HEPATITIS C COOPERATIVE RESEARCH CENTERS

Release Date:  May 26, 1999

RFA:  AI-99-007

National Institute of Allergy and Infectious Diseases
National Institute of Diabetes, Digestive and Kidney Diseases
National Institute of Alcoholism and Alcohol Abuse
National Institute of Drug Abuse

Letter of Intent Receipt Date:  August 1, 1999
Application Receipt Date:  November 24, 1999

APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE
PREPARED USING SPECIFIC INSTRUCTIONS IN AN NIAID BROCHURE ENTITLED
"INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" (APRIL 1999).

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), the
National Institute of Diabetes, Digestive and Kidney Diseases NIDDK), the
National Institute of Drug Abuse (NIDA), and the National Institute of
Alcoholism and Alcohol Abuse (NIAAA) invite applications for the establishment
of multi-project or single-project Hepatitis C Cooperative Research Centers
(HC CRCs).  The purpose of this RFA is to stimulate high quality,
multidisciplinary, innovative yet systematic, collaborative research on
hepatitis C virus (HCV).  Such clinical and basic research is meant to provide
further understanding of the stages and manifestations of hepatitis C
infection, disease, and recovery.  The HC CRCs also will have a mandate to
build on new findings to explore new vaccine and therapy strategies.

HEALTHY PEOPLE 2000

The Department of Health and Human Services (DHHS) is committed to achieving
the health promotion and disease prevention objectives of "Healthy People
2000," a DHHS-led national activity for setting priority areas.  This RFA,
Hepatitis C Cooperative Research Centers (HC CRCs), is related to the priority
area of immunization and infectious diseases. Potential applicants may obtain
a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic for-profit and non-
profit organizations, public and private institutions, such as universities,
colleges, hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Foreign organizations are not
eligible to apply but may be part of a collaborative arrangement. 
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this program
will be the Cooperative Agreement (single project U01 or multi-project U19),
an "assistance" mechanism, rather than an "acquisition" mechanism, in which
substantial NIH scientific and/or programmatic involvement with the awardee is
anticipated during performance of the activity.  Under the cooperative
agreement, the NIH purpose is to support and/or stimulate the recipient's
activity by involvement in and otherwise working jointly with the award
recipient in a partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity.

Details of the responsibilities, relationships, and governance of a study
funded under cooperative agreement(s) are discussed later in this document
under the section Terms and Conditions of Award.

The cooperative agreement-funding instrument can support HC CRC awards of
either a multi-project program or a single project program, and both types of
applications will be considered by NIAID.  Single project applications should
focus on a hypothesis driven discrete, circumscribed objective.

Essential elements of the Multi-project Cooperative Agreement mechanism
include:  (1) a minimum of three inter-related individual research projects
organized around a central theme; (2) collaborative efforts and interaction
among independent projects and their investigators to achieve a common goal;
(3) a single Principal Investigator who will be scientifically and
administratively responsible for the group effort; (4) a single applicant
institution that will be legally and financially responsible for the use and
disposition of funds awarded; and (5)support provided, as necessary, for
"core" resources or facilities, each  of which is expected to be utilized by
at least two research projects in  order to facilitate the research efforts. 
Applications for multi-project programs should describe in detail their
organizational and administrative structure.  Whereas multi-project programs
may take advantage of the "core" mechanisms to provide support for common
resources (e.g., laboratory or clinical facilities), it is understood that
support for such facilities will be included in the budget of a single project
application as required.

HC CRCs may involve collaboration among investigators at several institutions. 
These consortium arrangements should follow the NIH Guide outline in
"Guidelines for Establishing and Operating Consortium Grants, January 1989." 
These are available from the individuals listed under INQUIRIES.

The total project period for applications submitted in response to this RFA
may not exceed 5 years.  At this time, the NIAID has not determined whether
and how this solicitation will be continued beyond the present RFA.  If, by
the end of the third year of the award, the NIAID has not announced its
intent, due to budget uncertainties to reissue the RFA, incumbents should
contact program staff to seek advice on the most appropriate method of
application submission before preparing a recompeting application.

