INTERNATIONAL STUDIES OF AIDS-ASSOCIATED CO-INFECTIONS (ISAAC)

RELEASE DATE:  August 19, 2003

RFA Number: RFA-AI-03-036

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

CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:
No. 93.855, Immunology, Allergy, and Transplantation Research
No. 93.856, Microbiology and Infectious Diseases Research

LETTER OF INTENT RECEIPT DATE:  December 12, 2003
APPLICATION RECEIPT DATE:  January 13, 2004

THIS RFA CONTAINS THE FOLLOWING INFORMATION 

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The National Institute of Allergy and Infectious Diseases (NIAID), National 
Institutes of Health (NIH), invites applications for cooperative agreement 
(U01) grants from US based investigators to conduct International Studies of 
AIDS-associated Co-infections (ISAAC). The ISAAC grant will support clinical 
studies of co-infections with HIV and one or more pathogens (including but not 
limited to tuberculosis, other AIDS-defining opportunistic infections, malaria 
and other parasitic infections) endemic among adults and children in resource-
constrained tropical countries (countries that have territories within the 
geographically defined tropical zones, i.e. the countries with territories 
between the tropic of Cancer and the tropic of Capricorn characterized by hot 
climate) . The initial goal of this program is to conduct clinical research to 
determine the spectrum, incidence, clinical manifestations, and outcomes of 
these co-infections in a specific region, and evaluate the pathogenic 
interactions between HIV and endemic infections. Applications for projects 
addressing therapeutic goals will be acceptable if the epidemiology of the co-
infections is already adequately defined in the region. Long-term goals are to 
develop effective and sustainable clinical management strategies to improve 
local standards of care and to foster the integration of research for HIV and 
the relevant co-pathogens. In reviewing applications, a major emphasis will be 
placed on training, technology development, and enhancing independent research 
capacities in host country sites. Collaborative teams inclusive of research 
expertise in HIV and in tropical pathogens are required. Projects must be 
designed to increase relevant research experience of host country 
investigators and to enhance their ability to pursue scientific opportunities 
by training, study planning and performance, and improving technical ability.

RESEARCH OBJECTIVES

Background

The overlapping endemicity of infection by HIV and tropical pathogens in 
resource-constrained countries (annual per capita gross national product of 
$7,500 or less) results in a high rate of co-infection. Per capita gross 
national product (GNP) is based on World Bank data. Additional information on 
GNP can be obtained from the World Bank website at 
http://www.worldbank.org/depweb/english/modules/economic/gnp/data.html. HIV 
co-infections/opportunistic infections have been well characterized in the US 
and other industrialized countries. Prior to effective antiretroviral therapy, 
standards of care for HIV positive persons in the US focused on prevention and 
treatment of co-infections to reduce morbidity, slow HIV progression, and 
prevent death.  Similar characterization and clinical study of co-infections 
in tropical countries have been limited and standards of care have not been 
developed. Characterization of the interactions of HIV and endemic co-
infections and development of approaches for the effective clinical management 
of co-infected persons will be crucial in the effort to improve health care in 
resource-constrained tropical countries.  

Infectious diseases cause nearly half of all mortality in resource-constrained 
countries and approximately half of this mortality is attributed to HIV 
infection, tuberculosis and malaria. Co-infections with HIV and other endemic 
pathogens are common causes of morbidity and mortality. In addition, 
progression of HIV infection is accelerated by many co-infections, and the 
risk, severity, and complications of co-infections often are increased in the 
presence of HIV infection. Tuberculosis and malaria are examples of co-
infections for which previous methods of control and treatment are no longer 
as effective. These common co-infections also cripple economic development, 
perpetuate or exacerbate poverty, create substantial social burdens, and 
contribute to political instability. 

The majority of the HIV epidemic occurs in tropical countries, with 71% of 
HIV-infected persons worldwide living in sub-Saharan Africa. Although co-
infections with endemic pathogens are extremely common, the spectrum of co-
infections, co-pathogenesis, and the course and outcomes of co-infection with 
HIV and endemic pathogens have not been adequately studied in most regions. 
Very few studies have effectively addressed the safety and efficacy of 
treatment strategies for individuals co-infected with HIV and tropical 
pathogens. Data from well-designed studies are urgently needed to develop 
guidelines for treatment of co-infections in tropical countries with and 
without the ability to provide antiretroviral therapy.  

