MOUSE MODELS OF HUMAN CANCERS CONSORTIUM

Release Date:  July 29, 1998 (see reissue RFA-CA-04-002)

RFA:  CA-98-013

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  December 17, 1998
Application Receipt Date:  January 21, 1999

PURPOSE

The National Cancer Institute (NCI) invites cooperative agreement and NIH
intramural applications from groups of investigators who are capable of, and
interested in, becoming components of the NCI Mouse Models of Human Cancers
Consortium.  The purpose of implementing this Consortium is to accelerate the
pace at which mice with heritable malignancies that are accurate, reproducible
models of human cancers are made available to the research community for
further investigation or application.  To accomplish this, the NCI will
select, as components of the Consortium, groups of investigators whose
scientific and technical expertise will enable them to derive the models,
characterize them thoroughly, and validate them for various aspects of basic,
developmental, or applied cancer research.  The approaches used for
generating, characterizing, and validating the mice for cancer research
purposes will reflect the blend of experience and creativity of the Consortium
component groups, and will be originated by these investigators.  They will
contribute to the Consortium their collective knowledge of mouse genetics,
experimental genetic manipulation of mice and phenotypic and genotypic
analysis of the resulting strains, mouse genomics, animal husbandry, mouse and
human cancer pathology, basic studies of human malignancies, small animal
imaging technologies, and the clinical properties of human cancer that inform
the design of therapy, prevention, and early detection strategies.

Through formation of the Consortium, the component groups will have access to
resources, information, technologies, ideas, and expertise which are beyond
the scope of any single research team.  The ultimate goals of the Consortium
are to choose which existing mouse cancer models to characterize fully for
their relevance to human cancer, or which new models to derive de novo and to
characterize fully when no model exists for a given malignancy, and to define
the standards by which to validate the models for their relevance to human
cancer biology and for testing therapy, prevention, early detection, or
diagnostic imaging strategies.  As the models are developed and validated, the
NCI will provide the mechanism to disseminate the models and information
related to them to the research community.

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 Request for Applications (RFA),
Mouse Models of Human Cancers Consortium, is related to the priority area of
cancer.  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 REQUIREMENTS

Cooperative agreement applications may be submitted by domestic, for-profit
and non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and Local governments,
eligible agencies of the Federal Government, and small businesses. 
Applications may represent a single institution, or may involve several
institutions or organizations.  For this RFA, teams composed of NIH intramural
investigators are encouraged to submit intramural project applications to
become components of the Consortium, but they may not request or receive funds
from this program.  Applications from minority individuals, women, and persons
with disabilities as principal investigators are encouraged.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for non-NIH applicants to
this program will be a cooperative agreement (U01), an "assistance" mechanism
(rather than an "acquisition" mechanism), in which substantial NCI scientific
and/or programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the NCI's
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 the study to be funded under cooperative agreement(s) are discussed later
in this document under the section "Terms and Conditions of Award."  Funding
for NIH intramural applicants will be derived from existing intramural
resources.

Funding for successful U01 applications will be for up to five years.

FUNDS AVAILABLE

The NCI anticipates funding up to six U01 awards for project periods of five
years.  U01 application budgets may not exceed $500,000 direct costs in the
first budget period.  Should an applicant plan to include subcontracts to
other institutions or organizations, only the direct costs associated with the
subcontracts will be used to tally the direct costs that apply toward the cap
of $500,000; there is no cap on total costs in the first budget period.  For
further budget information, see the "APPLICATION PROCEDURES" section.  A total
cost of $4,500,000 is expected to be set aside for funding the U01 grants in
the initial year.  The number of U01 awards and level of support depend upon
receipt of a sufficient number of U01 applications of high scientific merit.

In addition, the NCI anticipates incorporating up to two NIH intramural
projects as components of the Consortium.  Although no funds from the amount
set aside for this RFA will be used to support intramural projects, NIH
intramural project applicants must verify that the amount of the resources
allocated from intramural sources does not exceed $500,000 direct costs.  For
further budget information pertaining specifically to NIH intramural
applications, see the "APPLICATION PROCEDURES" section "3.  Additional
Instructions for NIH Intramural Project Applicants."

Although this program is provided for in the financial plans of the NCI, U01
awards pursuant to this RFA are contingent upon the availability of funds for
this purpose in fiscal year 1999.  The anticipated award date is September 25,
1999.  At the present time, the NCI has not determined whether or how this
solicitation will be continued beyond the present RFA.

RESEARCH OBJECTIVES

Background

Genetic technology has advanced to the point that it is theoretically possible
to genetically engineer immune-competent mice that develop tumors that are
analogous to the major human cancers.  Such accurate models of human
malignancies would be especially valuable to analyze the initiation and
progression of specific cancers, to provide the framework for discovery of the
genes and cellular parameters that generate susceptibility or environmental
sensitivity or that provide resistance, to furnish targets for intervention
and treatment, and to permit prevention, detection, therapeutic, and imaging
strategies to be tested in the context of a normal tissue environment.

