CHEMOPREVENTION IN GENETICALLY-IDENTIFIED HIGH-RISK GROUPS:  INTERACTIVE RESEARCH
AND DEVELOPMENT PROJECTS

Release Date:  April 1, 1998

RFA:  CA-98-012

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  July 15, 1998
Application Receipt Date:  August 26, 1998

PURPOSE

The purpose of this initiative is to establish integrated, multidisciplinary
research programs that define and evaluate chemopreventive strategies in
asymptomatic subjects at high risk for cancer.  This Request for Applications
(RFA) seeks programs with at least three independent but integrated research
projects and the associated administrative core functions that share a common
focus directed at designing and evaluating chemopreventive strategies in
high-risk cohorts.  This includes groups with on-going clinical trials, core
functions and laboratory support such as cooperative groups, CCOP Research Bases,
NCI designated cancer centers, genetic testing programs and risk registries.  At
least two of the individual projects must involve Phase I/II or Phase II clinical
chemoprevention trials or translational research needed for chemoprevention
applications.

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),
Chemoprevention in Genetically-Identified High-Risk Groups: Interactive Research
and Development Projects, 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

Applications may be submitted by domestic and foreign for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal Government.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.  For those
respondents affiliated with the Community Clinical Oncology Program (CCOPs), it
is suggested that applications be submitted through the CCOPs mechanism.

MECHANISM OF SUPPORT

This RFA will use the research program cooperative agreement (U19) mechanism. 
The U19 is essentially the cooperative agreement version of the P01 (Program
Project Grant) funding mechanism.  Therefore the applicant should use The Interim
Guidelines for the Program Project Grant of the National Cancer Institute dated
February 1998 in preparing the application.  The P01 guidelines are available
from the NCI Referral Officer listed under APPLICATION PROCEDURES. The
cooperative agreement is an assistance mechanism in which substantial involvement
of the NCI program with the recipient is anticipated during the performance of
the planned activity.  The nature of the NCI's involvement is described under
SPECIAL REQUIREMENTS and in the TERMS AND CONDITIONS section.  Responsibility for
the planning, direction, and execution of the proposed project will be solely
that of the awardee.

The U19 cooperative agreement builds on the leadership of a key Principal
Investigator and the interaction of the participating investigators to integrate
the individual projects in a way that accelerates the acquisition of knowledge
beyond that expected from the same projects conducted separately, without
combined leadership or a common theme.  Individual investigators may apply their
specialized research capabilities to basic, developmental, and clinical aspects,
as they relate to the focused, central theme of the overall project.  This grant
mechanism also offers a way to achieve economy of effort through the sharing of
personnel, facilities, equipment, data, ideas, and concepts.

The total project period for an application submitted in response to this RFA may
not exceed five years.  The anticipated award date is March, 1999.  This RFA is
a one-time solicitation.  Future unsolicited competing continuation applications
will compete with all other investigator-initiated research applications and be
reviewed according to customary peer review procedures.  However, if it is
determined that there is a sufficient continuing need, the NCI will invite
recipients of awards made under this RFA in FY 99 to submit competing continuing
applications for review according to procedures described below under APPLICATION
PROCEDURES and REVIEW CONSIDERATIONS.

FUNDS AVAILABLE

Approximately $3 million in total costs for support of the first year of the
program will be committed specifically to fund applications submitted in response
to this RFA.  It is anticipated that three to four awards will be made.  Because
the nature and scope of the research proposed in response to this RFA may vary,
it is anticipated the sizes of awards will vary also.  Awards and level of
support depend on receipt of a sufficient number of applications of high
scientific merit.

Although this program is provided for in the financial plans of the NCI, awards
made pursuant to this RFA will be contingent on the continued availability of
funds for this purpose.

RESEARCH OBJECTIVES

Background

High risk for cancer may be attributable to inherited or acquired genetic
lesions, lifestyle or environmental factors, or combinations of these parameters. 
Program components include, but are not limited to (1) definition of cohorts, (2)
identification and characterization of early precancerous lesions/biomarkers that
may contribute to defining cohorts, serve as endpoints for clinical studies, or
both, and (3) clinical studies to evaluate the chemopreventive strategies.
Successful programs will require expertise in general and molecular cancer
epidemiology, genetics, molecular biology, descriptive and quantitative
pathology, pharmacology, oncology, and clinical science with attendant
capabilities in biostatistics, bioanalytical methodologies, data management and
clinical trials management. Support of the translational research needed to bring
relevant basic research findings to clinical application in the high-risk cohorts
is a major objective.