Research Objectives and Scope

Applications submitted in response to this RFA should focus on hypothesis-
driven, discrete objectives.  Clinical research in resource-constrained 
tropical countries that address one or more of the following objectives will 
be considered responsive: 1) Define the spectrum, incidence, and course of co-
infection with HIV and other pathogens disproportionately affecting 
populations living in tropical countries as they present with infectious 
syndromes, 2) Characterize the effect of endemic co-infections on HIV 
replication, disease progression, and transmission, and, reciprocally, the 
effects of HIV infection on disease expression and outcomes of endemic co-
infections, 3) Assess the safety, efficacy, and optimal therapeutic strategies 
for antiretroviral therapy in the presence of endemic co-infections, 4) Assess 
practical means for therapeutic monitoring, and for studying possible 
pharmacological interactions between therapeutic drugs targeting the different 
pathogens, 5) Improve the practical therapeutic management of endemic 
infections in the presence of HIV infection, including the development of 
affordable means of diagnosis and therapeutic monitoring and the evaluation of 
vaccines and chemoprophylaxis for eventual use in local primary care settings, 
6) Monitor the emergence of antimicrobial resistance among HIV and endemic 
pathogens in co-infected study subjects and the wider community, determine the 
relevant risk factors, and evaluate strategies to reduce the development of 
resistance to therapy and to manage resistant infections, 7) Characterize 
changes in immune response patterns in the presence of infection by HIV and 
endemic pathogens and the role of host immunity in the response to therapy of 
co-infections.

Studies may be proposed on the epidemiology, pathogenesis, immunopathogenesis 
of co-infections and may include phase II - IV preventive and therapeutic 
clinical trials.  Basic epidemiological data for the co-infections occurring 
in the region should be known, and is a pre-requisite for proceeding with 
therapeutic studies. In the absence of such data, gathering epidemiological 
data for co-infections in the region being studied should be a priority before 
any therapeutic studies are proposed. Examples of research projects that would 
be appropriate in response to this RFA include:

o   epidemiologic studies to define the incidence, clinical presentations, and 
outcomes of co-infections  with HIV and endemic pathogens in a specific 
region, 

o   studies to determine how specified co-infection(s) accelerate(s) HIV 
disease progression and practical interventions that may interrupt this 
response, such as the optimal strategy for application of antiretroviral 
therapy,

o   how HIV infection impacts co-infection outcomes, and 

o   defining the optimal therapy for co-infections at different stages of HIV 
infection, and the role of primary and secondary prophylaxis.

Collaborative partnerships between institutions in the US and the host 
countries are required. The US institutions must develop these collaborations 
such that host country (outside the US) investigators have substantial 
involvement in all aspects of the research, including planning, design, 
implementation, analysis, and reporting of each study. The majority of support 
must be expended in the host country. Performance of clinical studies in 
developed countries will not be supported. This RFA will support clinical 
studies requiring access to co-infected populations in resource-constrained 
tropical countries, and is not meant to support the conduct of research that 
can be done in US based centers. US applicant institutions will make their own 
arrangements for mutually acceptable affiliations with one or more 
collaborating institution(s) in resource-constrained tropical countries as 
well as other institutions in the US or other developed countries.

A major goal of all projects must be to enhance the independent research 
capacity of the host country. Projects should be relevant to the health needs 
of the local population. Appropriate expertise in epidemiology, clinical 
research, adult/pediatric HIV/AIDS management, tropical medicine, and 
microbiology will be required. One goal of the project will be to help to 
develop local specialized microbiology laboratory capabilities needed to 
accomplish the objectives of the proposed studies, if these capabilities are 
not currently available. The project sites will be required to interact with 
other appropriate NIAID-sponsored treatment, prevention, and vaccine research 
units in the same locality, and with the local HIV voluntary counseling and 
testing facilities and HIV care agencies.

