SMALL BUSINESS INNOVATION RESEARCH: ANIMAL MODELS OF HCV INFECTION

Release Date:  January 22, 1999

RFA NUMBER:  AI-99-001

P.T.

National Institute of Allergy and Infectious Diseases
National Cancer Institute
National Center for Research Resources
National Institute of Diabetes, Digestive and Kidney Diseases
National Institute of Alcohol Abuse and Alcoholism

Letter of Intent Receipt Date:  February 12, 1999
Application Receipt Date:       March 18, 1999

PURPOSE

This is a multi-Institute solicitation targeting the development/identification
of one or more small animal models of hepatitis C infection and disease
progression including acute and chronic states, fibrosis/cirrhosis, and liver
tumor development-not necessarily all in the same model.  Identification of a
small, inexpensive, reproducible, well-defined, and non-endangered mammalian
animal model for hepatitis C research is critical to the progress of exploration
of this pathogen. It is needed to study the pathogenesis, immunology, natural
history, and viral replication of hepatitis C as well as to act as a model for
the testing of new therapies and, hopefully, vaccine candidates. To date, the
chimpanzee, expensive and of limited access, is the only non-human model. This
Request for Applications invites grant applications for Small Business Innovation
Research (SBIR) projects with award duration and amounts greater than those
routinely allowed under the SBIR program.

This RFA must be read in conjunction with the Omnibus Solicitation of the Public
Health Service (Omnibus Solicitation) for Phase I SBIR Grant Applications (PHS
98-2) and the instructions for Phase II Grant Applications revised March 1998. 
All instructions and information in these documents also apply to applications. 
Recently the NIH has announced that applicants may request a larger budget and
period of support if necessary for completion of the project (See NIH Guide for
Grants and Contracts, February 13, 1998 at:
 http://grants.nih.gov/grants/guide/notice-files/not98-014.html

This RFA provides a flexible system within the SBIR program to cover the
extensive needs and complex development processes needed to identify/define and
develop a novel animal model of a hazardous infection-hepatitis C.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, SBIR: Animal Models of HCV
Infection, is related to the priority areas of immunization and infectious
diseases, HIV infection, sexually transmitted diseases, clinical preventive
services, maternal and infant health, diabetes and chronic disabling conditions,
and surveillance and data systems.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (Telephone 202-512-1800).

ELIGIBILITY

Eligibility requirements are described in the Omnibus Solicitation. Any small
business, independently owned and operated by United States citizens or permanent
resident aliens may apply.  It must be organized for-profit, cannot be dominant
in its field of expertise, and must have its principal place of business in the
United States.  Including any affiliates, the company can be the employer of no
more than 500 people.

MECHANISM OF SUPPORT - PHASE I

Phase I applications in response to this RFA will be funded as Phase I SBIR
Grants (R43) with modifications as described below. Responsibility for the
planning, direction, and execution of the proposed research will be solely that
of the applicant.  Applications for Phase I grants should be prepared following
the directions for Phase I SBIR applications as described in the Omnibus
Solicitation.  Phase II applications in response to this RFA will only be
accepted as competing continuations of previously funded NIH Phase I SBIR awards. 
The Phase II application must be a logical extension of the Phase I research. 
The Omnibus Solicitation and information on the FAST-TRACK process are available
on the Internet at: http://grants.nih.gov/grants/funding/sbir1/SBIR.HTM

A limited number of hard copies of the Omnibus Solicitation are available from:

PHS SBIR/STTR Solicitation Office
13685 Baltimore Avenue
Laurel, MD  20707-5096
Telephone:  (301) 206-9385
FAX:  (301) 206-9722
Email:  a2y@cu.nih.gov

PROJECT PERIOD AND AMOUNT OF AWARD

PHASE I:
Because the length of time and cost of research involving development and
evaluation of animal models for infectious diseases often exceeds that routinely
awarded for SBIR grants, the participating Institutes will entertain well-
justified Phase I applications for an SBIR award with a project period up to two
years and a budget not to exceed a total cost of $300,000 per year.

Consultant and contractual costs associated with Phase I:
The total amount of all consultant costs and contractual costs normally may not
exceed 33% of the total costs requested for Phase I SBIR applications. However,
we will entertain well-justified Phase I applications for an SBIR award with
greater than 33% contractual costs when those costs are necessary to support
development and evaluation of animal models.

Page Limitations: The 25-page limitation for Phase I applications applies (see
Omnibus Solicitation).

PHASE II:
Phase II applications in response to the second release of this RFA will be
awarded as Phase II SBIR grants (R44) or contracts (N44) with modifications as
described below.  Phase II applications in response to this RFA will only be
accepted as competing continuations of previously funded NIH Phase I SBIR awards.