FUNDS AVAILABLE

The estimated total funds (direct and F&A costs) available for the first year
of support for all HC CRC awards made under this RFA will be $4.4 million. The
final number of awards to be made is dependent upon the availability of funds.

In Fiscal Year 2000, the NIAID plans to fund approximately four to eight
awards -- the variability dependent upon both the nature (U01 or U19) and size
of the awards. The NIDDK, NIDA, and NIAAA each intend to fund one single-
project award. The initial year's total costs, including direct and F&A costs,
should not exceed $750,000 for each multi-project award and $250,000 for a
single-project award.  Exceptions to this budget limit must be discussed and
approved by Dr. Leslye Johnson. (See Inquiries below.) The usual NIH policies
governing grants administration and management will apply.  Although this
program is provided for in the financial plans of the NIAID, NIDDK, NIDA and
NIAAA, awards pursuant to this RFA are contingent upon the availability of
funds for this purpose and the receipt of a sufficient number of applications
of high scientific merit.  Funding beyond the first and subsequent years of
the grant will be contingent upon satisfactory progress during the preceding
years and availability of funds.

RESEARCH OBJECTIVES

Background

Hepatitis due to hepatitis C virus (HCV) is classified as an emerging
infectious disease (IOM Report, 1992).  After the cloning and sequencing of
HCV about ten years ago, investigators identified HCV as the most important
etiological agent of non-A, non-B hepatitis and its associated chronic liver
disease. HCV infection and disease disproportionately affect African-Americans
and Hispanics.  The incidence of HCV infection has fallen from a peak of
150,000 in the late 1980's to approximately 30,000 in recent years.  The major
risks of transmission stem from percutaneous exposure to blood and multiple
sexual partners.  For a small percentage of individuals the source of
infection remains unidentified.

Approximately 1.8% of Americans - 4 million people - are persistently infected
with HCV, i.e., are chronic carriers.  The same 1-2 percent carrier rate is
true around the world with the exception of a few high endemicity areas such
as some inner city areas in the U.S., Egypt, the Sudan, and isolated villages
in Asia.  In the U.S. the total direct and time lost cost for HCV infection
and chronic sequelae is estimated at $1.5 billion per year.

The course of infection and disease is variable at an individual level. In
general, the initial infection is often asymptomatic. Recovery from infection
is exceedingly rare and estimates are that 85% of those infected become
persistently infected, i.e., chronic carriers.  Infection progresses to liver
cirrhosis in 20-30% of individuals after about two decades of persistent
infection. For others progression is either slower or muted.

Since identification of HCV, considerable progress has been made. Molecular
biological techniques have enabled investigators to: 1) clone, sequence and
identify HCV genotypes and explore the importance of quasispecies; 2) identify
several viral proteins, how they are made, and their functions; and 3) probe
pathogenesis.  Diagnostic tools have been developed that have been
instrumental in: 1) verifying the agent causing liver disease in symptomatic
patients as well as identifying asymptomatic patients; 2) preventing
transmission in transfusion, transplantation and hemodialysis patients; and 3)
identifying important cofactors for infection and disease progression.  There
are efforts ongoing to explore and quantify modes of transmission such as from
mother to infant, from tattooing and body piercing and between monogamous
sexual partners.  Studies of (immuno) pathogenesis and viral replication are
beginning.

Despite these advances, infection and disease caused by HCV remain enigmatic. 
Available therapies - various interferons as well as interferon alpha in
combination with ribavirin - are woefully inadequate and have considerable
associated toxicity.  Research is needed to further explore viral replication
strategies, pathogenesis and disease outcomes, as well as to define possible
new therapeutic strategies.  Prevention of infection and disease, such as that
possible with vaccines for other infectious agents, is currently impossible
and there are numerous obstacles. One stems from the inadequate immune
response to natural infection -- viral clearance is exceedingly rare even
though neutralizing antibodies have recently been detected.  The large number
of HCV genotypes and their high rate of mutation as well as the existence of
genetic variants, i.e., "quasispecies", also pose obstacles both to prevention
and treatment.