Increasing knowledge of the 20 to 40 year process of human carcinogenesis is
providing many new opportunities for early intervention and prevention, and,
specifically, for chemoprevention.  A significant part of this knowledge is the
association of increased cancer risk with inherited or acquired genetic lesions. 
Genetic predisposition includes well-characterized germline mutations, many of
which are associated with lost tumor suppressor function.  Examples are APC
(familial adenomatous polyposis leading to colorectal cancer), BRCA1 and BRCA2
(breast and ovarian cancers), and p53 mutations resulting in Li-Fraumeni syndrome
(multiple cancers including breast, colorectal, brain and leukemia).  Other
cancer-predisposing genes such as MLH1 and MSH2 (both linked to hereditary
nonpolyposis colon cancer) cause defective DNA repair.  Also, recent cancer
epidemiology and pharmacogenetic studies have suggested the importance of genetic
polymorphisms affecting the ability to detoxify carcinogens e.g., glutathione
S-transferase (GSTM1, GSTM2, GSTP1), N-acetyltransferase (NAT1, NAT2), cytochrome
P450 (CYP450IAI), and steroid 5 alpha-reductase type II (SRD5A2).  Mutations and
changes in expression of tumor suppressors acquired during carcinogenesis are
also important.  Similarly, oncogenes and growth factors activated by mutation
or overexpressed during carcinogenesis (e.g., ras, EGFR, c-erbB2) are significant
genetic lesions in cancer as are mutations in cyclin and cyclin-related genes
implicated in cell cycle control. Besides these specific genetic lesions, general
indicators of genetic susceptibility have been developed, for example, mutagen
sensitivity as measured by bleomycin-induced DNA break frequency.  Although it
is not likely that any of these lesions will be eradicated by chemopreventive
agents, their presence and activity may be decreased by damping the signal
transduction pathways in which they participate, thereby selecting against
proliferation of progeny cells containing the lesions or inducing apoptosis in
these cells.

Environmental, hormonal, lifestyle and other etiological factors contribute to
cancer risk and may enhance the risks from genetic predisposition.  It is
estimated that while approximately 5 percent
of cancers are due to genetic predisposition and 15 percent occur spontaneously,
the remaining 80 percent are attributable to the environment and
environmental-genetic interactions.  Chemoprevention strategies should be useful
in these situations to reduce mutational frequency and clonal evolution.  For
example, smokers who are continually exposed to gene-damaging agents may be good
candidates for chemopreventive intervention with antimutagens.  Also, women at
high risk for breast cancer may benefit from chemopreventive intervention that
controls breast cell proliferation.

Scope and Objectives

The purpose of this initiative is establishment of integrated, multidisciplinary
research programs that define and evaluate chemopreventive strategies in subjects
at high risk for cancer.  This RFA is seeking programs with administrative core
functions supporting at least three independent research projects which share a
common focus directed at designing and evaluating chemopreventive strategies in
high-risk cohorts.  Program components might include, but are not limited to
groups with on-going administrative clinical trials core functions and laboratory
support such as cooperative groups, CCOP Research Bases and NCI designated cancer
centers.

The programs should be directed to further characterizing and defining high-risk
cohorts for major cancers, such as those listed above.  High-risk may be defined
by clinical and epidemiological criteria, linkage analysis or DNA testing or
combinations of these parameters.  Applications using clinical criteria or
linkage analysis should include provisions for tissue collection and storage for
future DNA testing.  Applicants are strongly encouraged to pursue research
objectives consistent with the Clinical Development Plans for chemopreventive
agents published by the NCI, DCPC Agent Development Committee (see Journal of
Cellular Biochemistry Supplement 20, 1994 and Supplement 26, 1996) for which
preclinical efficacy and toxicity information has been developed and for which
IND support and drug are available.  However, applications should reflect the
interests and insights of the investigators.  Applicants should include
preclinical in vitro or in vivo data to support their proposal.  If no
preliminary data is available, they might consider including a small pilot study
(Phase IIa) prior to the initiation of a Phase IIB trial.  Examples of theme
areas for which projects may be proposed, for the purpose of illustration only,
might include the following:

1.  Women at high risk for breast cancer with atypical epithelial hyperplasia or
epithelial hyperplasia and one or more of aneuploidy, elevated PCNA, EGFR or
hormone receptors, or mutated p53 by baseline fine-needle aspiration cytology
might be randomized to chemopreventive treatment and placebo groups.  Primary
endpoints of treatment might include cytology, nuclear/nucleolar morphometry,
PCNA, EGFR or hormone receptors, p53, and apoptosis (bcl-2/bax).  Additional
areas of investigation could include genetic analysis of BRCA-1, -2 relative to
function and penetrance, LOH at 11q12-13, methylation, other risk factor analysis
(e.g., hormone receptor types), and surveillance (e.g., as related to DCIS, LCIS,
and ovarian cancer), or other basic research questions explored using animal
model or cell culture techniques.  Correlative studies using NMR, digital imaging
mammography, sonoelastography, neoangiogenesis MRI, etc.  could also be
undertaken.

2.  Patients with familial adenomatous polyposis coli who are found at baseline
colonoscopy endoscopic biopsy to have 100 or more colorectal adenomas or APC
truncation mutation and 10 or more colorectal polyps of which two or more are
adenomas might be randomized to chemopreventive treatment (or compare treatments)
and placebo groups.  Primary endpoints of treatment might include colon polyp
incidence, colon crypt proliferation kinetics, and apoptosis.  Additional areas
of investigation could include translational research involving the MIN and MSH
mouse models and analysis of COX2 modulation through MIN and MOM pathways,
analysis of aberrant crypt formation and zonal proliferation, and other areas
relevant to HNPCC and mutational spectra.

3.  Former smokers (30 or more pack years) with moderate/severe bronchial
dysplasia on fluorescence bronchoscopy and random bronchial biopsy might be
randomized to chemopreventive treatment and placebo groups.  In addition to the
primary endpoint of treatment, bronchial dysplasia grade, investigations might
include nuclear polymorphism, ploidy, LOH at 3p and 5q, p53, rb, CDKN2,
microsatellite instability, PCNA, telomerase, apoptosis, and GST.  These
investigations might be undertaken in biopsy material and in the context of
developing transgenic animal models for lung dysplasia/cancer showing high
frequencies of tumor mutations.

At least two of the individual projects must be Phase I/II or Phase II clinical
chemoprevention trials or translational research needed for chemoprevention
applications.  Phase II studies should include molecular biomarkers or other
intermediate biomarkers as surrogate endpoints for cancer incidence (cancer
incidence may be beyond the scope and/or duration of this initiative for most
clinical situations). Translational research projects will primarily involve the
characterization, quantitation and evaluation of the early molecular biomarkers
that identify high-risk cohorts and serve as surrogate endpoints for cancer
incidence in chemoprevention trials in these populations.  The programs will
build on existing resources for identifying and recruiting participants to the
clinical studies (e.g., genetic testing programs, risk registries).

The NCI will conduct a safety and protocol review of the studies prior to their
initiation.  This review is required to assure that all safety, conduct,
monitoring, and reporting conform to FDA IND guidelines.  The awardee
institutions and Principal Investigators must agree to comply with the
recommendations of the review.

Core functions provided in the programs might include (1) tissue storage for
later analysis, (2) a data management system with validated statistical and
quality assurance procedures, and (3) safety and conduct monitoring of clinical
trials with oversight by scientists with expertise in genetic and epidemiological
research.