Applications for Phase II awards should be prepared following the instructions
for NIH Phase II SBIR applications. The Phase II SBIR instructions and
application may be found on the Internet at:
http://grants.nih.gov/grants/funding/sbir2/index.htm

Project Period and Amount of Award:
Because the length of time and cost of research involving animal model
development projects often exceeds that routinely awarded for SBIR grants,
participating Institutes will entertain well-justified Phase II applications for
an SBIR award with a project period up to three years and a budget not to exceed
$1 million per year total cost.

Consultant and contractual costs:
The total amount of all consultant costs and contractual costs normally may not
exceed 50% of the total costs requested for Phase II SBIR applications.  However,
participating Institutes will entertain well-justified Phase II applications for
an SBIR award with greater than 50% contractual costs when those costs are
necessary to support animal model development and evaluation, including clinical
studies in academic institutions.

FUNDS AVAILABLE

It is expected that 10-14 awards will be made in FY1999/FY2000, and $4.2 million
from the SBIR set-asides of the participating Institutes will be designated for
this purpose.  The number of awards will be dependent upon receipt of a
sufficient number and diversity of applications with high scientific merit.

RESEARCH OBJECTIVES

The participating Institutes invite applications for SBIR awards in the following
areas:

A.  Identification/creation of suitable animal models for studying one or more
key aspects of HCV infection, replication, and pathogenesis.  Suitability
includes animals that are easily housed and subject to experimental manipulation,
not protected species, and to the maximum extent possible small, inexpensive, and
easily procurable.

B.  Development and testing of animal models for HCV infection identified in part
A, from initial infection through chronic infection, liver disease, cirrhosis,
and liver cancer.  Such models should ideally mimic the full range of the disease
spectrum or, more realistically, one or more critical aspects of the following
phases of human disease by HCV: initial/acute infection; chronicity; disease
stages and progression including inflammation, fibrosis, cirrhosis and other
aspects of morbidity; and mortality causes such as liver failure or
hepatocellular cancer.

C.  Validation of such model systems, including the applicable properties
indicated in part B, by qualified independent investigators.

LETTER OF INTENT

Prospective applicants are asked to submit, by the receipt date listed at the
beginning of this RFA, a letter of intent that includes a descriptive title of
the proposed research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to which the
application may be submitted.  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 NIAID staff to estimate the potential review
workload and avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. Leslye D. Johnson, NIAID, at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants should follow the instructions for SBIR Phase I or Phase II submission
with the modifications as noted in this RFA.  An example of an outstanding SBIR
application can be found on the Web at
http://www.nhlbi.nih.gov/nhlbi/sbir/modelsbi.htm

This RFA must be read in conjunction with the OMNIBUS SOLICITATION OF THE PUBLIC
HEALTH SERVICE FOR SMALL BUSINESS INNOVATION RESEARCH GRANT (SBIR) APPLICATIONS
(PHS 98-2).  All of the instructions within the omnibus solicitation apply with
the following exceptions:

-Special receipt date
-Additional award considerations
-Increased award amount and duration

Applications received in response to this RFA are to be prepared as described in
the OMNIBUS SOLICITATIONS for the SBIR program.  OMNIBUS SOLICITATIONS are
available electronically through the NIH, Office of Extramural Research "Small
Business Funding Opportunities" Website:
http://grants.nih.gov/grants/funding/sbir.htm.  Hard copies, subject to
availability, may be obtained from the PHS SBIR/STTR Solicitation Office, phone
(301) 206-9385; FAX (301) 206-9722; email a2y@cu.nih.gov.  Helpful information
in preparation of the application can be obtained:
http://grants.nih.gov/grants/funding/sbirsttradvice.htm

Applications in response to this RFA are to be submitted on the applicable grant
application forms as follows:

SBIR Phase I - PHS 6246-1 (1/98)
http://grants.nih.gov/grants/funding/sbir1/SBIR.HTM

SBIR Phase II - PHS 6246-2 (1/98)
http://grants.nih.gov/grants/funding/sbir2/index.htm

The application forms are also located in the back pages of the OMNIBUS
SOLICITATIONS.  Applications will be accepted on or before March 18, 1999.  The
RFA title and number must be typed in line 2 on the face page of the application
form.

If an application is received after the application receipt date, it will be
returned to the applicant without review.  The Center for Scientific Review (CSR)
will not accept any application in response to this RFA that is essentially the
same as one currently pending review, unless the applicant withdraws the pending
application.  This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

SBIR projects submitted in response to this RFA must contain a Phase I
feasibility segment that must be successful prior to a Phase II award. 
Applications can be submitted for Phase I or Phase II support, or as a combined
Phase I and II (FAST TRACK).  Phase II applications will only be accepted as
continuations of previously funded Phase I grants.  The Phase II proposal must
be a logical extension of the Phase I research but not necessarily a Phase I
supported in response to this RFA.

Projects may be presented for SBIR support at all stages of the HCV animal model
discovery and development process.  Projects will be evaluated on overall
innovation and success potential of the research path proposed to animal model
identification/development.