Largely unexplored are such areas as the: 1) intricate host-viral interactions
that define recovery from and persistence of HCV infection; 2) role of host
genetics in outcome, 3) pathogenesis, 4) protective mechanisms keeping disease
at a minimum; 5) natural history and progression of disease, and 6) the impact
of co-infection, drug and alcohol use, and immunosuppression.  Finally, access
to resources such as model systems and adequately sized patient populations is
difficult.

Vaccination to prevent infection and therapeutic strategies to cure or
ameliorate persistent infection and disease are necessary to derive the
greatest benefit for those at risk and affected respectively.  For diseases
like hepatitis B they have been shown to be highly cost-effective.  Thus in
this RFA, the NIAID and other participating Institutes are interested in
research focused on acute and persistent disease or the role of alcohol,
drugs, and co-infections in the progression rather than on liver failure or
cancer therapy.

Research Objectives and Scope

This RFA seeks to support state-of-the-art, innovative research on hepatitis C
virus.  Using integrated approaches from multiple disciplines, the HC CRCs
will serve as foci for generating the knowledge needed to further
understanding of HCV infection, recovery, and pathogenesis.  Building on this
knowledge, the sponsoring ICs anticipate that the HC CRCs will devise original
preventive and therapeutic interventions.

The NIAID, NIDDK, NIDA and NIAAA expect clinical issues and needs to be a
strong driving force for research performed by the HC CRCs and hopes to
support research utilizing well-characterized clinical populations and/or
their specimens.  The NIAID also encourages research using available animal
model systems including the chimpanzee and/or research specimens from them.

The NIH is emphasizing the research areas identified below.  However,
applicants are not limited only to these areas.

A central focus is the host-virus interface, an area crucial for understanding
the immunology and pathogenesis of HCV infection and disease.  There is an
important balance struck between HCV and the host; this balance point set is
critical for both infection outcome and disease activity.  Hence, it is
important to identify the host and viral factors/variables/ markers, e.g.,
viral sequence and variability, host genetics, etc. and to explore mechanisms:

o  associated with and responsible for natural recovery from acute infection
and/or chronic infection;
o  of protective vs. injurious host responses especially immune responses as
well as epitopes, etc. required for protective immunity;
o  of responses, especially immune responses,  to repeat infections;
o  of recovery and non-recovery from chronic infection during treatment with
various therapies;
o  involved in gender and racial/ethnic differences in susceptibility to and
outcomes of infection;
o  of pathogenesis;
o  involved in moving from asymptomatic to symptomatic infection  determining
outcome and timing of disease progression including the impact of co-factors
such as alcohol, injection drug use and co-infection; and
o  that cause and exacerbate liver disease.

Research to enhance the understanding of immunological and pathological events
in the liver is encouraged.

With respect to the virus, it remains important to continue to:
o  develop an understanding of viral replication
o  identify key viral functions and conduct structure-function studies.

The use of infectious clones or virus in animal models such as the chimpanzee
currently is crucial to:
o  study immune responses and pathogenesis, and
o  investigate the relationship between specific viral sequences and
infectivity, immune responses, pathogenesis and natural history.

Investigation is still hampered by the lack of model systems. Hence, there is
continued interest in developing small animal model and in vitro systems with
relevance to basic research on recovery, persistence, pathogenesis, protective
immunity, co-factors, and replication as well as applied research on therapies
and vaccines.  Of particular interest are infectious models that reproduce the
full spectrum of human disease.