SPECIAL REQUIREMENTS

General

High risk for cancer may be attributable to inherited or acquired genetic
lesions, lifestyle or environmental factors, or combinations of these parameters. 
This initiative is interested in receipt of applications relevant to either
inherited or acquired genetic lesions.  This initiative is to establish
integrated, multidisciplinary research programs around a theme in an area of
defining and evaluating chemopreventive strategies in subjects at high risk for
cancer, including but not limited to, the definition of cohorts, the
identification and characterization of early precancerous lesions/biomarkers for
both cohort identification and endpoint analysis, and the clinical evaluation of
chemopreventive strategies.  This RFA is seeking programs with administrative
core
functions supporting at least three independent but integrated research projects
which share a common focus directed at designing and evaluating chemopreventive
strategies in high-risk cohorts. Studies may involve multiple institutions.  This
includes groups with on-going administrative clinical trials core functions and
laboratory support such as cooperative groups, CCOP Research Bases and NCI
designated cancer centers.  At least two of the individual projects
must involve Phase I/II or Phase II clinical chemoprevention trials or
translational research needed for chemoprevention applications.

Applications funded under this RFA will be supported through the cooperative
agreement (U19) mechanism.  An assistance relationship will exist between NCI and
the awardees to accomplish the research objectives.  It is expected that each
application will describe plans for a mixture of basic, developmental, and
clinical research activities, all directed to the meet the objectives of this
RFA.  As described more fully below, the recipients will have primary
responsibility for the development and performance of the research activities. 
However, there will be government involvement, particularly on clinical studies,
with regard to (1) assistance in securing an Investigational New Drug (IND)
approval from the Food and Drug Administration (FDA), (2) coordination and
assistance in obtaining the chemopreventive agent, and (3) monitoring of study
safety and conduct.  If an investigator anticipates requiring considerable
assistance in obtaining the chemopreventive agent and/or in securing an IND
permit from the FDA, documentation of such assistance should be sought in writing
to, and approved by, the NCI Program Director prior to submitting an application. 
Awards will not be made until all arrangements for obtaining the IND and the
agent are completed.  Cost of agent and necessary formulation should be included
in the budget.

Definitions

Program Director - the NCI Program Staff official (see INQUIRIES section if this
RFA) responsible for the stewardship and monitoring of the award.  The Program
Director may also function as the Staff Collaborator.

Staff Collaborator - the NCI Staff Collaborator responsible for contributing
expert advice on the scientific design and conduct of the research as defined in
the terms and conditions.

Advisory Committee - the committee composed of external, non-participating
scientists appointed by the Principal Investigator to oversee the research
activities and provide advice to the
Principal Investigator who is responsible for reporting progress to the NCI
Program Director.

Data Safety and Monitoring Committee - Composed of external, non-participating
scientists appointed by the Principal Investigator to monitor patient safety,
conduct data audits, and document progress to the NCI Program Director and
Advisory Committee.

Terms and Conditions of Award

A.  Applicability.  These special Terms and Conditions of Award are in addition
to and not in lieu of otherwise applicable OMB administrative guidelines, HHS
grant administration regulations in 45 CFR part 74 and 92, and other HHS, PHS and
NIH grant administration policy statements.

The administrative and funding instrument used shall be a cooperative agreement,
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.

Consistent with the above concept, the dominant role and prime responsibility for
the activity reside 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 Staff
Collaborator.

Under the cooperative agreement, a relationship will exist between the recipient
of these awards and the NCI, in which the performers of the activities are
responsible for the requirements and conditions described below, and agree to
accept program assistance from a named NCI Staff Collaborator in achieving
project objectives.

Failure of an awardee to meet the performance requirements, including these
special terms and conditions of award, or significant changes in the level of
performance, may result in a reduction of budget, withholding of support,
suspension and/or termination of the award.

B.  Awardee Rights and Responsibilities.

The Awardee is responsible for:

1.  Research design and protocol development, including definition of objectives
and approaches, planning, implementation, participant recruitment and follow-up,
data collection, quality control, interim data and safety monitoring, final data
analysis and interpretation, and publication of results.

2.  Establishing an external Advisory Committee to oversee projects and review
data.  The Principal Investigator will name external, non-participating
investigators to serve as members on an Advisory Committee and schedule meetings
periodically.  The NCI Staff Collaborator will be a non-voting member.