Although many mice have been designed or discovered to develop cancer, most
have been engineered to ask specific mechanistic questions about the functions
of single genes in the initiation or progression of cancer.  These mice
develop cancer at one or more sites, but the constraints of limited time and
funding often do not permit an in-depth, comprehensive analysis and
characterization of their phenotype and genotype.  Even fewer models are
tested for their response to treatment or prevention modalities or their
suitability for testing early detection or imaging applications.  The NCI
supports many individual projects that involve the derivation or study of mice
that develop cancer.  However, at the present time, the NCI does not support a
coordinated, collaborative effort to produce highly accurate mouse models of
human malignancy, particularly for the early design, derivation,
characterization, and validation phases of model building, and to ensure that
the models and the data relevant to them are readily available to the research
community for further investigation or application.

Objectives and Scope

The intent of this initiative is to assemble from U01 grants and NIH
intramural projects a cross-disciplinary, multi-institutional Consortium whose
component teams of investigators will derive or refine accurate cancer-prone
models of human malignancies, provide a comprehensive analysis of their
phenotype and genotype, validate them for their use by the cancer research
community for a variety of investigations, including for testing therapeutic,
prevention, early detection, or imaging strategies, and assure their
availability to the research community.

The Mouse Models for Human Cancers Consortium (MMHCC), when implemented from
the component funded U01 grants and selected NIH intramural projects, will,
through its Steering Committee:  set the priorities for the models which
should be derived; define the tumor sites for which appropriate models may
exist and select those which should be comprehensively characterized and
refined, if necessary; define the tumor sites for which no acceptable model
exists and a model or model must be designed, derived, and comprehensively
characterized; define the parameters by which the models will be validated
(standards for pathology, genotype, phenotype, etc., and for testing therapy,
prevention, early detection, and imaging); identify technological impediments
to accurate model design, and select strategies for implementation or
development to surmount them; and decide when a model is sufficiently
characterized and validated so that the model itself, and all available
accompanying data, can be distributed to the research community for individual
investigator-initiated projects.  The NCI will establish the required
distribution system, database resources, and information systems to accomplish
the dissemination of the models and information about them to the research
community.

To implement the MMHCC, the NCI will select as components up to six U01
applications and up to two NIH intramural projects, each supporting a multi-
disciplinary team.  Each team will be a self-assembled group of investigators
who contribute to the MMHCC effort a unique blend of complementary research
experience.  It is anticipated that an applicant team will incorporate an
appropriate mix of expertise which that team believes is needed to achieve
their own goals, and which will contribute substantially to achieving the
overall MMHCC goals.  Areas of expertise may include, but are not limited to: 
basic, translational, or clinical cancer investigations; mouse genetics and
genomics; cancer therapy, prevention, early detection, or diagnostic imaging
research; mouse or human cancer pathology; animal husbandry; genetic
technology; mouse models of human disease.

Teams of investigators composed of researchers in NIH intramural laboratories
may submit applications to be components of the MMHCC;  however, they may not
receive salary, equipment, supplies, or other remuneration from the RFA set-
aside funds for this program.  An NIH intramural PI must obtain the approval
of his/her NIH Institute Scientific Director to allocate resources to the
project, and must follow both the general application format instructions and
the additional guidelines for NIH intramural project applications under
"APPLICATION PROCEDURES".  NIH intramural project applications will be
reviewed and scored with the U01 applications.  The NIH intramural projects
selected by the NCI to be components of the MMHCC will participate in a manner
that is analogous to the U01 awardees.

Non-NIH applicant teams may identify researchers who are intramural staff of
the NIH Institutes or Centers as potential collaborators or consultants. 
However, for purposes of this RFA, no NIH intramural scientist may agree to
collaborate or consult with, commit time and effort to, or be a co-PI of, any
U01 application.  When the MMHCC is assembled from the component projects,
there may be NIH intramural investigators whose expertise is identified in the
funded U01 applications as necessary or desirable to achieve their individual
goals, or those of the MMHCC.  Those NIH intramural investigators must then
obtain the approval of their Institute's Scientific Director to collaborate
with the Consortium or one of its U01 components in a specified role,
including time and effort.  NIH intramural investigators who are designated in
this manner to collaborate in the Consortium will not serve on the MMHCC
Steering Committee.  The participation of any NIH intramural scientist,
including those on the Steering Committee who represent the NIH intramural
project components of the MMHCC, is independent of, and unrelated to, the role
of the NCI Program Director as described under "Terms and Conditions of
Award."  The NCI anticipates that NIH intramural investigators will contribute
substantially to the breadth of scientific and technical expertise of the
MMHCC.

To facilitate communications among the participants in the MMHCC and between
the MMHCC and the NCI, the NCI will establish and maintain an Internet-based
mechanism for rapid data and document transmission and electronic
communications for the MMHCC.