MECHANISM OF SUPPORT

This RFA will use the NIH 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.  The applicant will be solely 
responsible for planning, directing, and executing the proposed project.  This 
RFA is a one-time solicitation.  Future unsolicited, competing-continuation 
applications based on this project will compete with all investigator-
initiated applications and will be reviewed according to the customary peer 
review procedures.  The anticipated award date is June 2004.  Applications 
that are not funded in the competition described in this RFA may be 
resubmitted as NEW investigator-initiated applications using the standard 
receipt dates for NEW applications described in the instructions to the PHS 
398 application.  

The NIH U01 is a cooperative agreement award mechanism in which the Principal 
Investigator retains the primary responsibility and dominant role for 
planning, directing, and executing the proposed project, with NIH staff being 
substantially involved as a partner with the Principal Investigator, as 
described under the section "Cooperative Agreement 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.

This RFA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
the investigator is submitting an application with direct costs in each year 
of $250,000 or less, use the modular format.  Otherwise follow the 
instructions for non-modular research grant applications.  This program does 
not require cost sharing as defined in the current NIH Grants Policy Statement 
at http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. 

The US applicant institutions will support research at the institutions in 
resource-constrained countries through a consortium arrangement, and the 
programmatic, fiscal and administrative agreements involved should be 
described within the application. The applicant organization's administrative 
support must provide the necessary management for the transfer of funds and 
material to the off-site component. Travel, salaries, and fringe benefits will 
be subject to the applicant institution's rules and regulations. Only host 
countries with annual per capita gross national product (GNP) of $7,500 or 
less will be considered in response to this application. Annual per capita 
gross national product is based on World Bank data, and additional information 
can be obtained from the World Bank website at 
http://www.worldbank.org/depweb/english/modules/economic/gnp/data.html .

FUNDS AVAILABLE 

NIAID intends to commit approximately $3.0 Million in FY 2004 to fund 3 to 4 
new grants in response to this RFA. An applicant may request a project period 
of up to 5 years and a budget for total costs of up to $1.0 Million per year. 
At least 60% of the direct costs for this project should be expended in the 
host country, with no more than 40% of the direct costs expended in the US. 
Travel costs for US site staff should be included in the US budget. Because 
the nature and scope of the proposed research will vary from application to 
application, it is anticipated that the size and duration of each award will 
also vary. Although the financial plans of NIAID provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious applications. At 
this time, it is not known if this RFA will be reissued. Continued funding 
will be contingent upon satisfactory progress during the preceding year and 
availability of funds.

ELIGIBLE INSTITUTIONS

You may submit (an) application(s) if your institution has any of the 
following characteristics:

o   Applications may be submitted by domestic (US-based), for-profit and non-
profit organizations, public and private institutions, such as universities, 
colleges, hospitals, laboratories, etc.
o   Foreign institutions are not eligible to participate as the primary 
applicant. 
o   Racial/ethnic minority individuals and women are encouraged to apply as 
Principal Investigators.
o   The US grantee institution is responsible for developing affiliation(s) 
with (an) established institution(s) (e.g. university, research institute, 
federal or state health department, hospital) in the host country. 
o   Research activities on this project conducted at the foreign affiliate 
must be supported under a consortium arrangement by the award made to the US-
based institution. "Intent to create consortium"  is located at 
http://odoerdb2-1.od.nih.gov/gmac/topics/consortium_main.html
o   The host country investigators must have substantial input into all 
aspects of proposed research studies and programs and all projects must be 
acceptable to the overseas institutions.  The application will not be reviewed 
unless documentation of such affiliation and involvement is included.  
Linkages with host country health care policy and provision agencies are 
highly encouraged.
o   A plan must be submitted to outline how the US primary applicant plans to 
enhance and develop research abilities and increasingly transfer capacity to 
the host country.
o   Proposed studies will be reviewed to ensure that all study subjects must 
receive treatment and care for HIV infection and related complications and co-
infections at levels at least as high as that which is generally available in 
the host country.

INDVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, experience, and resources necessary 
to carry out the proposed research is invited to work with their institution 
to develop an application for support.  Individuals from underrepresented 
racial and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.
 