In order to hasten the application of information gained from basic and
clinical research to health care advances, this RFA encourages translational
research for purposes including, but not limited to, development of:

o  diagnostic tools or markers to determine the outcome of acute infection,
i.e., recovery vs. persistence as well as chronic infection, i.e., severity
and timing of progression;
o  surrogate correlates of protection;
o  multiple vaccine types so as to protect broadly from infection and disease
and/or to promote recovery from acute or chronic infection;
o  intervention strategies to broaden or enhance protective immunity or
subvert persistence mechanisms;
o  surrogate endpoints of recovery from chronic infection and liver disease;
and
o  new therapeutic approaches aimed at recovery from persistent infection.

Relevant Disciplines

In order to foster multidisciplinary research, each multi-project HC CRC
should include broad approaches from a range of disciplines such as virology,
immunology, cell and tissue biology, pathogenesis, clinical infection and
disease, model system development, and applied research.

Clinical Capability

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 and clinical experience with populations representing
different disease stages, transmission modes, racial/ethnic background, co-
factors, etc. All applicants are encouraged to include research utilizing
human subjects to address research questions and validate basic research
findings. The value of such basic research and clinical studies performed is
directly related to the care exercised in selection and characterization of
cases and controls. It is expected that HC CRCs investigators would provide
samples to other investigators in order to enhance overall research efforts.
Access to and experience with patient populations also will facilitate new
vaccine and therapy development.  NIAID, NIDDK, NIDA and NIAAA encourage: 1)
collaborative arrangements with on-going studies or clinical care capable of
providing the crucial patient populations, specimens and information; and 2)
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 PI or GCRC Program
Director respectively must be included in the application material.

HC CRC award funds may be utilized to support the following research-related
activities:

Optional Developmental Fund for Pilot Projects: NIAID strongly encourages
multi-project U19 HC CRCs applications to include a request for a
Developmental Fund. (Single project U01 applicants are not eligible.) This
option sets aside and restricts funds solely to cover partial salary and
research costs for pilot projects.

Such pilot projects might develop methods or resources capable of enhancing
basic and clinical research progress, follow-up on new observations and
hypotheses, or perform short term high risk - high benefit research.  It is
envisioned that availability of funds for pilot studies will increase
flexibility and responsiveness to important new technologies, scientific
observations and opportunities and medical research findings.  It will also
permit entry of new investigators into the field and allow for the collection
of preliminary data needed for submission of R01s.  (See below: "APPLICATION
PROCEDURES" for more details on the preparation of requests.)

Pilot studies need not be restricted to the awardee institution.  IT IS
EMPHASIZED THAT PILOT STUDIES AWARDED FROM THE DEVELOPMENTAL FUND ARE DISTINCT
FROM INDIVIDUAL HC CRC RESEARCH PROJECTS.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

The following terms and conditions will be incorporated into the award
statement and provided to the Program Director 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 Parts 74 and 92, and other HHS, and NIH Grant Administration policy
statements.

The administrative and funding instrument used for this program is the Multi-
project (U19) or Single-project (U01) Cooperative Agreement or, an
"assistance" mechanism (rather than an "acquisition" mechanism), in which
substantial NIH scientific and/or programmatic involvement with the awardee is
anticipated during the performance of the activity. Under the Multi-project
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 coordinator.

Awards will be made to an institution on behalf of a Program Director who will
be responsible for the coordination of HC CRC scientific and administrative
activities.  Support of all HC CRC activities will be coordinated through a
Central Operations Office located within the applicant organization.

1. Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research objective,
approaches and details for the project within the guidelines of the RFA and
for performing the scientific activity.  Awardees agree to accept close
coordination, cooperation, and participation of NIAID staff in all aspects of
scientific and technical management of the project as stated below under NIAID
Staff Responsibilities. Awardees will retain custody of and have primary
rights to the data developed under these awards, subject to Government rights
to access consistent with current HHS, PHS and NIH policies.

Under the Cooperative Agreement, a partnership relationship exists between the
recipient of the award and NIAID in which successful applicants are responsive
to the guidelines and conditions set forth in the RFA.  At the same time,
investigators are expected to define research objectives and approaches in
accord with their own interests and perceptions of novel and exploitable
approaches to the research which ultimately is likely to result in improved
prevention and control of hepatitis C.