SPECIAL REQUIREMENTS FOR THE RFA

I.  Definitions

ARBITRATION PANEL:  A panel that is formed to review any scientific or
programmatic  disagreement (within the scope of the U01 award or NIH
Intramural project), between U01 awardees or NIH intramural projects and the
NCI.  The panel will be composed of three members:  one selected by the
Steering Committee (with the NCI Program Director not voting), or by an
individual U01 awardee or NIH intramural project in the event of an individual
disagreement; a second member selected by the NCI; and, the third member
selected by the two prior selected members.

AWARDEE:  The institution to which a cooperative agreement (U01) is awarded.

COOPERATIVE AGREEMENT (U01):  An "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NCI scientific and/or
programmatic involvement with the awardee is anticipated during performance of
the activity.  Under the cooperative agreement, the NCI 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.

MMHCC:  The NCI Mouse Models for Human Cancers Consortium, which will have as
its components both U01 grants and NIH intramural projects.

NCI MOUSE MODELS ADVISORY GROUP:  A committee of NCI and NIH extramural staff,
who represent the breadth of scientific expertise and program responsibilities
that relate to the goals of the MMHCC, will meet regularly to review the
progress of the MMHCC, to advise the NCI Program Director of emerging
scientific and technological advances that could enhance the goals of the
MMHCC, and to collaborate on the design and implementation of MMHCC workshops
and symposia.

NCI PROGRAM DIRECTOR:  A scientist administrator of the NCI extramural staff. 
The NCI Program Director will provide normal stewardship for the U01 grants
awarded under this RFA, as well as have substantial scientific and
programmatic involvement to assist, guide, coordinate, and participate in the
conduct of the Consortium activities and serve as a voting member of the
Steering Committee, as defined under "Terms and Conditions of Award."

PRINCIPAL INVESTIGATOR (PI):  The investigator who is designated by the
applicant organization to direct the project to be supported by the U01 grant
or NIH intramural project in  response to this RFA.  The PI will assume
responsibility and accountability to the applicant organization officials and
to the NCI for the performance and proper conduct of the research supported by
the U01 or the NIH intramural project in accordance with the terms and
conditions that are stated in the RFA.  The PI will coordinate the activities
of the U01 or NIH intramural project with the MMHCC, and will be one of two
investigators from the U01 or NIH intramural project to serve as a voting
member of the Steering Committee.

STEERING COMMITTEE:  This committee will be the main governing body of the
MMHCC.  Its voting members will include the PI and an additional senior
investigator from each U01 or NIH intramural project, the NCI Program
Director, and three members of the NCI Mouse Models Advisory Group.  The
Steering Committee will meet twice a year, once in the Washington, DC area,
and once at a location that the Steering Committee selects and with which the
NCI concurs.

II.  Special Application Format

The PHS 398 application must be used for this RFA, and the format must be
modified as described under "APPLICATION PROCEDURES."

III.  Terms and Conditions of Award

The following terms and conditions will be incorporated into the U01 award
statement, and will be provided to the PI and the awardee institutional
official at the time of award.  These terms and conditions will be provided to
the PI of the NIH intramural project and the NIH Institute Scientific Director
at the time of selection to be an MMHCC component.

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.  [Part 92 applies when state and local governments are
eligible to apply as a "domestic organization."]

1.  The administrative and funding instrument used for the non-NIH applicants
to this program is a cooperative agreement (U01), an "assistance" mechanism
(rather than an "acquisition" mechanism) in which substantial NIH scientific
and/or programmatic involvement with the awardee is anticipated during
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 awardee(s) for the project as
a whole, although specific tasks and activities in carrying out the studies
will be shared among the awardees and the NCI Program Director.  NIH
intramural project applicants will be supported by existing intramural
resources.

2.  Awardee Rights and Responsibilities

o  The PI of a U01 or NIH intramural project will have primary authority and
responsibility to define objectives and approaches, and to plan, conduct,
analyze, and publish results, interpretations, and conclusions of studies
conducted under the terms and conditions of the cooperative agreement award or
NIH intramural project.

o  The PI of a U01 or NIH intramural project will assume responsibility and
accountability to the applicant organization officials and to the NCI for the
performance and proper conduct of the research supported by the U01 or the NIH
intramural project in accordance with the terms and conditions of the award.

o  The PI, and another senior investigator from the U01 or NIH intramural
project, will serve as voting members of the Steering Committee, will attend
the Planning Meeting and two Steering Committee meetings in the first year,
and two Steering Committee meetings a year in subsequent years.

o  The PI of a U01 or NIH intramural project will be responsible for accepting
and implementing the goals, priorities, procedures, and policies agreed upon
by the Steering Committee.

o  The PI of a U01 or NIH intramural project will be responsible for close
coordination and cooperation with the other components of the MMHCC and with
the NCI staff.

o  Awardees will retain custody of, and have primary rights to, the data
developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies.  Investigators conducting
biomedical research frequently develop unique research resources.  The policy
of the PHS is to make available to the public the results and accomplishments
of the activities that it funds.  All awardees must adhere to PHS policy for
the distribution of unique research resources produced with PHS funding that
was published in the NIH Guide for Grants and Contracts (NIH Guide, Vol. 25,
No. 23, July 12, 1996), and is available at the following Internet address: 
http://www.nih.gov/grants/guide/1996/96.07.12/notice-public-health006.html.