3.  Designating Clinical Study Protocol Chairs.  The Principal Investigator shall
designate a single Protocol Chairperson (if the P.I. does not assume this role)
for each protocol within the described research plan.  The Protocol Chairperson
shall function as the scientific coordinator for the protocol and shall assume
responsibility for developing and monitoring the protocol.  All proposed
protocols and modifications will be submitted by the Chair through the Principal
Investigator to the NCI Program Director, for review and approval, subject to
negotiation with the awardees.

4.  Implementing the data collection method and strategy.

5.  Establishing mechanisms for quality control and monitoring.  Awardees are
responsible for ensuring accurate and timely assessment of the progress of each
study, including development of procedures to ensure that data collection and
management are:  (1) adequate for quality control and analysis; (2) for clinical
trials, as simple as appropriate in order to encourage maximum participation of
physicians and patients and to avoid unnecessary expense; and (3) sufficiently
staffed.

6.  Submitting interim progress reports, when requested, to the NCI Program
Director including as a minimum, summary data on protocol performance.  The
Advisory Committee may require additional information.  Such reports are in
addition to the annual awardee noncompeting continuation progress report.

7.  Establishing procedures, where applicable, to comply with FDA regulations of
21 CFR Part 312 for studies involving investigational agents and to comply with
the requirements of 45 CFR Part 46 for the protection of human subjects.  For
IND's sponsored by the NCI, the Principal Investigator is responsible for
obtaining approval from both the Institutional Review Board and the NCI Program
Director to enroll patients and to change the protocol.  The Principal
Investigator is also responsible for all aspects of investigational drug
acquisition, formulation, distribution, etc.

8.  Cooperating in the reporting of the study findings.  The NCI will have access
to and may periodically review all data generated under an award.  Where
warranted by appropriate participation, plans for joint publication with NCI of
pooled data and conclusions, are to be developed by the Principal Investigator
or Advisory Committee, as applicable. NIH policies governing possible
co-authorship of publications with NCI staff will apply in all cases.  In
general, to warrant co-authorship, NCI staff must have contributed to the
following areas:  (a) design of the concepts or experiments being tested; (b)
performance of significant portions of the activity; and (c) preparation and
authorship of pertinent manuscripts.  The awardee(s) 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.

C.  NCI Staff Responsibilities

It is expected that the dominant role and prime responsibility for the activity
will reside 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 Staff Collaborator who will provide expert advice to the
awardee on specific scientific and/or analytic issues as described below.  The
NCI Staff Collaborator will be named later based upon the subject matter of the
award.  However, the NCI Program Director will retain overall programmatic
responsibility for the award and will be the contact point for all facets of
interaction with the awardee related to stewardship and monitoring of the award.

Program Director Responsibilities will include:

1.  Interacting with the Principal Investigator(s) on a regular basis to monitor
study progress Monitoring may include:  regular communications with the Principal
Investigator and staff, periodic site visits for discussions with awardee
research teams, observation of field data collection and management techniques,
quality control, fiscal review, and other relevant matters; as well as attendance
at Advisory Committee and related meetings.  The NCI retains, as an option, the
right to act as Sponsor for an IND filed to support the clinical research and to
conduct periodic external review of progress.

2.  The NCI Program Director will monitor protocol progress, and may request that
a protocol study be closed to accrual for reasons including:  (a) accrual rate
insufficient to complete study in a timely fashion; (b) accrual goals met early;
(c) poor protocol performance; (d) patient safety and regulatory concerns; (e)
study results that are already conclusive; and (f) emergence of new information
that diminishes the scientific importance of the study question. The NCI will not
permit further expenditures of NCI funds for a study after requesting closure
(except for patients already on-study).

3.  Making recommendations for continued funding based on: a) overall study
progress, including sufficient patient and/or data accrual; b) cooperation in
carrying out the research (e.g., attendance at Advisory Committee meetings,
implementation of group decisions, compliance with the terms of award and
reporting requirements); and/or c) maintenance of a high quality of research,
which will allow pooling of data and comparisons across multiple cooperative
agreement awards for common data elements.

Staff Collaborator responsibilities will include:

1.  Participating in the Advisory Committee meetings.  The NCI Staff Collaborator
will be an invited attendee and a participant on the Advisory Committee and, if
applicable, subcommittees, but will not have a vote on any committee.