It is the primary responsibility of the Program Director to clearly state the
objectives and approaches of the research, to plan and conduct the research
stipulated in the proposal, 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.

The multi-disciplinary and collaborative nature of the HC CRCs creates an
extraordinary opportunity for information exchange and scientific advancement
in hepatitis C research.  Program Directors are expected to take advantage of
this opportunity by participation in both formal events established expressly
for this purpose and informal investigator-initiated dialogues.

2. NIAID Staff Responsibilities

The NIAID will have substantial scientific/programmatic involvement during the
conduct of this activity, through technical assistance, advice and
coordination above and beyond normal program stewardship for grants, as
described below.

The NIAID will work closely with the Program Directors and shall be
represented by the Scientific Coordinator (Program Officer).  The Scientific
Coordinator will be the Hepatitis Program Officer in the Enteric and Hepatic
Diseases Branch of NIAID.  During the award period, the NIAID Scientific
Coordinator may provide appropriate assistance, advice, and guidance in:

o  overall design of studies, e.g., prospective or intervention especially
those undertaken jointly by the HC CRCs,
o  linkage to special populations and vaccine production facilities funded
through NIAID contracts, NIAID's data collection and analysis contracts,
NIAID's repository contract, and staff capabilities with respect to Master
File and IND filing,
o  coordination and facilitation of information, technology, reagent and
pedigree specimen exchange between HC CRCs themselves and other grantees and
contractors
o  assistance in review and selection of developmental fund awardees; and
o  technical and administrative activities of HC CRCs.

However, it is again emphasized that the role of NIAID will be to facilitate
and not to direct the activities of the HC CRCs. It is anticipated that
decisions in all activities outlined within this RFA will be reached by
consensus of the investigators and that the NIAID Scientific Coordinator will
be given the opportunity to offer input to this process.

3. Collaborative Responsibilities

The HC CRC Program Directors and NIAID Scientific Coordinator will form a
Steering Committee that will meet at the NIH in Bethesda, Maryland (or at a
site designated by NIAID) twice a year.  Its functions include, but are not
limited to: tracking and reviewing activities/progress over the six months
between meetings, planning for the next six months and beyond, maintaining
focus, and developing collaborative efforts.  Issues for discussion and
agendas will be a collaborative responsibility.  The first such meeting will
occur shortly Post Award.

Three times during the project period and in conjunction with a semi-annual
steering committee or other pertinent meeting, workshops for the Program
Directors and Project Leaders will be convened to share hepatitis C research
advances, to discuss research needs and opportunities, and to develop
collaborations.  It is likely that workshops will be convened towards the end
of Years 1-3 of the project period at the NIH in Bethesda, Maryland (or at a
site designated by NIAID).

A critical element of the HC CRCs' success is the degree of communication
among its members.  Therefore, additional informal meetings among participants
from different HC CRCs as well as regular telephone and written communication
will be encouraged.

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 United States Food and Drug Administration. 
To facilitate this, reports of data generated by the HC CRC 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
Scientific Coordinator upon request.  Such reports will be in final draft form
and include background information, methods, results, and conclusion. 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.

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 composed of three members -- one
selected by the Program Director, a second member selected by the NIAID, and
the third member with relevant expertise and selected by the two prior members
and will be formed to review any scientific or programmatic issue that is
significantly restricting progress.  While the decisions of the Arbitration
Panel are binding, these special arbitration procedures will in no way affect
the awardee's right to appeal an adverse action in accordance with PHS
regulations at 42 CFR part 50, subpart D, and HHS regulation at 45 CFR part
16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

A strong emphasis is placed on studying hepatitis C in populations that are
disproportionately affected.  These populations include African-Americans and
Hispanics.  Subjects may be recruited or specimens obtained from domestic
sites or through collaborations with foreign institutions if the collaboration
is beneficial to the foreign country and offers the potential for collection
of hepatitis C data that are pertinent to U.S. populations and could not be
generated as effectively in the United States.