o  The NCI reserves the right to require the transfer of appropriate mouse
stocks, related reagents, and pertinent data that are generated as the result
of participation in research supported under these awards to an eligible third
party, in order to preserve the mouse models and data about them and/or to
continue the research.  Third parties supported under these awards must be
informed of this right.

o  Effective conduct of the MMHCC goals will require considerable electronic
communication of data and other information among the MMHCC components and
between the components and the NCI.  Awardees are responsible for assuring
that the activities supported under the cooperative agreement will not be
adversely affected by Year 2000 problems as detailed in the "Notice Regarding
the Year 2000 Computer Problem" that was published in the NIH Guide for Grants
and Contracts, April 3, 1998, and is available at the following Internet
address:  http://www.nih.gov/grants/guide/notice-files/not98-046.html

3.  NCI Extramural Staff Responsibilities

o  The NCI Program Director will coordinate and facilitate the MMHCC programs,
will attend and participate as a voting member in all meetings of the MMHCC
Steering Committee, and will provide liaison between the Steering Committee,
the MMHCC, and the NCI.

o  The NCI Program Director will regularly consult with the NCI Mouse Models
Advisory Group on the scientific progress of the MMHCC, and collaborate with
them to implement the workshops and symposia recommended by the Steering
Committee.

o  The NCI Program Director and the NCI will ensure that there is an
effective, Internet-based mechanism to enable electronic communication among
the MMHCC components, and with the NCI.

o  The NCI Program Director will assist the Steering Committee in developing
and drafting operating policies and policies for dealing with recurring
situations that require coordinated action.

o  The NCI Program Director will review the scientific progress of individual
U01 grants, and review them for compliance with the operating policies
developed by the Steering Committee, and may recommend withholding of support,
suspension, or termination of a U01 award for lack of scientific progress or
failure to adhere to policies established by the Steering Committee.

o  The NCI Program Director will transmit to the appropriate NIH Institute
Scientific Director any recommendation from the Steering Committee concerning
failure of an NIH intramural component of the MMHCC to adhere to policies
established by the Steering Committee.

o  NCI and NIH extramural staff with relevant scientific expertise, or who
manage research grant programs that relate scientifically to the goals of the
MMHCC, will form the NCI Mouse Models Advisory Group.  The Group will meet
regularly to review the progress of the MMHCC, and to advise the NCI Program
Director of scientific developments and opportunities that may enhance the
achievement of the MMHCC goals.

o  The NCI Mouse Models Advisory Group will collaborate with the NCI Program
Director to suggest participants for and to implement the workshops and
symposia recommended by the MMHCC Steering Committee, and to provide liaison
between the cancer research community and the MMHCC.

5.  Collaborative Responsibilities

Steering Committee

The NCI Program Director and the U01 grants and NIH intramural projects that
comprise the MMHCC will be responsible for forming a Steering Committee as
defined below.  An arbitration system, as detailed below, will be available to
resolve disagreements between the NCI Program Director and the members of the
Steering Committee.

The Steering Committee will be the main governing board of the MMHCC.  It will
function to  set priorities for model derivation, define the parameters for
model validation, identify technological impediments to success and strategies
to overcome them, and decide when models should be made available to the
cancer research community for individual investigator-initiated projects.

o  The Steering Committee will be composed of the PI and a Co-PI or other
senior investigator from each U01 and NIH intramural project, the NCI Program
Director, and three members of the NCI Mouse Models Advisory Group.  The two
investigators from each U01 or NIH intramural project, the NCI Program
Director, and the three NCI/NIH staff will each have one Steering Committee
vote.  The chairperson, who will be someone other than an NCI or NIH staff
member, will be selected by the Steering Committee.

o  The Steering Committee may, when it deems it to be necessary, invite
additional, non-voting scientific advisors to the meetings at which research
priorities and opportunities are discussed.  The NCI reserves the right to
augment the scientific or consumer expertise of the MMHCC when necessary.

o  There will be two Steering Committee meetings annually, one in July in the
Washington, DC area, and the other at a time and site agreed upon by the
Steering Committee and the NCI.