2.  Serving as a resource with respect to other ongoing NCI activities that may
be relevant to the protocol to facilitate compatibility and avoid unnecessary
duplication of effort.

3.  Involvement assisting in the design and coordination of research activities
for awardees as elaborated below:

a. Assisting by providing advice in the management and technical performance of
the investigations, coordinating clearances for investigational agents held by
NCI.  The NCI reserves the right to crossfile or independently file an
Investigational New Drug Application form with the FDA.

b.  Through participation in the Advisory Committee and with the agreement of the
Principal Investigator, the NCI Staff Collaborator may assist in the design,
development, and coordination of the research or clinical protocol, in the
statistical evaluations of data, in the preparation of questionnaires and other
data recording forms, and in the publication of results.

c.  Reviewing and approving protocols to insure they are within the scope of peer
review and for safety considerations, as required by Federal regulations.

d.  Reviewing and providing advice regarding the establishment of mechanisms for
quality control and study monitoring.

D.  Collaborative Responsibilities

In addition to the interactions defined above, NCI Staff and Awardees shall share
responsibility for the following activities:

1. Advisory Committee.  The Advisory Committee organized by the Principal
Investigator will be the main oversight body of the proposed research.

The Advisory Committee has primary responsibility to oversee research activities
and provide advice to the Principal Investigator.  The Principal Investigator
will document progress in written reports to the NCI Program Director, and will
provide periodic supplementary reports upon request.

The Advisory Committee will be composed of external, non-participating peer
Investigators, including the NCI Staff Collaborator.  An initial meeting of the
Advisory Committee will be convened early after award by the Principal
Investigator.  The final structure of the Advisory Committee will be established
at the first meeting.  The NCI Staff Collaborator will attend and participate in
the Advisory Committee, and as appropriate, its subcommittees but will not be a
voting member of any committee.  Such a committee usually will meet at least
annually.

2.  Data Safety and Monitoring Committee.  The Principal Investigator shall
appoint a Data Safety and Monitoring Committee for the study.  The NCI Program
Director will facilitate and the awardee shall allow for interim data auditing
and patient safety monitoring.  The Data Safety and Monitoring Committee may
assist in clinical protocol coordination and IND submission, subject to
discussion with the Principal Investigator, and will review interim results
periodically and report to NCI and the Advisory Committee, as appropriate.

E. Arbitration

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

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is NIH policy 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.

All investigators proposing research involving human subjects should read the
"NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register, March 28, 1994 (59
FR 14508-14513) and in the NIH GUIDE FOR GRANTS AND CONTRACTS, March 18, 1994,
Volume 23, Number 11.  Copies may be obtained from the Program Staff listed under
INQUIRIES.  Program Staff may also provide additional relevant information
concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by July 15, 1998, a letter of intent
that includes a descriptive title of the proposed research and a list of titles
for the anticipated components of the U19.  The name, address, and telephone
number of the Principal Investigator, other key personnel and participating
institutions, the number and title of the RFA in response to which the
application is being submitted, and the projected approximate costs for each
year.

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 to:

Gary J. Kelloff, M.D.
Division of Cancer Prevention and Control
National Cancer Institute
6130 Executive Boulevard, Suite 201
Bethesda, MD  20892
Rockville, MD 20852 (for express/courier services)
Telephone:  (301) 496-8563
FAX:  (301) 402-0553
Email:  kelloffg@dcpcepn.nci.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these cooperative agreements.  Applications 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 301/435-0714,
email: ASKNIH@od.nih.gov.

The RFA label available in PHS-398 application must be affixed to the bottom of
the face page of the application.  Failure to use this label could delay
processing of the application such that it may not reach the review committee in
time for review.  In addition, the RFA title "CHEMOPREVENTION IN
GENETICALLY-IDENTIFIED HIGH-RISK GROUPS:  INTERACTIVE RESEARCH AND DEVELOPMENT
PROJECTS" and number must be typed in line 2 of the face page of the application
form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the Checklist
and three signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies 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  20852 (for express/courier service)

Applications must be received by August 26, 1998.  If an application is received
after that date, it will be returned to the applicant without review.  The Center
for Scientific Review (CSR) will not accept any application in response to this
RFA that is essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The CSR will not accept any
application that is essentially the same as one already reviewed.  This does not
preclude the submission of substantial revision of 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.