SPECIAL REQUIREMENTS

Travel:  It is expected that investigators and research staff from the US 
institution will travel to the foreign research site(s) for substantial 
periods of time in support of the research funded through this RFA. It is 
expected that the Principal Investigator will travel to the foreign research 
site(s) at least once a year. The application must include a plan describing 
how much time the US collaborators plan to spend in the host country. The 
applicant must present a comprehensive and convincing package to include the 
expertise of the research team (both in the US and in the host country), 
outlining the level of effort of key personnel and how much time they will 
spend at the host site, to demonstrate that there will be adequate expertise 
and oversight on the team at all times, to successfully conduct the research 
proposed. The Principal Investigators (from both the US and the host country) 
and 1 or  2 key staff should plan on traveling to the Washington DC 
metropolitan area at least once a year to discuss progress and findings with 
the Scientific Coordinator and other NIAID Program staff.

Available infrastructure, including experience level of staff, availability of 
major pieces of equipment and or support required for these should be clearly 
stated in as much detail as possible.

The applicant must submit concept sheet(s) describing at least one proposed 
clinical study. A sample outline of a concept sheet is available for review, 
and is included in the "SUPPLEMENTAL INSTRUCTIONS" section of this document. 
The concept sheet(s) should be included as an appendix to the application, and 
it will be considered in evaluating the application.

COOPERATIVE AGREEMENT 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 special 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.

For all studies involving human subjects, the following special requirements 
apply: 
 
Awardees must comply with the Clinical Terms of Award that will be 
incorporated in their Notices of Grant Award. Potential applicants are 
encouraged to contact appropriate National Institute of Allergy and Infectious 
Diseases (NIAID) program staff concerning this Policy. NIAID's Clinical Terms 
of Award delineate awardee responsibilities including submission of the 
required documentation to NIAID. These terms apply to all NIAID-supported 
clinical research involving human subjects, including the development of new 
technologies using human subjects or materials derived from patients or 
volunteers; studies into the mechanisms of human disease using patient or 
volunteer samples; therapeutic interventions, clinical trials, and any studies 
that require institutional review board (IRB) or independent ethics committee 
(IEC) approval to collect samples from patients or volunteers; epidemiologic 
and behavioral studies; and outcomes and health services research. These 
Clinical Terms of Award define specific timelines for approvals related to the 
initiation of a trial or study and timelines for reporting events related to 
its progress. It is the responsibility of the awardee to submit required 
documentation to the responsible program or project officer according to these 
timelines.  AN UPDATED NIAID policy was published in the NIH Guide on July 8, 
2002 and is available at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. 
The full policy, including terms and conditions of award, is available at: 
http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.

The administrative and funding instrument used for this program is a 
cooperative agreement (U01), an "assistance", 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 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(s) from the Division of Acquired 
Immunodeficiency Syndrome (DAIDS) and the Division of Microbiology and 
Infectious Diseases (DMID).

1. Monitoring Clinical Studies

When clinical studies or trials are a component of the research proposed, 
NIAID policy requires that studies be monitored commensurate with the degree 
of potential risk to study subjects and the complexity of the study. AN 
UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is 
available at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. 
The full policy, including terms and conditions of award, is 
available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.

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 
the RFA and for performing the scientific activity.  Specifically, awardees 
have primary responsibility as described below:

(a)  Clearly stating the rationale, objectives and methods for proposed 
research projects in the research design and protocol development.  This 
includes, for example, definition of objectives and approaches, planning, 
implementation, participant recruitment and follow-up, data collection, 
quality control, interim data and safety monitoring, final data analysis and 
interpretation, and publication of results.

(b)  Maintaining a mutually acceptable arrangement with the host country 
affiliate institutions and any relevant governmental agencies.  Communicating 
with, seeking required approvals, and complying with all requirements of 
regulatory and health governmental agencies in the host country.

(c)  Preparing detailed protocols, informed consent documents, and relevant 
procedure manuals for timely submission of initial versions and all required 
amendments to the Scientific Coordinator (Program Officer/Medical Officer), 
Institutional Review Boards at relevant US and foreign institutions, and all 
relevant regulatory agencies for approval.  Decisions regarding the need for a 
US FDA IND, (and who would hold the IND when needed), will be made by NIAID.  
When NIAID holds the IND, the Principal Investigator will be required to 
provide NIAID with all the necessary information and documentation for filing 
the IND with the FDA, to amend as necessary after comments are provided by the 
Program Officer, local IRB, and regulatory authorities, and to submit safety 
reports and annual IND reports. 