o  The first meeting of the MMHCC will be a Planning Meeting, which will take
place in the Washington, DC area very shortly after award of the U01 grants
and selection of the NIH intramural projects.  At the Planning Meeting, the
Steering Committee will be formed and select a chairperson from among the
members who represent the U01 awardees.  At the Planning Meeting, the Steering
Committee may:

a.  draft a charter to detail policies and procedures, a process for
monitoring compliance with the policies and procedures, and a process for
recommending that the NCI Program Director  act on evidence of non-compliance
of any Consortium component with Steering Committee policies;
b.  agree upon the terms of the charter;
c.  decide which individual NIH intramural investigators identified as
collaborators or consultants in the funded U01 grants will collaborate in the
MMHCC, and define their roles;
d.  discuss the models and approaches that were proposed in the U01 and NIH
intramural project applications, and any relevant new information, and set
initial priorities for the models to be derived and for new technologies to be
developed;
e.  discuss and set initial genotypic and phenotypic parameters required to
characterize the models and to define their comparability to human
malignancies;
f.  discuss and set initial standards for validating the models for further
biological studies and such uses as testing prevention or early detection
strategies, or therapies, or diagnostic imaging technologies.
At the first meeting of the Steering Committee following the Planning Meeting,
the NCI will demonstrate an Internet-based electronic communications mechanism
for discussion by the Steering Committee, and will implement the system for
the MMHCC with any appropriate changes.

o  At their first meeting each year, the Steering Committee will formulate
plans for any workshops or symposia to be held.  They will discuss pilot
projects to be pursued jointly with funds set aside from the individual U01
grant or NIH intramural project budgets, decide which, if any, should be
pursued, and determine what percentage of funds (up to 10% of the annual
direct costs of each budget, excluding the first year) should be allocated for
this purpose.

o  At the second and subsequent meetings, the Steering Committee will refine
the MMHCC scientific objectives and characterization and validation
strategies, as necessary, consistent with progress in the MMHCC components and
other laboratories, and with the goals of identifying available models with
sufficient promise for further testing, or defining those human malignancies
for which models must be created de novo.

o  At any time during the MMHCC project, the Steering Committee may examine
the characterization and validation data for models derived by the MMHCC
components, and decide when a model is sufficiently validated that it may be
distributed to the research community for further investigations or
applications.  The NCI will provide the means to disseminate the models
themselves and the information related to them.

o  The Steering Committee will plan one or several workshops a year to which
non-MMHCC participants will also be invited to enable the MMHCC to explore
scientific or technologic innovation that occurs during the course of the
project.

o  For the second and subsequent years of operation of the MMHCC, the Steering
Committee will plan a symposium to inform the research community of the
progress made toward derivation or refinement of models, their
characterization and validated uses, and any technological advances related to
design and derivation of mouse models.  The NCI Program Director, the NCI
Mouse Models Advisory Group, and other NCI staff will provide the Steering
Committee with advice on participants for the workshops and symposia, and
manage the logistics for these meetings.

o  The Steering Committee may establish subcommittees, as it deems
appropriate; the NCI Program Director and the other NCI/NIH staff who are
Steering Committee members will serve on subcommittees as they deem
appropriate.

Arbitration Panel

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the U01 award or NIH intramural project), between U01 awardees or NIH
intramural projects and the NCI may be brought to arbitration.  An arbitration
panel will be composed of three members:  one selected by the Steering
Committee (with the NCI Program Director not voting), or by the individual U01
awardee or NIH intramural project in the event of an individual disagreement;
a second member selected by the NCI; and, the third member selected by the two
prior selected members.  For U01 awardees, 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.

RESEARCH INVOLVING HUMAN SUBJECTS

The primary objective of this RFA is to derive mouse models for cancer
research that will be analogous to human malignancies.  Therefore, there may
be instances in which applicants must  collect or use pathology specimens
derived from human subjects, or clinical or epidemiological data from projects
involving human subjects, to inform the design of the models or to derive the
standards that validate them as models of human cancer.  In those instances,
the NIH policies below apply and must be addressed in the application.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations 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 were published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994, and are available at the following Internet address: 
http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that children (i.e., individuals under the age of
21) must be included in all human subjects research, conducted or supported by
the NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.  All investigators proposing research involving
human subjects should read the "NIH Policy and Guidelines on the Inclusion of
Children as Participants in Research Involving Human Subjects" that was
published in the NIH Guide for Grants and Contracts, March 6, 1998, and is
available at the following Internet address:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by December 17, 1998, a letter of
intent that includes a descriptive title of the proposed research; the name,
mailing address, telephone number, and email address of the Principal
Investigator, 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 subsequent applications, the information allows NCI
staff to estimate the potential review workload and to avoid conflict of
interest in the review.

The letter of intent is to be sent (by mail, FAX, or email) to:

Cheryl L. Marks,  Ph.D.
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 501
Bethesda, MD  20892-7381
Telephone:  (301) 435-5226
FAX:  (301) 496-8656
Email:  [email protected]

APPLICATION PROCEDURES

Applicants for either U01 grants or NIH Intramural projects must use the
research grant application form PHS 398 (rev. 5/95), with the modified format
that is described below.  In addition, NIH intramural project applicants must
follow the information in section "3.  Additional Instructions for NIH
Intramural Project Applicants" below.  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, MD 20892-7910, telephone
301/710-0267, Email: [email protected].  PHS 398 application kits are also
available at:  http://www.nih.gov/grants/funding/phs398/forms_toc.html

1.  General Application Format Instructions

The form PHS 398 should be modified as follows.  The "Research Plan", sections
a. to d., should be divided into four parts, each with a separate budget.  The
number of pages allowed for the "Research Plan" is increased from 25 to 35
pages; budget pages, budget justifications, and letters from collaborators and
consultants and their biosketches are not included in this limit.  With the
exception of the requirement for set-aside funds in Part 4 in the second and
subsequent budget periods, the apportionment of funds among the four parts is
at the discretion of the applicants.