APPLICATION PROCEDURES

The general instructions provided in PHS-398, in conjunction with the NCI P01
guidelines (available from the NCI Referral Officer listed in the APPLICATION
PROCEDURES section of this RFA), are to be used for the preparation of
applications.  Because the Terms and Conditions of Award (discussed in the
SPECIAL REQUIREMENTS Section), will be included in all awards issued as a result
of this RFA, it is critical that each applicant provide specific plans for
responding to the terms and conditions of award and requirements stated in the
RFA.  Plans must take into account NCI staff involvement as well as how all the
responsibilities of awardees will be fulfilled.

The following items apply to all applications:

1.  Clinical trial designs should include an adequate number of participants and
should be of sufficient duration to assure statistical power to address the study
questions of chemopreventive efficacy, long-term safety and acceptability, and
surrogate endpoint biomarker (SEB) validation.  To this end, biostatistics and
clinical trial design expertise should be included from the first efforts in
study planning and design.

2.  A discussion of the evaluation of genetic lesions and SEBs, including
relevance to the test agent and target population should be provided for the
basic research and clinical components of the projects.

3.  A rationale for each test agent should be provided, including relevant
epidemiological and laboratory data. Preclinical and clinical toxicity data
should also be presented.  Where the availability or safety of the agent are in
doubt, the applicant should consult with the NCI Program Director or the
manufacturer prior to preparing the application.  As noted above, applicants
anticipating the need of considerable assistance in obtaining the chemopreventive
agent(s) to be studied or in securing IND approval, e.g. with respect to adequate
preclinical toxicology data, should seek this assistance from the NCI Program
Director in writing.  The request should be made to the Program Director prior
to submission of the application.

4.  A rationale for selection of the target patient cohort and an estimate of the
number of participants required to complete the clinical studies should be
provided.  Criteria and calculations used to estimate sample size should be
included.  The patient cohort should be described and its selection justified. 
The cohort should be defined, as appropriate by age, sex, race, dietary customs,
education, geographic location, occupational or lifestyle risk factors, and
relevance to a specific cancer problem or its prevention by the test agent. 
Particularly, the genetic lesion under study should be carefully described and
characterized. Accrual rate should be estimated.  If multiple institutions are
involved, the proposal should include verification of the co-investigators'
willingness to participate, and pertinent additional information regarding the
cooperating institutions' staff qualifications, resources, research plans,
including patient availability and data flow, as well as corresponding budget
requirements.

5.  Clinical chemistry and biologic aspects of the studies should be completely
described, including sample collection, storage, handling, analysis, and quality
control.  The methods and equipment to be used and the technical qualifications
and experience of the personnel involved should be addressed.  If these aspects
of the studies are to be conducted by groups other than at the applicant's
institution, a letter from the cooperating institutions indicating their
willingness to participate should be included.

6.  Any known or potential toxicity considerations should be described, along
with the techniques and procedures to monitor any adverse events and dose
modifications to be made based on toxicity.

7.  Methods to monitor patient compliance and, as appropriate, methods to
document nutrient intake should be specified.

8.  A willingness to work cooperatively with the NCI Program Director in the
implementation and conduct of the study should be indicated.

9.  Applicants from institutions that have a General Clinical Research Center
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the GCRC as a resource for conducting the proposed research.  If so, a
letter of agreement from either the GCRC Program Director or Principal
Investigator could be included with the application.

REVIEW CONSIDERATIONS

A. Review Method

Upon receipt, applications will be reviewed by the CSR for completeness and by
the NCI for responsiveness.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.

Applications that are complete and responsive to the Request for Applications
will be evaluated for scientific and technical merit in accordance with the
review criteria stated below by an appropriate peer review group convened by the
NCI.  As part of the initial merit review, all applications will receive a
written critique and may undergo a process in which only those applications
deemed to have the highest scientific merit will be discussed, assigned a
priority score, and receive a second level review by the National Cancer Advisory
Board.