It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43.

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994. Available on the web at:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html.

Investigators may obtain copies of the policy from these sources or from
program staff listed under INQUIRIES who may also provide additional relevant
information concerning the policy.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects: that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by August 1, 1999, a letter of
intent that includes a descriptive title of the overall proposed research, the
name, address including institution, and telephone number of the Program
Director as well as those of all project leaders and collaborators, and the
number and title of this RFA.  Although the letter of intent is not required,
is not binding, does not commit the sender to submit an application, and does
not enter into the review of subsequent applications, the information that it
contains allows review to estimate the potential review workload and to avoid
conflict of interest in the review.  The letter of intent is to be sent to Dr.
Madelon Halula at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants for multi-project (U19) grants must follow special application
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS (April 1999); this brochure is available from NIAID staff
listed in INQUIRIES below an via the WWW at:
http://www.niaid.nih.gov/ncn/grants/multibron.htm

Applicants are strongly encouraged to contact program staff listed under
INQUIRIES with any questions regarding the responsiveness of their proposed
projects to the goals of this RFA.

Clinical Capabilities and Laboratory Facilities: In describing the clinical
capabilities and laboratory facilities, the application should include
specific information on present patient load, projections for patient
involvement in future clinical investigations, history of recruitment and
study of subjects, and disease category and prevalence as well as on the
availability of appropriate biohazard facilities and safety procedures.

Collaborative Organization

The application should include a plan to maintain close collaboration and
communication among members of the HC CRC as well as an organizational chart
showing the name, the organization and the scientific discipline of the
Program Director, the Project Leaders, and the key personnel for the projects
and cores.  The application must also include a signed letter of agreement
from each collaborator and/or consultant to the program indicating willingness
to participate in the program and a description of the exact nature of the
participation.

Budget and Related Issues

Travel:  It is expected that HC CRC Program Directors will attend two (2)
meetings each year with the NIAID Scientific Director.  It is expected that HC
CRC Project Leaders will attend HC CRC meetings/workshops three times during
the program period.  Such meetings will include scientific, technical and
administrative topics of interest to the NIAID, Program Directors and Project
Leaders.  It is anticipated that they will provide greater synergy for the
overall HC CRC program.  Funds for travel to all meetings must be included in
application budget.  (See: SPECIAL REQUIREMENTS, Terms and Conditions of
Award, 3. Collaborative Responsibilities.)

Budget Issues

Budget requests within each project may include research-related costs for
supplies, patient involvement and medical care that are not covered by the
patient's medical insurance plan, funds for limited investigator travel, and
costs of publication.  Proposals for studies that do not receive the majority
of funding through the HC CRC will not be counted as a project but may support
a project.  There must be concordance between the science proposed and the
budget requested.  Furthermore, if additional sources of funding have been
identified for a project, then letters documenting a funding commitment must
be included in the application.

The applicant Program Director must commit sufficient time to the
administration of the HC CRC.  The application must provide a written plan
explaining how the Program Director will successfully and fully meet the
responsibilities demanded by this endeavor.

Developmental Funds Pool (U19 applications only):

There is a ceiling of $60,000 per year in direct costs on the dollar amount of
the developmental funds pool. Once identified as developmental funds these
monies constitute a restricted portion of the total HC CRC budget and will not
be available for other HC CRC activities. Funds reserved for pilot projects
may not be rebudgeted into other budget categories except in unusual
circumstances and following approval from the Grants Management Specialist and
the Scientific Coordinator.

The size of individual developmental awards is $20,000 and may be used for
salary, technical support, laboratory supplies, and small equipment.  Supplies
and equipment expenditures for each award may not exceed $10,000 annually.
Projects and investigators funded under the developmental core may not receive
subsequent awards from this pool. The duration of support for each study
typically would be one year, but may be up to two years.  If the project or
investigator achieves independent funding including, but not limited to, a
traditional research grant (R01) award prior to the end of the developmental
award, pilot study support from the developmental fund must be terminated, and
unexpended funds must be returned to the developmental funds pool. Finally,
the HC CRC must maintain detailed records of disbursements and expenditures of
the Developmental Fund and report on progress.