For U01 applicants who do not request funds to support the activities in a
particular part of the application, the applicants should indicate the source
of funds (institutional, R01, P01, P30, etc.) that permit them to accomplish
the project goals.  The U01 applications should also have a composite budget,
which summarizes the budget categories for each part of the "Research Plan." 
Biosketches and "Other Support" pages should be included for key personnel. 
For any part of the "Research Plan" in which the budget contains a
subcontract, the subcontract budget should be a separate page, and the
subcontract indirect costs should be calculated and listed in the usual place
as part of the direct costs of the budget for that part of the parent
application and in the composite budget.  However, only the direct costs
associated with each subcontract will count toward the direct costs cap of
$500,000 on the budget for the first year.  The total costs for the U01
applications are not capped.

NIH intramural project applicants should supply budget information and a
composite budget as described in section "3.  Additional Instructions for NIH
Intramural Project Applicants" below.

Part 1.  Infrastructure.  In this part of the "Research Plan", applicants
should detail the specialized or unique facilities, fundamental
infrastructure, research expertise, and core resources and services that are
available to support the planned mouse model derivation, characterization, and
validation.  If facilities at more than one institution are required,
applicants should thoroughly describe them, and obtain the appropriate
assurances.  The roles and expertise of all key personnel, collaborators, and
consultants who are associated with this part of the application should be
well documented; letters from collaborators and consultants and their
biosketches should directly follow this part of the application.

Part 2.  Model Derivation.  In this part of the "Research Plan," applicants
should describe their rationale for the design and derivation of a new mouse
model or models, or for altering and improving an existing model or models,
based on their experience with mouse models of human disease, and their
knowledge of basic, translational, and clinical cancer research.  Applicants
should describe the extent to which they plan to characterize any models they
derive or refine; the methods that they will use to characterize the models;
the rationale for choices of methods; and, how generally applicable the
methods are, or will be, for all mouse cancer models.  In this part as well,
applicants are expected to identify the standards they will apply to validate
a model or models; the rationale for the choices; how generally applicable the
validation standards are, or will be, for all mouse cancer models; and, the
purpose(s) for which they anticipate their models may be used.  The roles and
expertise of all key personnel, collaborators, and consultants who are
associated with this part of the application should be thoroughly documented;
letters from collaborators and consultants and their biosketches should
directly follow this part of the application.

Part 3.  Technology.  In this part of the "Research Plan," applicants should
define the technologic approaches they will use, or any technology that they
propose to develop, to achieve the goals of model derivation or refinement,
characterization, and validation.  The roles and expertise of all key
personnel, collaborators, and consultants who are associated with this part of
the application should be thoroughly documented; letters from collaborators
and consultants and their biosketches should directly follow this part of the
application.

Part 4.  Interactions with Other MMHCC Components.  In this part of the
"Research Plan," applicants should describe how they believe their unique
blend of experience can contribute to the collective efforts of the MMHCC. 
They should identify pilot projects for research or technology development
that they believe should be goals of MMHCC after it has been assembled from
the U01 and NIH intramural project components.  Applicants should not plan to
budget any funds for collective MMHCC pilot projects in the first year. 
However, in the second and subsequent years of funding, applicants should plan
to set aside up to 10% of the direct costs of the project to pursue scientific
goals, such as high-risk technology development, that should be joint efforts
pursued by the MMHCC.  At their first meeting every year, the Steering
Committee will decide upon the percentage of funds (no more than 10% of the
direct costs of each project budget) to allocate for these activities, and
will identify and select the project(s) to be funded with the set-aside funds. 
In this part of the "Research Plan," applicants should describe their
experience with, and capability for, Internet-based communication, and their
ideas about how to facilitate electronic communication and other interactions
among the MMHCC components and the NCI, and with the cancer research
community.

Specific issues related to cooperative agreements must also be addressed as
follows.

o  Applicants must budget for travel and per diem expenses for Steering
Committee meetings.  In the first year, applicants should plan for two
investigators, the principal investigator and an additional senior
investigator, to attend a Planning Meeting and two Steering Committee
meetings.  In the second and subsequent years, applicants should plan for the
PI and another investigator to attend two Steering Committee meetings per
year.

o  Applicants must budget for travel and per diem expenses for participation
in MMHCC workshops and symposia.  Applicants should plan that at least five
investigators will attend a workshop or symposium every year in years 2-5.

o  In Part 4, applicants must include their specific plans for responding to
the "Terms and Conditions of Award" section.  Applicants should state their
willingness to collaborate and share data freely with the other MMHCC
components, to participate in planning and attending workshops and symposia,
to serve on the Steering Committee and be bound by its decisions, particularly
those which relate to setting priorities for model development and the
standards for characterization and validation, and to be able and willing to
share data and communicate with each other and the NCI in an Internet
environment.  Applicants should also describe how they will comply with the
involvement of the NCI Program Director, and how they will fulfill the
responsibilities of Consortium components to work together cooperatively.

