Full Text CA-97-005
 
CHEMOPREVENTION IN GENETICALLY-IDENTIFIED HIGH-RISK GROUPS:
INTERACTIVE RESEARCH AND DEVELOPMENT PROJECTS
 
NIH GUIDE, Volume 26, Number 7, March 7, 1997
 
RFA:  CA-97-005
 
P.T. 34

Keywords: 
  Chemopreventive Agents 
  Chemoprevention 
  Cancer/Carcinogenesis 
  Risk Factors/Analysis 
  Biomedical Research, Multidiscipl 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  April 3, 1997
Application Receipt Date:  May 22, 1997
 
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
administrative core functions supporting at least three independent
but integrated research projects that share a common focus directed
at designing and evaluating chemopreventive strategies in high-risk
cohorts.  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.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
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 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.  Applications from
minority and women investigators are encouraged.  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 NCI P01 guidelines in preparing the
application.  The P01 guidelines are available from the NCI Referral
Officer (Ms. Toby Friedberg), 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 applications submitted in response to
the present RFA may not exceed five years.  The anticipated award
date is September 1997.  This RFA is a one-time solicitation.  Future
unsolicited competitive continuation applications will compete with
all other investigator-initiated research applications and be peer
reviewed by a study section in the Division of Research Grants (DRG),
NIH.  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 97 to submit competitive 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 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.  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 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 submission 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 perm it from the FDA, documentation of such
assistance from the NCI should be obtained, 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.
 
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 assigned by the NCI Program Director 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.
 
NCI Staff 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.  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.
 
3.  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.
 
4.  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.  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).
 
d. Reviewing and providing advice regarding the establishment of
mechanisms for quality control and study monitoring.
 
5.  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.
 
D. Collaborative Responsibilities
 
In addition to the interactions defined above, NCI Staff and Awardees
shall share responsibility for the following activities:
 
1.  Advisory Committee.  An 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 yearly.
 
2.  Data Safety and Monitoring Committee.  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 awardee, a second member
selected by NCI, and the third member selected by the two prior
selected members.  These special arbitration procedures in no way
affect 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 (Section 492B of Public Law 10-43) and
supersedes and strengthens previous policies (Concerning the
Inclusion of Women in Study Populations), which have been in effect
since 1990.
 
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 was 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.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by April 3, 1997, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the names of other key personnel, the participating
institutions, and the number and title of this RFA.
 
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, it is requested
to provide an indication of the number and scope of applications 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.nih.nci.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 9/95) is to be used
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 301/710-0267, email:
ASKNIH@odrockm1.od.nih.gov.
 
The RFA label available in PHS-398 must be affixed to the bottom of
the face page.  Failure to use this label could delay processing of
the application such that it may not reach the review committee in
time for review.  Additionally, the title of the RFA, CHEMOPREVENTION
IN GENETICALLY-IDENTIFIED HIGH-RISK GROUPS:  INTERACTIVE RESEARCH AND
DEVELOPMENT PROJECTS, and the RFA number CA-97-005, must be typed in
line 2 of the face page and the YES box must be marked.
 
A signed, typewritten original of the application, including the
Checklist and three signed, clear, and single-sided photocopies must
be submitted in one package to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892
BETHESDA, MD 20817 (for express/courier service)
 
At the same time, two additional copies of the application must also
be sent to:
 
Ms. Toby Friedberg
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 May 22, 1997.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) 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 DRG will not accept
any application that is essentially the same as one already reviewed.
this does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
 
Preparation of the Application
 
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), should 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 Procedures
 
Upon receipt, applications will be reviewed by the Division of
Research Grants (DRG) 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
 
Review Criteria for the Overall Proposed Research
 
o The significance and importance of the objectives.  Basic and
clinical scientific significance, as well as originality of the
proposed research.
 
o The qualifications of the Principal Investigator to serve as both
the scientific and administrative leader of the overall proposed
research.  The Principal Investigator should be an established
scientist with a substantial record of independent research.
 
o The adequacy of the commitment (percent effort) of the Principal
Investigator to the proposed research.  There should be a specific
commitment to both the scientific and administrative aspects of the
proposed research though it is not mandatory that the Principal
Investigator be a project leader of an individual research project.
 
o The presence of an organizational and administrative structure
appropriate for effective attainment of the proposed research
objectives.
 
o The mechanisms for internal quality control of the research.
Adequacy of methods for data and tissue collection and storage.
 
o The institutional environment in which the research is conducted,
including the availability of space, equipment and patients as well
as the physical proximity of program participants.
 
o The appropriateness of the size of the proposed research. The
proposed research should be large enough to achieve synergy and
economies not provided by a collection of separate research grants.
The proposed research must consist of three or more scientifically
meritorious projects.  On the other hand, the proposed research
should be small enough to focus efforts on a central theme and to
allow the effective scientific and administrative direction by the
Principal Investigator.
 
o Adequacy of adherence to guidelines for including gender and
minority representation in any study population. Documentation of
prior successful accrual.
 
Review Criteria for Projects - The significance of the specific
scientific objectives or hypotheses of the project in the context of
the proposed research.
 
o The quality of the experimental approach and research plan.  This
may be supported by results from preliminary or related studies.
 
o The qualifications, experience and commitment (percent effort) of
the project leader and investigators responsible for the individual
research project.  Project leaders must demonstrate a capability for
independent research, often evidenced by a record of peer-reviewed
support.
 
o The adequacy of the proposed means for early detection of and
protection against potential adverse effects upon humans, animals, or
the environment.
 
o The appropriateness of the statistical design and mechanism for the
rigorous management and verification of research data.
 
o The appropriateness of the budget.  A realistic budget reflects the
project leader's understanding of the scope of work.
 
AWARD CRITERIA
 
The earliest feasible start date for the initial awards will be
September 1997.  Besides technical merit, NCI will base funding
decisions on how well the applicant institutions meet the goals and
objectives of the program described in the RFA, as well as on
availability of resources and study populations.
 
INQUIRIES
 
Written and telephone inquiries concerning the RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.
 
Inquiries regarding programmatic issues may be directed 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.nih.nci.gov
 
Inquiries regarding fiscal matters may be addressed 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
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance Number 93.399, Cancer Control.  Awards will be made under
authority 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 258); and
administered under PHS grant policies and Federal Regulations 42 CFR
Parts 52 and 45 CFR Part 74.  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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