HEPATITIS C COOPERATIVE RESEARCH CENTERS

RELEASE DATE:  August 5, 2004

RFA Number:  RFA-AI-04-028 

Update: The following update relating to this announcement has been issued:

  April 7, 2009 - This RFA has been reissued as (RFA-AI-09-025).

EXPIRATION DATE:  November 23, 2004

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH) 
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Allergy and Infectious Diseases (NIAID) 
 (http://www.niaid.nih.gov)
National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) 
 (http://www.niddk.nih.gov)
National Institute on Drug Abuse (NIDA) 
 (http://www.nida.nih.gov)

CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:
No. 93.855, Immunology, Allergy, and Transplantation Research
No. 93.856, Microbiology and Infectious Diseases Research
No. 93.848, Digestive Diseases and Nutrition Research
No. 93.273, Drug Abuse Research Programs

LETTER OF INTENT RECEIPT DATE:  October 22, 2004 
APPLICATION RECEIPT DATE:  November 22, 2004   

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism 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 Supplementary Instructions
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), the 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and 
the National Institute on Drug Abuse (NIDA) invite applications for the 
establishment of multi-project Hepatitis C Cooperative Research Centers (HC 
CRCs). 

The purpose of this RFA is to foster and stimulate high-quality, multi-
disciplinary collaborative research that is focused on developing tools to 
prevent and cure hepatitis C virus (HCV) infection and disease. The goal is 
to generate research findings that will be directly applicable, particularly 
to the development of vaccines and (immune) therapeutics. This RFA calls for 
new approaches for the rapid utilization and validation of research findings 
using a combination of basic, animal model, and clinical research approaches. 
The HC CRCs are encouraged to engage in early translational research so as to 
address hepatitis C public health needs. Together, the HC CRCs will form a 
consortium to: 1) conduct research of direct relevance to the objectives 
outlined; 2) foster interactions among established hepatitis C investigators; 
and 3) support Pilot Projects to evaluate new promising approaches related to 
this RFA.

RESEARCH OBJECTIVES

Background

At least 2% of the world’s population is infected with Hepatitis C virus 
(HCV); over 75% of infections never resolve, resulting in persistent virus 
carriage. Over time, this chronic infection can lead to liver fibrosis and, 
progressively, to severe and fatal diseases including liver cirrhosis and 
primary liver cancer. The Institute of Medicine classifies HCV as an emerging 
disease agent in the USA, with 1.7 million individuals already chronically 
infected and 30,000 more, newly infected, every year (IOM report, 1992). In 
the USA, the economic cost of this medical burden is estimated at 
approximately $1.0 billion per year.

At present, in the USA, almost all transmission stems from the use of 
contaminated needles in intravenous drug abuse. Thus, most new infections are 
likely to occur among relatively young people. HCV infection resulting from 
intravenous drug abuse is frequently complicated by co-infection with HIV. In 
particular, chronic HCV infection and associated liver disease are reported 
to develop at a higher rate in the presence of HIV. 

HCV is an RNA virus which circulates as a complex mixture of related but 
genetically heterogeneous quasi-species. There are at least 6 distinct 
genotypes of HCV, which further adds to the heterogeneity and which may 
influence differences in clinical outcomes - such as persistence, chronic 
liver disease, immune responses, and the response to interferon treatment.  

Currently, the treatment of choice for hepatitis C is long-acting alpha 
interferon given in combination with the antiviral drug, ribavirin. However, 
there are wide differences in the response to alpha interferon depending on 
the genotype of HCV. The lowest response rate (only ~ 46%), is observed in 
patients infected with HCV genotype-1, which is the genotype most prevalent 
in the USA. Studies also indicate a lower cure rate among African Americans, 
a population group which has a significantly higher rate of chronic infection 
than others in the USA.