2.  Additional Materials to Include in the Application

The RFA label available in the PHS 398 (rev. 9/95) application form must be
affixed to the bottom of the face page of the application.  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, MOUSE MODELS FOR HUMAN CANCERS CONSORTIUM, and number, RFA CA-98-013,
must be typed on line 2 of the face page of the application form and the YES
box must be marked.

For U01 applicants only (NIH intramural project applicants must use the
address in section "3.  Additional Instructions for NIH Intramural Project
Applicants" below), submit a typewritten, signed 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 signed photocopies of the
application must also be sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892
Rockville, MD  20850 (for express/courier service)

Applications must be received by January 21, 1999.  If a U01 application is
received after that date, it will be returned to the applicant without review. 
The Center for Scientific Review (CSR) will not accept any U01 application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR will not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of a substantial
revision of an application already reviewed, but such an application must
follow the guidance in the PHS Form 398 application instructions for the
preparation of revised applications, including an introduction addressing the
previous critique.

3.  Additional Instructions for NIH Intramural Project Applicants

NIH intramural project applicants must use the PHS 398 application form and
the modified format and content described above under "1.  General Application
Format Instructions," with the following additional modifications.

o  On the Face Page, fill out only items 1., 2., 3.  (leave 3c. blank), 4.,
and 5.  The remainder of the items should be left blank, and the application
must not be signed by either the PI or an NIH Institute official.  The RFA
label must be affixed to the bottom of the Face Page, as described above in
section 2.

o  Do not submit "Other Support", Checklist", "Personnel Report", or "Personal
Data" pages.

o  The PI must obtain the approval of his/her NIH Institute Scientific
Director for applying, for collaboration, for participating as a component of
the MMHCC under the terms and conditions of the RFA, and for complying with
the policies of the Steering Committee.  A copy of that letter of approval
must be provided as part of a cover letter, addressed to the NCI Referral
Officer, for the application.

o  The composite budget page and the individual budget pages for each part
should supply the time and effort for each project participant, but no other
budget figures should be included.  The resources available for the project
and the research environment should be carefully described, but no budget
figures should be included.  The NIH Institute Scientific Director, as part of
the letter of approval for participation, must verify that no more than
$500,000 direct costs of intramural resources will be allocated to the project
described in the application, and provide assurance that the conduct of the
project will comply with the DHHS regulations for research involving human
subjects (if applicable) and with the PHS policy on vertebrate animal
research.

o  Submit an unsigned, typewritten original of the application, and five
photocopies to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892
Rockville, MD  20850 (for express/courier service)

Do not send the application or any copies to the Center for Scientific Review. 
NIH intramural project applications must be received by January 21, 1999.  If
an application is received after that date, it will be returned to the
applicant without review.

REVIEW CONSIDERATIONS

General Considerations

All U01 and NIH intramural project applications will be judged on the basis of
the scientific merit of the proposed project and the documented ability of the
investigators to meet the "RESEARCH OBJECTIVES" of the RFA.  Although the
technical merit of the proposed protocol is important, it will not be the sole
criterion for evaluation of a study.  Other considerations, such as the multi-
disciplinary nature of the studies, will be part of the evaluation criteria.

Factors considered to be important for review include demonstrated expertise
in mouse genetics and pathology, as applied to the design and derivation of
mouse models of human disease; a multi-disciplinary team of collaborators;
substantial interactions among collaborating researchers; demonstration of
appropriate facilities and resources; willingness to share data and reagents
freely.

Review Method

Upon receipt by the CSR, U01 applications will be reviewed for completeness;
incomplete applications will be returned to the applicant without further
consideration.  Upon receipt by the NCI Referral Office, NIH intramural
project applications will be reviewed for completeness; incomplete
applications will be returned to the applicant without further consideration. 
Complete U01 or NIH intramural project applications will be reviewed for
responsiveness by NCI staff.  If a U01 or NIH intramural project application
is not responsive to the RFA, NCI staff will contact the applicant to inform
him/her of that decision and will return the application.

Applications may receive a preliminary scientific peer review to determine
their relative competitiveness by an NCI-convened peer review group.  The NCI
will withdraw from further competition those applications judged to be
non-competitive and notify the Principal Investigator and applicant
institution official or NIH Institute Scientific Director.  For applications
that are complete and responsive, and judged to be competitive, the NCI will
convene an appropriate peer review panel to provide further scientific merit
review in accordance with the criteria stated below for scientific/technical
merit.  The second level of review for the U01 and NIH intramural project
applications will be provided by the National Cancer Advisory Board at their
September, 1999 meeting.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about how
best to meet the goals of the Consortium, and are expected to address issues
identified under "SPECIAL REQUIREMENTS FOR THE RFA."  The peer review group
will assess the scientific merit of the applications and related factors,
including:

1.  Significance.  Do the model or models proposed for derivation/
characterization/validation address an important need for the cancer research
community.  What is the immediacy of the research opportunity?  Over the
project period, is there potential for the group to develop models other than
those specified in the application?