Potential awardees and specific pilot research projects to be pursued need not
be identified in the application.  However, the application should include a
one-page description of the kind of project that might be funded under this
mechanism and how it might interdigitate with other CRC projects. The
application also must provide a description of the proposed review process and
selection criteria for proposed projects.  Examples of criteria are scientific
merit of the proposal, medical relevance and need for data to advance the
research objectives of the HC CRC and the field.  It is recommended that a
small committee be formed to review, rank and recommend pilot projects.  It is
also suggested that the committee include local individuals who are not part
of the HC CRC but are part of the funded institution(s) and exclude
individuals applying for a pilot project. The Scientific Coordinator will
review both the proposed studies and the review committee recommendations make
specific recommendations for funding.  Like all other NIH supported projects
studies involving Human Subjects or animals will require prior approval by the
Institutional Review Board or the Institutional Animal Care and Use Committee
respectively.  Approval of the developmental funds portion of the application
does not in any way commit the program directors to the execution of the
sample project.

The annual direct costs of the developmental fund should be entered in the
OTHER category in the Consolidated Budget (see pages 15 and 21 in the NIAID
Multi-project brochure).

Before preparing an application, the applicant should carefully read the new
information brochure accompanying each RFA, NIAID Program Project Grants and
Multi-project Cooperative Agreements (April 1999.)  Instructions for
formatting the application as outlined in the brochure should be followed
carefully.  Failure to follow the instructions may result in unnecessary
delays in the review process.

Applications are to be submitted on the standard research grant application
form PHS 398 (rev. 4/98).  Application kits are available at most
institutional offices of sponsored research and may be obtained from the
Division of Extramural Outreach and Information Resources, National Institutes
of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, Maryland, 20892-7910,
telephone (301) 710-0267, email: [email protected]; and on the internet at
https://grants.nih.gov/grants/funding/phs398/phs398.html.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES" and the RFA number "AI-99-007" and the words
"HEPATITIS C COOPERATIVE RESEARCH CENTERS HC CRCs)" must be typed in.

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

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

Applications from multi-component consortia must contain a single face page,
an overall budget page, and separate budget pages for each institution
involved.  Each consortium institution is allowed 25 pages for the research
plan if different plans are proposed by the different member institutions. 
For additional information, refer to page 13 of the PHS 398 application form.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6001 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 appendix material must be sent to Dr. Madelon
Halula listed below in INQUIRES.

Applications must be received by the official receipt date as indicated in the
RFA heading.  All components, subparts and sections of the application must be
collated into the application, and the packages sent to the CSR and to the
NIAID must each be complete in themselves.  Applications that are not received
as a single package on the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified and
superseded by the special instructions below) will be judged non-responsive
and will be returned to the applicant.

Current NIH policy permits a component research project of a multiproject
grant application to be concurrently submitted as a traditional individual
research project (R01) application.  If, following review, both the
multiproject 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 multiproject grant.  This is a NIH policy intended
to preserve the scientific integrity of a multiproject grant, which may be
seriously compromised if a strong component project(s) is removed from the
program.  Investigators wishing to participate in a multiproject grant must be
aware of this policy before making a commitment to the Program Director and
awarding institution.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for responsiveness by NIAID staff; those judged to
be incomplete or non-responsive will be returned to the applicant without
review.  Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer review
group convened by the NIAID in accordance with the review criteria stated
below.  As part of the initial merit review, a streamlining process may be
used by the initial review group in which applications receive a written
critique and undergo a process in which only those applications deemed to have
the highest scientific merit, generally the top half of applications under
review will be discussed, assigned a priority score, and receive a second
level of review by the National Advisory Allergy and Infectious Diseases
Council.