The development of a vaccine to prevent infection by HCV is beset by complex 
problems. Immune pressure leads to continual selection, and diversification, 
of viral variants that escape the host defenses. In addition, HCV directly 
inhibits both innate and adaptive host immune responses. Even in the small 
proportion of infected individuals who clear the infection there is usually 
insufficient immunity to prevent a subsequent re-infection. On the other 
hand, vaccine studies in chimpanzees have shown that induction of high titers 
of antibodies against virus envelope proteins E1 and E2 is associated with 
reduced severity of liver disease. Particularly encouraging for vaccine 
development are findings from prospective studies in intravenous drug users, 
that individuals who clear an initial HCV infection are less susceptible to 
viral persistence following a subsequent infection. 

Like several other viruses, HCV has evolved multiple strategies for blocking 
interferon responses, simultaneously compromising both innate and adaptive 
immune responses against it. Current evidence indicates that broad HCV-
specific T cell responses can occur in infection, and that the breadth of the 
response corresponds with more benign outcomes following infection. However, 
it is not clear what particular responses are significant in terms of 
protective immunity, and why the responses vary within and among, 
individuals.

Finally, recent HCV-replicon technology now allows in vitro screening for 
antiviral drugs that target virus RNA replication, but not yet for those that 
might interfere with the subsequent steps of virus morphogenesis and with 
infection. The development of in vitro systems for virus propagation, and 
small-animal infection models, would greatly facilitate the ultimate goals of 
developing new therapies and vaccines against HCV.

Objectives and Scope

This RFA will support integrated projects to study the virus-host 
interactions that determine the outcome of infection, treatment associated 
recovery, and pathogenesis. These projects include: multi-disciplinary 
research for understanding mechanisms; in vivo studies for validation of in 
vitro findings; the use of particular patient cohorts and/or specimens from 
patients in clinical research relevant to these objectives; and early 
development and preclinical evaluation of vaccine and therapeutic strategies. 
Applications should address specifically one or more of the objectives listed 
below and may address other closely related questions.  

1. Elucidate the mechanisms and key steps by which HCV deregulates and evades 
the host immune response at the time of initial infection and during chronic 
infection, e.g., the role of HCV proteins in blunting the innate immune 
response, inhibiting dendritic cell maturation, or setting up an anergic 
state. 

2. Identify early determinants of spontaneous clearance of infection, 
including specific T-cell and B-cell responses, as compared with, and in 
contrast to, lack of clearance. 

3. Examine the role of immune responses associated with delayed and more 
benign outcomes of chronic HCV following multiple exposures to virus, e.g., 
in intravenous drug users, as compared to aggressive and severe outcomes. 

4. Elucidate the role of host factors (including genetic) and viral factors 
in the establishment and rate of progression of chronic infection and their 
interactions with each other.  

5. Construct prototype vaccine candidates to induce specific immune responses 
to HCV - identified through human clinical studies, and predicted to be 
important in viral clearance - and evaluate these responses in appropriate in 
vitro and in vivo model systems.

6. Devise cell-culture systems for the synthesis of complete, infectious 
particles, and determine their potential usefulness for research and 
development.

7. Identify, test, develop and use HCV animal models, including surrogates, 
to evaluate neutralizing antibodies, and as screening systems for new 
antiviral agents.

8. Identify and define a receptor / receptor complex for HCV. 

Clinical Studies

To address objectives 1-4 effectively and to determine the clinical relevance 
of any observations, it is necessary, in parallel, to undertake clinical 
studies in well defined cohorts of patients in whom HCV infection, clearance 
or persistence, and the progression of liver disease can be meaningfully and 
systematically studied, with particular reference to immunological 
parameters. Such patient cohorts include, but may not be limited to, those 
infected during intravenous drug abuse, minority populations who may be more 
susceptible to chronic infection and liver disease, those who show poor 
response to interferon therapy, and those co-infected with HIV. Therefore, 
applications for studying questions 1-4 in ”Objectives and Scope” must 
contain an integrated, scientifically related, clinical project. 

