on-study and 
final data analysis and reporting).

(vi) reviewing and providing advice regarding the establishment of 
mechanisms for quality control and study monitoring for multi-center 
clinical trials.

4.  Collaborative Responsibilities

In addition to the interactions defined above, awardees and NIAID staff 
shall form a Scientific Planning Committee (SPC) formed by the Unit 
Principal Investigators or their designees, 1-2 representative(s) from 
the Statistical and Coordinating Center, and a NIAID representative.  

The AIEDRP SPC will coordinate collaborative AIEDRP activities, 
including multi-unit clinical projects, through e-mails, conference 
calls, and meetings..  The AIEDRP SPC serves to facilitate information 
exchange, foster collaboration, and coordinate activities to minimize 
duplication.  Additionally, the AIEDRP should have the capability and 
flexibility to conduct multi-unit clinical trials involving a larger 
number of patients (Phase II studies) as scientific opportunities become 
available.  The AIEDRP SPC will identify the highest priority research 
questions requiring multi-unit study.

An initial meeting will be convened early after award by the NIAID 
Program Official.  The final structure of the committee will be 
established at the first meeting.  The NIAID representative(s) will have 
voting membership on the committee and, as appropriate, its 
subcommittees, but may not serve as Chair of a committee or 
subcommittee.

The SPC should meet at least quarterly, either in person or by 
conference call, to:

o Discuss issues related to enrollment in AIEDRP protocols.

o Review and approve multi-unit concept sheets submitted by AIEDRP 
investigators. 

o Develop and approve collaborative projects.

o Make decisions regarding future research directions.

o Create focus groups to address specific aspects of the AIEDRP 
  research agenda, with emphasis on multi-unit collaborative projects.

o Designate a Protocol Chairperson for each multi-unit research study.

o Define core data collection strategies, as well as methods and 
  approaches to cross-study analyses.

o Review publications resulting from multi-unit trials.

5.  IND Responsibilities 

For pilot studies, either the Principal Investigator or a pharmaceutical 
company may file an Investigational New Drug (IND) application to the 
United States Food and Drug Administration.  The sponsor of the IND has 
responsibility for the conduct of trials under that IND, which includes 
adhering to applicable Federal regulations. For large scale, multi-unit 
(Phase II) studies, NIAID will retain the option to cross-file or 
independently file an IND.  Reports of data generated by the AIEDRP or 
any of its members required for inclusion in INDs and Clinical Brochures 
and for cross-filing purposes will be submitted by the Principal 
Investigator to the NIAID Program Official upon request.  Such reports 
will be in final draft form and include background information, methods, 
results, and conclusions.  They will be subject to approval and revision 
by NIAID and may be augmented with test results from other Government-
sponsored projects prior to submission to the appropriate regulatory 
agency.

If NIAID holds the IND for a trial, a NIAID Medical Officer or his/her 
designee will monitor the safety of the treatment(s) being evaluated.  
Regulatory responsibilities will be the responsibility of NIAID.  
Standard procedures (e.g., registration of sites participating in 
clinical trials) will apply.  Interim and final reports on toxicities 
for all sponsored clinical trials will be routinely provided through the 
NIAID Program Official to the NIAID Medical Officer.

In addition, when NIAID holds the IND for a trial, a DAIDS pharmacist 
may participate on the protocol team, consult on the pharmaceutical 
aspects of protocol development, and will interact with pharmaceutical 
companies to ensure product availability.  DAIDS will not provide study 
agents or permit expenditure of NIAID funds for disapproved protocols.

6.  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 Scientific Planning Committee or by 
the individual awardee in the event of an individual disagreement, a 
second member selected by the NIAID, and a third member who has 
expertise in the relevant area and who is selected by the two other 
members.  The panel will review any scientific or programmatic issue 
that is significantly inhibiting progress.  While the decisions of the 
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

This initiative will focus on recruitment and long-term follow-up of 
individuals with acute and early HIV infection.  Long-term follow-up 
will be essential to determine whether the benefits of very early 
intervention outweigh the risks of toxicity associated with therapy.

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, compelling rationale and justification are 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).

The changing demographics of the HIV epidemic have led to the majority 
of new infections now occurring in minorities and increasingly in women, 
with half of new infections in the past year in the United States 
occurring in persons under 25 years of age.  It is therefore essential 
that applicants develop plans to capture this group in their study 
population. 