(d)  Establishing procedures, where applicable, for all participating 
institutions to comply with FDA regulations for studies involving 
investigational agents or devices, and to comply with the requirements of 45 
CFR Part 46 for the protection of human subjects.

(e)  Investigators and performance sites must demonstrate the ability to 
perform overall project management and implement the proposed clinical 
research protocol.  This includes the development of adequate plans for 
quality assurance/quality control, data management, drug distribution and drug 
accountability (pharmacy plans), and  appropriate laboratory procedures and 
standards.  Plans will be required to provide and document necessary training 
for clinical research staff in protection of human subjects, Good Clinical 
Practices, regulatory adherence, protocol specific procedures, and other 
training as needed, e.g., for trial-related medical management issues.

(f)  Awardees must present and carry out plans for a data management and 
analysis center, and preparation of statistical reports for Data and Safety 
Monitoring Boards (DSMBs).  The requirements, criteria, and procedures for SAE 
reporting and any other types of study safety monitoring reporting as 
determined by NIAID must be followed for each study.

(g)  Awardees are responsible for ensuring the accurate and timely assessment 
of the progress of research.  This includes, but is not limited to the 
development of adequate internal QA/QC procedures for data collection and 
management and laboratory performance, and generation of periodic reports 
addressing study conduct quality and progress.  Clinical research support 
services under contract with DAIDS may be tasked to provide training, 
expertise and assistance with the development of these procedures.  The 
investigator will make study documents (e.g., consent forms, drug distribution 
forms, CRFs) and pertinent hospital or clinic records readily available for 
inspection by the local IRB, the site monitors under contract to NIAID, the 
FDA, the NIAID, the Office for Human Research Protections (OHRP), the 
pharmaceutical sponsors, or the sponsor's designee for confirmation of the 
study data. 

(h)  Awardees must adhere to the NIH policy regarding sharing of data.  
Guidance regarding this policy is available at 
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm.

(i)  Where relevant, work with NIAID staff to facilitate the development of 
repositories of research reagents.  This may involve the collection and 
transportation of pathogen specimens, vectors, and/or human material.

(j)  Cooperate in the reporting of the study findings.  It is specifically 
intended that publications resulting from collaborative research will be co-
authored by involved foreign scientists(s) and that the data will be made 
readily available to the government of the host country.  The NIAID will have 
access to and may periodically review all data generated under an award.  NIH 
policies governing possible co-authorship of publications with NIAID staff 
will apply in all cases.

3. NIAID Staff Responsibilities

NIAID staff assistance will be provided by the Division of Acquired 
Immunodeficiency Syndrome (DAIDS) and the Division of Microbiology and 
Infectious Diseases (DMID) program staff , who will serve as NIAID's 
Scientific Coordinators.  The NIAID Scientific Coordinator will have 
substantial scientific/programmatic involvement during the conduct of the 
project through technical assistance, advice, and coordination above and 
beyond normal program stewardship for grants, as described below.  

Other program staff will be assigned as needed.  NIAID staff will serve as a 
resource with respect to relevant ongoing NIAID-sponsored research in order to 
facilitate compatibility, information sharing, and avoidance of unnecessary 
duplication.  The NIAID will provide on-site study monitoring of clinical 
research projects as required.

The Scientific Coordinator will interact with the Principal Investigator(s) on 
a regular basis to monitor study progress.  Monitoring may include:  (a) 
regular communications with the Principal Investigator and staff, (b) periodic 
site visits for discussions with research teams, and (c) observation of field 
data collection and management, quality control, fiscal review, and other 
relevant matters.  The NIAID retains, as an option, periodic external review 
of progress.

The Scientific Coordinator will provide substantial assistance in the design 
and conduct of research activities, including provision of: (a) advice on the 
design, development, and technical performance of clinical protocols and 
statistical evaluations of data, (b) access to and use of reagents, assays, 
and other resources available through NIAID contractors and awardees, as 
appropriate, and (c) advice and assistance with meeting FDA requirements for 
investigational agents (with the assistance of Regulatory Affairs staff).