Exclusions

This RFA is not intended to support basic molecular studies on the 
replication of HCV RNA or HCV protein expression, or their regulation, unless 
such studies are demonstrated to relate directly to the purposes of this RFA, 
as outlined. Studies involving the use of genomic or proteomic technologies 
will only be considered if a credible and logical plan is presented for 
analyzing and applying the results to furthering the objectives of this RFA. 
In addition, clinical trials for new drugs or vaccine candidates will not be 
supported under this RFA. However, research questions that are best addressed 
by studying clinical specimens from or in patients in defined populations or 
cohorts are especially encouraged.

CRC Research Component:  A CRC must consist of two or more related, 
multidisciplinary projects utilizing molecular biological and immunological 
approaches.  These approaches may include experiments using animals such as 
mice, macaque monkeys and chimpanzees.  Each project must be led by a Project 
Leader.  These projects may or may not be within the same institution.  The 
CRC Director must be the Project Leader at the applicant organization, and 
will have responsibility for the scientific direction, coordination, and 
administrative management of the CRC.

Scientific Core:  Scientific core facilities/resources may be proposed if 
they will be utilized by at least two of the research projects. Resources 
include reagents (e.g., antibodies, peptides, etc.), special technology and 
databases.  Scientific cores should be well justified and clearly non-
duplicative of other services or facilities available to the CRC 
investigators.  If appropriate to the particular CRC, repositories for cells, 
tissues, reagents, or large data sets may be funded as Core Facilities.  In 
this case, applications should include methods to obtain, protect and archive 
relevant clinical and family history information. 

Administrative Core:  An Administrative Core is required for the management 
of the CRC program.  The Administrative Core should include plans for 
organization, decision-making, periodic evaluations within the CRC, and data 
sharing.  An Administrative Core budget should be included to provide for the 
required support staff, preparation of manuscripts for publication, 
telecommunications, and travel for participation in annual meetings of the 
CRCs (see SPECIAL REQUIREMENTS section below for annual meetings).  

MECHANISM OF SUPPORT

This RFA will use the NIH multi-project cooperative agreement (U19), an 
"assistance" mechanism, rather than an "acquisition" mechanism. 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 30, 
2005. 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 U19 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.

This RFA uses just-in-time concepts. It also uses the modular budgeting 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 budget format. Otherwise follow the 
instructions for non-modular budget research grant applications. This program 
does not require cost sharing as defined in the current NIH Grants Policy 
Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. 

Applicants for U19 grants must follow special application guidelines in the 
NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS; this brochure is available via the WWW at 
http://www.niaid.nih.gov/ncn/grants/multibron.htm.

FUNDS AVAILABLE 

The participating ICs intend to commit approximately $6,400,000 in FY 2005 to 
fund 5 to 7 new and/or competing continuation 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 $1,250,000 per year. 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 the ICs 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. Funding for the 
Development Program for Pilot Projects is in addition to the total costs. 
Details on the Development Program are provided in the “SPECIAL REQUIREMENTS” 
section below.  

At this time, the NIAID has not determined whether or how this solicitation 
will be continued beyond the present RFA. 

ELIGIBLE INSTITUTIONS

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

o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic institutions/organizations
o Foreign institutions are not eligible to apply, but may be part of a 
collaborative arrangement.
o Faith-based or community-based organizations

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, 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

1.  Steering Committee

The HC CRC Program Directors and the NIAID Scientific Coordinator will 
constitute the Steering Committee for this research program, with 
responsibility for reviewing progress and future plans, revising the research 
focus if appropriate, and developing collaborative efforts among the 
awardees.  The Steering Committee and the Project Leaders will meet at least 
annually at the NIH in Bethesda, Maryland (or at a site designated by the 
NIAID Scientific Coordinator), and will hold quarterly conference calls to 
facilitate interaction and collaboration across CRCs.  The first such meeting 
will be held shortly after award and will be scheduled by the NIAID 
Scientific Coordinator.  At this meeting, a Steering Committee Chair will be 
selected from among the non-Federal members.  

Funds for the travel to the annual meetings for the Program Directors, 
Project Leaders and other key CRC scientific staff should be included in the 
Administrative Core budget.