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.

For the purpose of this RFA, participation in AIEDRP clinical research 
studies is open to persons 13 years of age and older.  The NIH has other 
programs for HIV clinical research in children less than 13 years of 
age.

Investigators may obtain copies from these sources or from Dr. Frederick 
Batzold, listed in INQUIRIES below, who also may 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 August 16, 2001, 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, 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 plan 
the review.  

The letter of intent is to be sent to Dr. Hagit David at the address 
listed under INQUIRIES by the letter of intent receipt date listed.

APPLICATION PROCEDURES

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 form PHS 398 
(rev. 4/98).  These forms are available at most institutional offices of 
sponsored research and 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, as well as 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-01-008" 
and the words "ACUTE INFECTION AND EARLY DISEASE RESEARCH PROGRAM" must 
be entered on the face page.

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 two pages) and Other Support pages 
should be listed 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 as appendices as detailed in the PHS 398 (Rev. 
4/98) 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 AIEDRP should not be included.

For both the AIEDRP units and the SCC, the Research Plan (Items a-d) is 
not subject to the page limitation in the PHS Form 398.  This section of 
the application should not exceed 170 pages.

Applications must be received by October 10, 2001.  Applications not 
received as a single package on the receipt date or not conforming to 
the instructions contained in PHS 398 (rev. 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 all five sets of any appendix material must be sent to:

Dr. Hagit David, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room Number 2152, MSC-7616
6700-B Rockledge Drive
Bethesda, MD  20892-7616

Applications must be received by the application receipt date listed in 
the heading of this RFA.  If an application is received after that date, 
it will be returned to the applicant without review.

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.

REVIEW CONSIDERATIONS

General Considerations

Upon receipt, applications will be reviewed for completeness and 
adherence to the Special Instructions above by the NIH Center for 
Scientific Review and for responsiveness by NIAID staff, those judged to 
be incomplete or non-responsive will be returned to the applicant 
without further consideration.

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 Division of Extramural Activities, NIAID in 
accordance with the review criteria stated below. 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 Allergy and Infectious 
Diseases Council.

Review Criteria

The criteria to be used in the evaluation of grant applications are 
listed below.  To put those criteria in context, the following 
information is contained in instructions to the peer reviewers.

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health. 
In the written comments reviewers will be asked to discuss the following 
aspects of the application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals. Each of these criteria will be addressed and considered in 
assigning the overall score, weighting them as appropriate for each 
application. Note that the application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score. For example, an investigator may propose 
to carry out important work that by its nature is not innovative but is 
essential to move a field forward.

A.  AIEDRP Units

1.  Significance:  Is the proposed research of scientific, technical, 
and clinical significance, and based on an original concept?  Do the 
proposed projects take advantage of unique features of the AIEDRP or 
make optimal use of collaborative arrangements?

2.  Approach:  Are the experimental approach and the methodology 
proposed to carry out the research appropriate and adequate?  
Specifically, the reviewers should evaluate the adequacy and feasibility 
of the applicant’s plans, methods, approaches and strategies to: 1) 
identify, screen, and recruit individuals with acute or early HIV 
infection that are representative of the demographics of the catchment 
area, 2) follow subjects for the long term and retain them in research 
studies, and 3) perform and quality assure laboratory assays in support 
of these studies.  Does the applicant demonstrate the ability to enroll 
and retain an adequate number of subjects (in particular, acutely 
infected individuals), given the proposed scientific agenda?

3.  Innovation:  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 
technologies?

4.  Investigator:  Do the Principal Investigator and key staff have 
adequate qualifications and research experience in the area of the 
proposed research, specifically: 1) expertise and experience in 
conducting clinical research on the pathogenesis and treatment of acute 
HIV infection, and 2) experience in performing virology, immunology and 
pharmacology assays in support of state-of-the-art pathogenesis research 
and HIV clinical trials?  Are the investigators appropriately trained 
and well suited to manage and direct local and AIEDRP-wide research?  
Are they well suited to engage in collaborative interactions with other 
AIEDRP investigators and with investigators external to the AIEDRP who 
desire to utilize AIEDRP data and specimens?  Is the work proposed 
appropriate to the experience level of the Principal Investigator and 
other researchers?  Has the Principal Investigator budgeted sufficient 
time to ensure that adequate attention is paid to these AIEDRP-wide 
scientific issues?