NIAID will retain the option to cross-file or independently file an 
application for investigational clinical trial, i.e. an Investigational New 
Drug Application (IND) to the United States Food and Drug Administration.

The Scientific Coordinator or other appropriate NIAID staff will provide 
timely review of all submitted documents (initial and amended protocols, 
informed consent documents, IRB approvals and adverse events and study 
progress reports) and promptly notify the PI of the outcome of such reviews.  

The NIAID Program Director will review progress through consideration of 
annual progress reports and periodic reports on ongoing progress, findings, 
and future plans presented during meetings and conference calls, publications, 
site visits, etc., and will have primary responsibility to make 
recommendations for continued funding based on: (a) overall progress, 
including study subject and/or data accrual; (b) cooperation in carrying out 
the research (e.g., compliance with regulations, terms of award and reporting 
requirements); and/or (c) maintenance of a high quality of research.

4. 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 formed to review any scientific 
or programmatic issue that is significantly restricting progress.  The panel 
will be composed of three members -- one selected by the awardee, a second 
member selected by the NIAID, and the third member with expertise in the 
relevant area and selected by the two prior members.  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.

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.  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.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants. Inquiries may fall into three 
areas: scientific/research, peer review, and financial or grants management 
issues:

o Direct your questions about scientific/research issues to:

Dr. Elizabeth Higgs
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room 5067, MSC-6603
6610 Rockledge Drive
Bethesda, MD 20892-6603
Telephone: (301) 496 2544
FAX: (301) 402 0659
Email: eh63a@nih.gov

Dr. Richard Hafner, M.D.
Division of Acquired Immunodeficiency Syndrome
National Institute of Allergy and Infectious Diseases
Room 5107, MSC-7624
6700-B Rockledge Drive
Bethesda, MD 20892-7624
Telephone: (301) 435-3766
FAX:    (301) 402-2304
Email:  rh23v@nih.gov

o Direct your questions about peer review issues; address the letter of 
intent; mail two copies of the application and all five sets of appendices to:

Dianne Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2148, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 496-0818
FAX:       (301) 402-2638
Email:      dt15g@nih.gov

o Direct your questions about financial or grants management matters to:

Laura Eisenman
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2120, MSC-7614
6700-B Rockledge Drive  
Bethesda, MD 20892-7614
Telephone: (301) 402-5541
Fax: (301) 480-3780
Email: le55d@nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator (locally 
in the US as well as in the host country)
o Names of other key personnel
o Participating institutions
o Number and title of this RFA

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows IC staff to estimate the potential review workload and plan 
the review.

The letter of intent is to be sent by the date listed at the beginning of this 
document. The letter of intent should be sent to:

Dianne Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2148, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 496-0818
FAX:       (301) 402-2638
Email:      dt15g@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com. The DUNS number should 
be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document 
is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, Telephone 
(301) 435-0714, Email: GrantsInfo@nih.gov.
 
SUPPLEMENTAL INSTRUCTIONS 

A Sample outline of a concept sheet appears below, and must be submitted with 
the application as requested in the "SPECIAL REQUIREMENTS" section of this 
document.
Sample Outline of a concept
Title:
Population:
Co-infection(s):
Intervention (if any):   
Test agents/interventions and comparators:
Dosing:
Duration of therapy:
Duration of administration:
Background/rationale:
Study objectives:
Hypothesis to be tested:
Study design (not all parts may be relevant):
            Eligibility/exclusion criteria:
            Randomization/stratification plan:
            Sample size with justification:
            Anticipated duration of recruitment phase:
            Anticipated duration of study:
            Interim study progress and safety monitoring plan, if applicable:
            Primary endpoints/outcomes:
            Secondary endpoints/outcomes:
            Study visit schedule and primary evaluations (including any 
            performed by a central laboratory):
Any proposed sub-studies:
Data analyses planned:
Party responsible for data management and site monitoring:
Clinical sites:

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application. Type the RFA number on the label. 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. In addition, the RFA title and number 
must be typed on line 2 of the face page of the application form and the YES 
box must be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, 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/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:

Dianne Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2148, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Bethesda, MD 20817 (for express mail or courier service)

Applications must be received on or before January 13, 2004.  Applications 
that are not received as a single package on the receipt date will be judged 
non-responsive and will be returned to the applicant.