2.  Development Fund (DF) for Pilot Projects

The NIAID has established a CRC DF to respond to unanticipated scientific 
needs and opportunities. The goal of the DF is to provide some opportunity 
for exploring novel and promising ideas related to the overall objectives of 
this RFA – to develop methods or resources to enhance basic and clinical 
research, to follow up on new observations and hypotheses, to initiate risky 
projects with high potential benefit, or to stimulate collaborative efforts.

Under the DF, an additional $225,000 will be available for Pilot Projects to 
a maximum of $75,000 each in direct costs. Each Pilot Project will be funded 
for up to 3 years to cover partial salary and research costs.  Indirect Costs 
will not be allowed for Pilot Projects.

Pilot Projects are not part of the CRC application; therefore, budgets for 
Pilot Projects should not be included in the application.

At the initial meeting of the CRC Directors, the Steering Committee will 
select one of the CRC Directors to serve as the DF Administrator. The DF 
Administrator will appoint a Scientific Review Committee - which includes the 
Steering Committee and additional expert(s) from the scientific community as 
may be appropriate - to establish criteria for the evaluation of proposed 
Pilot Projects, and to solicit, review and select applications for funding. 

NIAID approval will be required for the appointment of the Scientific Review 
Committee and the final selection of projects for funding. If the quality of 
applications received is not deemed to be sufficiently high, NIAID may decide 
not to fund any of the projects. Approved projects need not necessarily be 
carried out at one of the HC CRCs; however, all Pilot Projects supported must 
relate to the specific objectives of this program. 

Continued support after the first year will be dependent on review of 
satisfactory progress. A separate progress report on each developmental 
project must be included in the annual report of the CRC.
3.  Clinical Component

In order to undertake basic and clinical approaches in a complementary and 
synergistic manner, HC CRCs will need access to well-characterized and 
diverse patient samples, as well as clinical experience with populations 
representing different disease stages, transmission modes, racial/ethnic 
background, co- factors, etc. All applicants are encouraged to include 
research utilizing well defined patient cohorts to address clinical questions 
and to make correlations with laboratory observations.  Applications 
addressing one or more of objectives 1-4, as defined under “Objectives and 
Scope,” must include a clinical component. For such studies, detailed 
proposals, including study objectives, study design, population, clinical 
sites, and data analysis plan must be presented in the application.

NIAID encourages: 1) collaborative arrangements with ongoing studies or 
clinical care settings capable of providing the crucial patient populations, 
specimens and information; and 2) the use of General Clinical Research 
Centers (GCRC) facilities supported by the NIH National Center for Research 
Resources as a resource for conducting research. If existing studies/cohorts 
or GCRC facilities will be used, letters of collaboration or agreement from 
the study Principal Investigator or GCRC Program Director respectively must 
be included in the application. 

4. Sharing of Resources

Restricted availability of unique research resources upon which further 
studies are dependent can impede the advancement of research and delivery of 
medical care. 

NIH policy expects investigators to make unique research resources readily 
available for research purposes to qualified individuals within the 
scientific community when they have been published [NIH Grants Policy 
Statement (http://grants.nih.gov/grants/policy/nihgps/); Principles and  
Guidelines for Recipients of NIH Research Grants and Contracts on obtaining 
and Disseminating Biomedical Research Resources:  Final Notice, December 1999 
(http://www.ott.nih.gov/policy/rt_guide_final.html)]. 

Accordingly, biomaterials and other patentable research resources (e.g., 
genetically encoded reporters, vectors, embryonic cell lines, etc.) produced 
in projects funded by this RFA are expected to be made available and 
distributed to the broader scientific community.

Intellectual Property Rights 

NIH is interested in ensuring that the research resources developed through 
this RFA become readily available to the research community. With regard to 
patentable research results, such as genetically encoded reporters, cell 
lines, and vectors, the NIH expects applicants who respond to this RFA to 
develop a plan addressing if, or how, they will exercise their intellectual 
property rights while making available to the broader scientific community 
research resources produced in projects funded under this RFA. This is 
expected to include an elaboration of the applicant’s anticipated plans to 
generate, or not generate, patents and/or exclusive or non-exclusive 
licensing of biomaterials and other patentable subject matter created in 
projects funded under this RFA. This plan should be consistent with the 
applicant’s institution’s policies on intellectual property rights.  
Applicants are reminded that funding recipients must not enter into any 
agreements with third parties that are inconsistent with the terms and 
conditions of their NIH award, if awarded, and must revise any agreements 
with third parties that are inconsistent with the terms and conditions of an 
NIH award to remain in compliance with such NIH award.