The review group will assess the scientific merit of the studies using the
following review criteria:

B. Review Criteria

Peer review emphasizes a synthesis of two major aspects of the program project
application: 1) review of the program as an integrated research effort focused
on a central theme and 2) review of the merit of individual research projects and
core components in the context and environment of the proposed program.  In
arriving at an overall score for the program project, reviewers will consider the
likelihood that the proposed research will have a substantial impact on the
scientific field.

As of October 1, 1997, the review criteria for both overall program and the
individual projects are Significance, Approach, Innovation, Investigators and
Environment (NIH Guide, Vol. 26, Number 22, June 27, 1997).  The sections below
give more detail about how these five criteria are applied to the overall program
and the individual projects.

A. Review Criteria for the Overall Program

o  Significance: The significance of the program overall and its potential to
advance scientific knowledge in the field.

o  Approach: The adequacy and quality of the experimental approaches proposed in
the projects and the overall design of the program project.

o  Innovation: The degree to which the overall program applies novel concepts and
innovative approaches.

o  Investigators: The qualifications of the Principal Investigator and the
program leadership.

o  Environment: Scientific, organizational and administrative environment.

o  The adequacy of the commitment (percent effort) of the Principal Investigator
to the program  project.  There should be a specific commitment to both the
scientific and administrative aspects of the program project.  Though desirable
it is not mandatory that the Principal Investigator be a project leader of an
individual research project.

o  The ability of the Principal Investigator to select individual projects for
both scientific excellence and relatedness to the theme of the program project
(as demonstrated by the included projects) and actively promote interactions and
collaborations.  Components not recommended for further consideration impact
negatively on the evaluation of the program leadership skills and scientific
judgment of the Principal Investigator.

o  The mechanisms for internal quality control of the research.

o  The anticipated synergy of the program project above that provided by a
collection of separate research grants.

o  The appropriateness of the proposed project budget and the duration; the
adequacy of plans to include 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; and the safety of the research
environment.

B.  Program as an Integrated Effort

o  The coordination, interrelationship and synergy among the meritorious research
projects and core component as related to the common theme of the program
project.

o  The advantages of conducting the proposed research as a program project rather
than through separate research efforts.

o  The mechanisms for regular communication and coordination among investigators.

o  For competing renewals, evidence of productive collaborations.

C. Review Criteria for Projects

o  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?

o  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?

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

o  Investigators: Is the project leader appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the project leader and other researchers (if any)?

o  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?

(NOTE: Synergy and thematic relatedness between the projects and cores, and the
significance of the project for the program as a whole, will be described and
evaluated under þProgram as an Integrated Effortþ and/or in the þOverall
Critiqueþ sections.)

D. Review Criteria for Core(s)

o  The utility of the core to the program project.  Each core must provide
essential facilities or services for two or more projects judged to have
substantial merit.

o  The quality of the facilities or services provided by this core (including
procedures, techniques, and criteria for prioritization).

o  The qualifications, experience, and commitment of the personnel involved in
this core.

o  Appropriateness of the budget. Accountability for distribution of costs to
projects. A realistic budget reflects the core directorþs understanding of the
score of the work.

AWARD CRITERIA

The earliest feasible start date for the initial awards will be March 1999. 
Applications recommended by the NCI Advisory Board will be considered for award
based upon (a) scientific and technical merit; (b) program balance, including in
this instance, sufficient compatibility of features to make a successful
collaborative program a reasonable likelihood; and (c) availability of funds.

SCHEDULE

Letter of Intent Receipt:       July 15, 1998
Application Receipt Date:       August 26, 1998
Review by NCAB Advisory Board:  January 1999
Anticipated Award Date:         March 1999

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Gary J. Kelloff, M.D.
Division of Cancer Prevention and Control
National Cancer Institute
6130 Executive Boulevard, Suite 201
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-8563
FAX:  (301) 402-0553
Email:  kelloffg@dcpcepn.nci.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Carolyn Mason
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Suite 243
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-7800 Ext. 259

Direct inquiries regarding review matters to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Number
93.399, Cancer Control.  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 grant 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 requirement 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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