It is highly recommended that the appropriate NIAID program contact be 
consulted before submitting the letter of intent and during the early stages 
of preparation of the application.  (See program contact under INQUIRIES).

APPLICATION PROCESSING: 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.

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique.  However, when a previously 
unfunded application, originally submitted as an investigator-initiated 
application, is to be submitted in response to an RFA, it is to be prepared as 
a NEW application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text must 
not be marked to indicate the changes.  While the investigator may still 
benefit from the previous review, the RFA application is not to state 
explicitly how.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by NIAID. 

Incomplete and/or non-responsive applications 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 
NIAID in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the National Advisory Allergy and 
Infectious Diseases Council

REVIEW CRITERIA

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 your application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals:

o Significance
o Approach
o Innovation
o Investigator
o Environment
   
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your 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, you may propose to carry out 
important work that by its nature is not innovative but is essential to move a 
field forward.

SIGNIFICANCE: Does this study address an important problem? If the aims of the 
application are achieved, how will scientific knowledge be advanced? What will 
be the effect of these studies on the concepts or methods that drive this 
field?

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project? Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

INNOVATION: Does the project employ novel concepts, approaches or methods? Are 
the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

INVESTIGATOR: Is the investigator appropriately trained and well-suited to 
carry out this work? Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success? Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements? Is there evidence of institutional support?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation in 
the proposed research will be assessed. (See criteria included in the section 
on Federal Citations, below).

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans 
to include subjects from both genders, all racial and ethnic groups (and 
subgroups), and children as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria included in the section on Federal 
Citations, below).

ADDITIONAL CONSIDERATIONS

DATA SHARING: The adequacy of the proposed plan to share data. FINAL NIH 
STATEMENT ON SHARING RESEARCH DATA can be found in 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

BUDGET: The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

OTHER REVIEW CRITERIA

(a) Strength of the proposed collaborative relationships including 
administrative structure, communications, defined roles and responsibilities 
and decision-making processes

(b) The potential for the project to enhance the clinical research capacity at 
the host site, including strengthening of administrative, laboratory, or 
clinical infrastructure and strengthening capacity of the host country 
research team to function independently on this and other research projects

(c) Adequacy of the proposed plans for the conduct of clinical research.  
Applicants may wish to include a concept document or abbreviated protocol 
document that specifically identifies the rationale, primary and secondary 
objectives for the study, primary study endpoint, study design, a description 
of the proposed population, the number of subjects and the duration of follow-
up.

(d) Adequacy of the time and effort proposed by the Principal Investigator and 
host country lead investigator(s)

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    December 12, 2003
Application Receipt Date:         January 13, 2004
Peer Review Date:                 May, 2004
Council Review:                   June, 2004
Earliest Anticipated Start Date:  July, 2004

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  Scientific merit of the proposed project as determined by peer review
o  Availability of funds
o  Programmatic priorities

REQUIRED FEDERAL CITATIONS

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

MONITORING PLAN AND DATA AND SAFETY MONITORING BOARD: Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a 
clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.   
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community. The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy 
requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  
You will find this policy announcement in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA.  
It is important for applicants to understand the basic scope of this 
amendment. NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application.  
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.  NIH has provided guidance in the 
FINAL NIH STATEMENT ON SHARING RESEARCH DATA at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH processes 
involving the review, funding, and progress monitoring of grants, cooperative 
agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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.  Furthermore, we 
caution reviewers that their anonymity may be compromised when they directly 
access an Internet site.

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 RFA is 
related to one or more of the priority areas.  Potential applicants may obtain 
a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic Assistance at 
http://www.cfda.gov/ in the following citations: No. 93.855, Immunology, 
Allergy, and Transplantation Research and No. 93.856, Microbiology and 
Infectious Diseases 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 NIH Grants Policy Statement is available at 
http://grants.nih.gov/grants/policy/policy.htm. This document includes general 
information about the grant application and review process; information on the 
terms and conditions that apply to NIH Grants and cooperative agreements; and 
a listing of pertinent offices and officials at the NIH.  All awards are 
subject to the terms and conditions, cost principles, and other considerations 
described in the NIH Grants Policy Statement.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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