CRITERIA:  The general criteria for multi-project (U19) cooperative agreement
applications are presented in the NIAID BROCHURE. The criteria to be used in
the evaluation of single project applications are listed below. To put those
criteria in context, the following information is contained in instructions to
the peer reviewers.  In addition, applicants are expected to address research
priorities, objectives, and other requirements stated in this RFA.  Additional
language has been added to the basic aims to more closely focus them to the
goals of this RFA.

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

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? Specifically the understanding of HCV infection, recovery, persistence
and pathogenesis.

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?  Is there adequacy in the proposed plan for coordination
and communication within the applicant HC CRC and NIAID and other HC CRCs? 
Are there documentation of integration of research with clinical capability,
adequate and appropriate patient populations, disease prevalence, and
historical success of recruitment and retention of subjects?
Innovation. Does the project employ novel concepts, approaches or method? Are
the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

Investigator(s). Are the investigator and team (U01) or the Program Director,
the Project Leaders and key project and core personnel (U19) 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
researcher?

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?  Is
there documented sponsoring institution commitment to the cooperative program?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include children and
both genders and minorities and their subgroups as appropriate for the
scientific goals of the research and plans for the recruitment and retention
of subjects; the provisions for the protection of human and animal subjects;
and the safety of the research environment.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical merit
as determined by peer review, program balance, and the availability of funds. 
Program balance takes into account the need for multiple approaches and areas
of study.  The earliest anticipated date of award is August 1, 2000.

INQUIRIES

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

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

Dr. Leslye Johnson
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A-22  MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-7051
FAX:  (301) 402-1456
Email:  [email protected]

Tommie Sue Tralka
Clinical Trials Program
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6-AN-12K, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8879
Email:  [email protected]

Thomas F. Kresina, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC-7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-6537
FAX:  (301) 594-0673
Email:  [email protected]

Henry Francis, M.D.
Center on AIDS & Other Medical Consequences of Drug Abuse
National Institute on Drug Abuse
6001 Executive Boulevard, Room 5198, MSC 9593
Bethesda, MD  20892-9593
Telephone:  (301) 443-1801
FAX:  (301) 594-6566
Email:  [email protected]

Direct inquiries regarding review issues and special instructions for
application preparation, address the letter of intent to, and mail two copies
of the application and all five sets of
appendices to:

Dr. Madelon Halula
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6000-B Rockledge Drive, Room 2150, MSC 7616
Bethesda, MD 20892-7616
Bethesda, MD  20817 (for express/courier service)
Telephone: (301) 402-2636
FAX: (301) 402-2638
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Ms. Victoria Putpush
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B29, MSC 7610
Bethesda, MD 20892-7610
Telephone: (301) 402-6245
FAX: (301) 480-3780
Email: [email protected]

Donna Huggins
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6-AS-49J, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8848
FAX:  (301) 480-3504
Email:  [email protected]

Linda Hilley
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, MSC 7003
Bethesda, MD 20892-7003
Telephone: (301) 443-0915
FAX:  (301) 443-3891
Email: [email protected]

Gary Fleming, JD
Chief, Grants Management Branch
National Institute on Drug Abuse
6001 Executive Blvd., Room 3131, MSC 9541
Bethesda, MD 20892-9541
Telephone: 301-443-6710
FAX: 301-443-6847
Email: [email protected]

Schedule

Letter of Intent Receipt Date:  August 1, 1999
Application Receipt Date:       November 24, 1999
Scientific Review Date:         March 1, 2000
Advisory Council Date:          May 1, 2000
Earliest Award Date:            August 1, 2000

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.855 Immunology, Allergic and Immunological Diseases Research and 93.856
Microbiology and Infectious Diseases Research.  Grants are awarded under the
authority of the Public Health Service Act, Section 301 (42 USC 241) and
administered under PHS grants policies and Federal Regulations, most
specifically at 42 CFR Part 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of the Executive Order
12372 or Health Systems Agency review.

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

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