The majority of transfers to not-for-profit entities should be implemented 
under terms no more restrictive than the Uniform Biological Materials 
Transfer Agreement (UBMTA). In particular, recipients are expected to use the 
Simple Letter Agreement (SLA) provided at 
http://www.ott.nih.gov/policy/rt_guide_final.html, or another document with 
no more restrictive terms, to readily transfer unpatented tools developed 
with NIH funds to other recipients for use in NIH-funded projects. If the 
materials are patented or licensed to an exclusive provider, other 
arrangements may be used, but commercialization option rights, royalty reach-
through, or product reach-through rights back to the provider are 
inappropriate. Similarly, when for-profit entities are seeking access to NIH-
funded tools for internal use purposes, recipients should ensure that the 
tools are transferred with the fewest encumbrances possible. The Simple 
Letter Agreement may be expanded for use in transferring tools to for-profit 
entities, or simple internal use license agreements with execution or annual 
use fees may be appropriate. 

Applicants also are reminded that the grantee institution is required to 
disclose each subject invention to NIH within two months after the inventor 
discloses it in writing to grantee institutional personnel responsible for 
patent matters. The awarding institute reserves the right to monitor awardee 
activity in this area to ascertain if patents or patent applications on 
protocols, cell lines, vectors, or other patentable subject matter are 
adversely affecting the goals of this RFA.

As noted earlier, Principles and guidelines for recipients of NIH research 
awards on obtaining and disseminating biomedical research resources can be 
found at http://www.ott.nih.gov/policy/rt_guide_final.html.

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.

The administrative and funding instrument used for this program is the multi-
project cooperative agreement (U19) 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.

1. Monitoring Clinical Studies

When clinical studies 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; and the DMID Policies 
and Guidance for Data and Safety Monitoring at 
http://www.niaid.nih.gov/dmid/clinresearch/. Award of a cooperative agreement 
does not constitute approval for initiation of human subjects research.  HC 
CRC investigators will be required to develop and conduct all studies 
involving human subjects using Good Clinical Practice Standards as defined 
and published by the International Conference on Harmonization (ICH) and 
adopted by the FDA (Federal Register Vol.62 No. 90 (5/9/97) ICH protocol 
requirements outlined in part 6 of the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice website http://www.ich.org  or at 
http://www.mch.com/doctors_caregivers/research/Forms/ICH%
20Guidlines%20for%20Research%20Protocols.pdf

2. Awardee Rights and responsibilities 
(http://www.fda.gov/oc/gcp/guidance.html).

Prior to study initiation, NIAID staff will review all studies involving 
human subjects at two stages.  The first stage will be a review of the 
research concept and the second review will be during protocol development.  
Both stages will be reviewed for scientific content, design, safety, 
feasibility, statistical, and regulatory compliance.  Use of the NIAID 
protocol template, found at the International Clinical Studies Support Center 
website (http://icssc.org/rel_links.htm#templates), is encouraged.

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.

It is the primary responsibility of the awardee Program Director to clearly 
state the objectives and approaches of the research, to plan and conduct the 
research stipulated in the application, and to ensure that the results 
obtained are analyzed and published in a timely manner.  NIAID may 
periodically review and generate internal reports from data and progress 
reports developed under this cooperative agreement. The data obtained will, 
however, be the property of the awardee. 

Awardees will retain custody of and have primary rights to data collected 
under this award, subject to Government rights of access consistent with 
current U.S. Department of Health and Human Services(DHHS), Public Health 
Service(PHS) and National Institutes of health (NIH) Policies.
 