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed and appropriate to the aims of the project?  Does the
applicant acknowledge potential problem areas and consider alternative
tactics?  Can these approaches be used to derive mouse models of cancer for
other malignancies in addition to those proposed?  Are the parameters chosen
to characterize the model(s) sufficient and appropriate?  Are these parameters
generally applicable to all mouse cancer models?  Are the standards chosen to
validate the model(s) for its relevance to a human malignancy or for testing
therapy, prevention, early detection, or imaging appropriate and adequate? 
Are these standards generally applicable to all mouse cancer models?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Is the project original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?  Will the approaches
advance the field of mouse or other model development?

4.  Investigators.  Are the principal investigator and his/her collaborators
appropriately trained and well suited to carry out this work?  To what extent
do these investigators have the necessary complementary skills?  Have
collaborations been established or consultants identified to provide the
appropriate depth and breadth of scientific expertise required for the
project?  Will this team of investigators contribute unique skills to the
overall Consortium?

5.  Environment.  Are the facilities for mouse maintenance and experimentation
appropriate to support the endeavor?  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 and incorporate the best use of collaborative arrangements?  Is
there evidence of institutional support?

Additional Considerations

6.  Interactions.  Are there adequate plans for effective interaction and
coordination among Consortium components and the NCI?  Do the investigators
state their willingness to collaborate extensively and share information
fully?  Do the investigators state their willingness to abide by the
priorities and policies agreed upon by the Steering Committee?  Have the
applicants proposed sound strategies for communication among themselves, with
the other MMHCC components, and with the NCI?

7.  Budget.  For U01 applications, does the apportionment of the budget among
fundamental infrastructure, model development, characterization, and
validation, and technology development indicate that the applicants understand
the requirements of managing this sort of model-building enterprise?  For the
NIH intramural project applications, is the commitment of effort appropriate
to the scope of the project, and are the resources and environment adequate to
support the project?

AWARD AND SELECTION CRITERIA

The intent of this RFA is to enable the NCI to assemble a Consortium composed
of highly qualified teams of investigators whose complementary scientific
skills and expertise will enable them to achieve the goal of deriving
validated mouse models that are analogous to human malignancies.  The NCI will
choose the teams who will collectively provide for the Consortium the most
creative approaches to mouse model design, and the range of research
experience, technology, and resources to ensure that the models that are
validated as appropriate for various aspects of cancer research are derived
rapidly.

U01 applications recommended by the National Cancer Advisory Board will be
considered for award based upon (a) scientific and technical merit; (b) the
importance of the proposed models for cancer research; (c) the degree of
originality and innovation in model design; (d) the creativity of the
approaches and technologies for model derivation, characterization, and
validation; (e) the likelihood for substantial contribution by the applicants
to a successful collaborative MMHCC; (f) the evidence for willingness to work
cooperatively; (g) the quality and availability of animal research
infrastructure and resources; and (h) the availability of funds.

NIH intramural project applications recommended by the National Cancer
Advisory Board will be selected as components of the MMHCC based upon (a)
scientific and technical merit; (b) the importance of the proposed models for
cancer research; (c) the degree of originality and innovation; (d) the
creativity of the approaches and technologies; (e) the likelihood for
substantial contribution by the applicants to a successful collaborative
MMHCC; (f) the evidence for willingness to work cooperatively; (g) the quality
and availability of animal research infrastructure and resources; and (h) how
well the project augments or complements the scientific and technologic
expertise available in the U01 applications, or provides unique expertise or
technology.

SCHEDULE

Letter of Intent Receipt:       December 17, 1998
Application Receipt Date:       January 21, 1999
Review by NCAB Advisory Board:  September 1999
Earliest Award Date:            September 25, 1999

INQUIRIES

Due to the unusual application format and complexity of this RFA, the NCI
encourages potential applicants to take the opportunity to clarify any issues
or questions.  Written and telephone inquiries concerning the RFA are welcome.

Direct inquiries regarding programmatic issues to:

Cheryl L. Marks,  Ph.D.
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 501
Bethesda, MD 20892-7381
Telephone:  (301) 435-5226
FAX:  (301) 496-8656
Email:  [email protected]

Because of the multi-disciplinary scientific nature of the RFA, potential
applicants may be referred to additional NCI extramural program staff for
further advice and clarification of the intent of the RFA.

Direct inquiries regarding fiscal matters to:

Mr. William Wells
Grants Management Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800 ext. 250
FAX:  (301) 496-8601
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.396, Cancer Biology.  Awards are made under authorization of the Public
Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public
Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR Parts 52 and 45 CFR Part 74 [and Part 92 when
applicable for State and Local governments].  This program is not subject to
the intergovernmental review requirements of 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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