Larger budgets could be considered for phase I if required for conduct of the
research and appropriately justified in the application.  The second year of
support will be contingent upon NIAID (or appropriate Institute) programmatic
evaluation to ensure that investigators are accomplishing milestones and time
lines presented in the original application.

PHASE II: Continuing support for development of HCV animal infection models and
for establishment of model validity by in-house and by independent investigators
knowledgeable of animal model characteristics. Potential animal model candidates
may extend to assessment for use in studies in immunology including autoimmune
diseases, alcohol and drug abuse, pathogenesis, natural history studies,
antiviral screenings, etc.  This may include the identification of surrogate
endpoints to define success of therapeutic treatments or efficacy of vaccine
candidates.  Outside of presently licensed therapies, NIAID has the potential to
provide novel antiviral compounds for testing in proven models.

Phase II awards may be for up to three years at $1 million, total costs, per
year.  As with Phase I, requests for larger budgets may be considered, and
support for years four and five is dependent upon Institute Programmatic review
of progress and achievement of proposed milestones and evaluation of additional
information not required in the original application.

FAST TRACK: Due to the complex nature of the HCV animal
identification/development process, it is recommended that only well defined and
more advanced projects be proposed for support through this mechanism.

FAST TRACK applications must specify clear, measurable goals for Phase I that
should be achieved prior to Phase II funding.  Failure to provide measurable
goals in the Phase I application and/or sufficient detail in the Phase II
application may be sufficient reason for the peer review committee to exclude the
Phase II from consideration.  If so, the applicant may apply later for Phase II
support.

Special provisions described in this RFA pertaining to Phase I and Phase II also
apply to FAST TRACK applications.

The completed original application and two single sided copies must be sent or
delivered 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)

For purposes of identification and processing, the title and number of this RFA
must be shown in item 2 on the face page of the SBIR Phase I applications and in
item 1A of the face page of Phase II grant applications (i.e., "SBIR: HCV Animal
Models of Infection," AI-99-001).  Follow the mailing instructions in the Omnibus
Solicitation for Phase I applications.  Follow the mailing instructions in the
Phase II application package for Phase II applications.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Upon receipt, applications will be reviewed for completeness by the
NIH Center for Scientific Review.  Incomplete applications will be returned to
the applicant without further consideration.

Applications will be reviewed for scientific and technical merit by an initial
review group convened by the Center for Scientific Review, in accordance with the
standard NIH peer review procedures.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit will be discussed
and assigned a priority score.

REVIEW CRITERIA

Review criteria are described in the Omnibus Solicitation.  The Phase I
application should specify clear, measurable goals (milestones) that should be
achieved prior to initiating Phase II.

AWARD CRITERIA

The following will be considered when making funding decisions: quality of the
proposed project as determined by peer review, program balance among research
areas of the announcement, the availability of funds, and the commercialization
status where the small business concern has received more than 15 Phase II awards
in the prior five (5) fiscal years, if applicable (see this application
requirement under "Prior SBIR Phase II Awards" found in the "Introduction and
Application Instructions" portion of the Omnibus Solicitation).

ADVICE ON SUBMITTING APPLICATIONS:

Potential applicants are strongly encouraged to contact program staff for pre-
application guidance and/or for more specific information on the research topics
described in this RFA.  They are also encouraged to read the advice and
information on SBIR programs located on the Internet at: 
http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf

INQUIRIES

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

Inquiries regarding programmatic issues may be directed to:

Dr. Leslye D. Johnson
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3A22
Bethesda, MD  20892-7630
Telephone:  (301) 496-7051
FAX:  (301) 402-1456
Email:  lj7m@nih.gov

Dr. John Cole III
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 540
Bethesda, MD  20892-7209
Telephone:  (301) 496-1718
FAX:  (301) 496-2025
Email:  jc121b@nih.gov

Dr. Neal West
Comparative Medicine
National Center for Research Resources
6701 Rockledge Drive, Room 6166
Bethesda, MD  20892-7965
Telephone:  (301) 435-0749
FAX:  (301) 480-3819
Email:  nealw@ncrr.nih.gov

Dr. Judith M. Podskalny
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 6AN12E
Bethesda, MD  20892-6600
Telephone:  (301) 594-8876
FAX:  (301) 480-8300
Email:  PodskalnyJ@extra.niddk.nih.gov

Dr. Leslie Isaki
Division of Basic Research
National Institute of Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Room 402
Bethesda, MD  20892-7003
Telephone:  (301) 594-6228
FAX:  (301) 594-0673
Email:  lisaki@niaaa.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Maryellen Connell
Grants Management Branch
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B28
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  mc40u@nih.gov

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service Act,
Sec. 301(c), Public Law 78-410, as amended.  The Catalogue of Federal Domestic
Assistance Numbers are 93.855 and 93.856.  Awards will be administered under PHS
grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.  This
program is not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems 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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