3. NIAID Staff Responsibilities

NIAID staff assistance will be provided by the Hepatitis Program Officer in 
the Enteric and Hepatic Diseases Branch, Division of Microbiology and 
Infectious Diseases, who will serve as the NIAID Scientific Coordinator.  The 
NIAID Scientific Coordinator will have substantial scientific/programmatic 
involvement during the conduct of this activity through technical assistance, 
advice and coordination above and beyond normal program stewardship for 
grants, particularly with regard to the following aspects:

Participation as a member of the HC CRC Steering Committee and attendance at 
annual Steering Committee meetings;

Participation as a member of the Scientific Review Committee to evaluate and 
select Pilot Projects for funding;

Overall design of studies, especially those undertaken jointly by the HC 
CRC’s linkage to special populations;

NIAID staff will also facilitate liaison with existing NIAID contracts and 
interaction with other investigators within and outside the HC CRCs for:  
vaccine production; data collection and analysis; HCV reagent repository; 
resource and reagent sharing; HCV sequence database; and pedigreed specimen 
exchange. 

The NIAID Scientific Coordinator will serve as a liaison/facilitator between 
the awardee, pharmaceutical and biotechnology companies, and other government 
agencies (e.g., the U.S. Food and Drug Administration (FDA), the U.S. 
Department of Agriculture, the Centers for Disease Control and Prevention) 
and will serve as a resource for scientific and policy information related to 
the goals of the awardee's research. However, the role of NIAID will be to 
facilitate and not to direct the activities. It is anticipated that decisions 
in all activities will be reached by consensus and the NIAID staff will be 
given the opportunity to offer input into this process. The manner of 
reaching this consensus and the final decision-making authority will rest 
with the Principal Investigator.

An NIAID Program Official will be assigned to perform normal program 
stewardship responsibilities for this award. The Program Official may serve 
as the NIAID Scientific Coordinator. 

4. Collaborative Responsibilities

The HC CRC Program Directors and the NIAID Scientific Coordinator will 
constitute the Steering Committee for this research program and will meet at 
least annually to review progress and future plans, revise the focus if 
required, and develop collaborative efforts.

The NIAID Scientific Coordinator will work with the HC CRC Program Director 
selected to serve as the Development Fund Administrator to appoint a 
Scientific Review Committee; both will participate in the review and 
selection of applications for Pilot Projects.

Special Consideration: In the event that research supported by the 
Cooperative Agreement results in development of a therapeutic or other 
medical intervention, NIAID will retain the option to cross-file or 
independently file an application for an investigational clinical trial 
(i.e., an Investigational New Drug Application [IND]) to the FDA. To 
facilitate this, reports of data generated by the HC CRCs or any of its 
members, which are required for inclusion in INDs and Clinical Brochures and 
for cross-filing purposes, will be submitted by the Program Director to the 
NIAID Scientific Coordinator 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.

5. Arbitration

Any disagreement that may arise on scientific/programmatic matters (within 
the scope of the award) between award recipients and I/C may be brought to 
arbitration. An arbitration panel will be composed of three members – one 
chosen by the awardee, a second member selected by the IC, and the third 
member selected by the two prior selected members. This special arbitration 
procedure in no way affects the awardee's right to appeal an adverse action 
that is otherwise appealable in accordance with the PHS regulations at 42 CFR 
Part 50, Subpart D and HHS regulation at 45 CFR Part 16.

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 Parts 74 and 92, and other HHS, PHS, and NIH Grant 
Administration policy statements.

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 questions about scientific/research issues to:

Rajen Koshy, PhD
Enteric and Hepatic Diseases Branch
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room Number 4010, MSC-6603
6610 Rockledge Drive
Bethesda, MD 20892-6603
Telephone: 301 402 8550
FAX: 301 402 1456
Email: rk133f@nih.gov

o Direct questions about peer review issues to:

Gerald McLaughlin 
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3119, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 435-2766 
FAX: (301) 402-2638
Email: gm145a@nih.gov

o Direct questions about financial or grants management matters to:

Celeste Kerner
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2253, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 402-6213
FAX: (301) 480-3780
Email: ck103k@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
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:

Gerald McLaughlin 
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3119, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 435-2766 
FAX: (301) 402-2638
Email: gm145a@nih.gov

SUBMITTING AN APPLICATION

Applicants for U19 grants must follow special application guidelines in the 
NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS; this brochure is available via the WWW at 
http://www.niaid.nih.gov/ncn/grants/multibron.htm.