5.  Environment:  Are necessary resources to conduct the proposed 
research available?

Additional Review Criteria for This RFA

6.  Are the scientific goals set forth in this application feasible 
considering the challenges of recruitment and the predicted outcomes?  
Have existing AIEDRP units achieved their goals?  Are the plans adequate 
for recruiting and following study subjects, obtaining data, and sending 
data to the SCC?  Are the plans adequate for maintaining good 
relationships with community groups relevant to the AIEDRP?  Are the 
plans adequate for participating in key AIEDRP organizational 
structures, such as the SPC?  Are the plans adequate for working with 
the SCC to ensure appropriate standardization and quality control of 
data collected at each site?  Are the site-specific plans adequate for 
participation in AIERDP-wide activities?

7.  Is the study design adequate for the representation of women, 
adolescents, and/or minorities in study design?

8.  Are the plans adequate for collaborative projects that might be 
conducted among multiple AIEDRP units and evidence of collaborations in 
other current or recent projects?

9.  Have recompeting applicants appropriately described their 
qualifications based on past and present activities within the AIEDRP?  
Those applicants who are not currently a member of the AIEDRP should 
describe their participation in comparable projects (e.g., group 
participation, pharmaceutical studies).

B.  Statistical and Coordinating Center

1.  Does the application provide evidence of statistical expertise that 
complements the goals of the AIEDRP?  Does the biostatistical 
methodology set forth in this application represent the most relevant 
manner in which the data obtained from the units and from collaborators 
may be analyzed to advance understanding of acute HIV infection and 
early HIV disease?

2.  Does the applicant demonstrate data management expertise including 
procedures for collecting and managing a database of core data from the 
AIEDRP clinical units?  Are the conceptual framework, design, methods, 
and analyses adequately developed, well integrated, and appropriate to 
the aims of the AIEDRP?  Is the approach for managing data appropriate 
and optimal?  Does the applicant acknowledge potential problem areas and 
consider alternative tactics?

3.  Are the applicant"s plans adequate for providing operational support 
for administrative functions of the AIEDRP and particularly its 
Scientific Planning Committee?  Has the applicant appropriately 
addressed the responsibility of developing the logistics necessary for 
the SPC to develop and coordinate the scientific agenda?

4.  Is the overall SCC management plan appropriate?  Are the 
investigators appropriately trained and well suited to perform the data 
management, data analyses, study design, and AIEDRP-wide coordinating 
roles central to the functioning of SCC?  Are the experience levels of 
the Principal Investigator and other key personnel appropriate for the 
proposed work?

The Initial Review Group also will examine: the appropriateness of the 
proposed project budget and duration, the adequacy of plans to include 
children (ages 13 years and above) and both genders and minorities and 
their subgroups as required for the scientific goals of the research, 
the plans for the recruitment and retention of subjects, the provisions 
for the protection of human and animal subjects, and plans for ensuring 
the safety of the research environment.

Schedule

Letter of Intent Receipt Date:  August 16, 2001
Application Receipt Date:       October 10, 2001
Scientific Review Date:         February, 2002
Advisory Council Date:          May, 2002
Earliest Award Date:            July 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 July 
1, 2002.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  The 
opportunity to clarify any issues or questions from potential applicants 
is welcome.

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

Dr. Frederick Batzold, Ph.D.
Clinical Research Management Branch/Division of AIDS
National Institute of Allergy and Infectious Diseases  
Room 5154, MSC-7624
6700-B Rockledge Drive
Bethesda, MD  20892-7624
Telephone:	(301) 402-0143
FAX:	(301) 480-4582
E-Mail:	fbatzold@niaid.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:
  
Dr. Hagit David, Ph.D.
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2152, MSC-7616
6700-B Rockledge Drive
Bethesda, MD  20892-7616
Telephone:	(301) 402-4596
FAX:	(301) 402-2638
E-Mail:	hdavid@niaid.nih.gov

Direct inquiries regarding fiscal matters to:  

Ms. Linda Shaw
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2125, MSC-7614
6700-B Rockledge Drive
Bethesda, MD  20892-7614
Telephone:	(301) 402-6611
Fax:	(301) 480-3780
E-mail:	lshaw@niaid.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic 
Assistance No. 93.856.  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.



Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.