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 D&B number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The D&B 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.

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:

Gerald McLaughlin 
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3119, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
BETHESDA, MD 20817 (for express mail or courier service)

Applications that are not received as a single package on or before November 
22, 2004 or that do not conform to the instructions contained in PHS 398 
(rev. 5/01) Application Kit (as modified in, and superseded by, the NIAID 
BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), 
will be judged non-responsive and will be returned to the applicant.

SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA:

Applicants for U19 cooperative agreements must follow special application 
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR 
MULTI-PROJECT AWARDS; this brochure is available from NIAID listed under 
INQUIRIES via the WWW at http://www.niaid.nih.gov/ncn/grants/multibron.htm.

This brochure presents specific instructions for sections of the PHS 398 
(rev. 5/01) application form that should be completed differently than usual. 
For all other items in the application, follow the usual instructions in the 
PHS 398.

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 NIH 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. 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 from the previous unfunded version of 
the application. While the investigator may still benefit from the previous 
review, the RFA application is not to state explicitly how.

CONCURRENT SUBMISSION OF AN R01 AND A COMPONENT PROJECT OF A MULTI-PROJECT 
APPLICATION: Current NIH policy permits a component research project of a 
multi-project grant application to be concurrently submitted as a traditional 
individual research project (R01) application. If, following review, both the 
multi-project application and the R01 application are found to be in the 
fundable range, the investigator must relinquish the R01 and will not have 
the option to withdraw from the multi-project grant. This is an NIH policy 
intended to preserve the scientific integrity of a multi-project grant, which 
may be seriously compromised if a strong component project(s) is removed from 
the program. Investigators wishing to participate in a multi-project grant 
must be aware of this policy before making a commitment to the Principal 
Investigator and awarding institution.

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 the 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 the NIAID in accordance with the 
review criteria stated below. As part of the initial merit review, all 
applications will:

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 written critique
o Receive a second level review by the National Advisory Allergy and 
Infectious Diseases Council

REVIEW CRITERIA

The general review criteria for U19 multi-project cooperative agreement 
applications are presented in the NIAID brochure entitled "INSTRUCTIONS FOR 
APPLICATIONS FOR MULTI-PROJECT AWARDS” at 
http://www.niaid.nih.gov/ncn/grants/multibron.htm.
 
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 in the sections on Federal Citations, 
below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.

ADDITIONAL REVIEW CONSIDERATIONS

SHARING RESEARCH DATA:  Applicants requesting $500,000 or more in direct 
costs, in any year of the proposed research, are expected to include a data 
sharing plan in their application. The reasonableness of the data sharing 
plan or the rationale for not sharing research data will be assessed by the 
reviewers. However, reviewers will not factor the proposed data-sharing plan 
into the determination of scientific merit or priority score. (See 
instructions and URL to policy in the Federal Citations, below.)

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

RECEIPT AND REVIEW SCHEDULE  

Letter of Intent Receipt Date:      October 22, 2004 
Application Receipt Date:           November 22, 2004
Peer Review Date:                   March 15, 2005
Council Review:                     May 2005
Earliest Anticipated Start Date:    June 30, 2005

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

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on Humane Care 
and Use of Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA 
Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

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

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants. (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).

SHARING RESEARCH DATA: Investigators submitting an NIH application seeking  
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing or state why this is not possible 
http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule. Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

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 are 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. 

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. This policy announcement is 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.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://stemcells.nih.gov/index.asp and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). 
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s) for the hESC line(s) to be used in the proposed research. 
Applications that do not provide this information will be returned without 
review.

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.

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). 

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, Transplantation Research; No. 93.856, Microbiology and Infectious 
Diseases Research; and No. 93.848, Digestive Diseases and Nutrition 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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