Full Text CA-96-011
 
COOPERATIVE FAMILY REGISTRY FOR EPIDEMIOLOGIC STUDIES OF COLON CANCER
 
NIH GUIDE, Volume 25, Number 20, June 21, 1996
 
RFA:  CA-96-011
 
P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Epidemiology 
  Registries+ 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  August 6, 1996
Application Receipt Date:  September 20, 1996
 
PURPOSE
 
The Extramural Programs Branch, Epidemiology and Biostatistics
Program, Division of Cancer Epidemiology and Genetics, National
Cancer Institute (NCI), and the Early Detection Branch, Division of
Cancer Prevention and Control, NCI invite Cooperative Agreement
applications from investigators to participate, with the assistance
of the NCI, in a network of organizations constituting a Cooperative
Family Registry for Colorectal Cancer Studies (CFRCCS).
 
The purpose of the proposed awards is to stimulate a cooperative
effort to:
 
1. Collect pedigree information, epidemiological data and related
biological specimens from patients with a family history of colon
cancer in order to provide a registry resource for interdisciplinary
studies on the etiology of colon cancer, and to encourage
translational research in this area.
 
2. Identify a population at high risk for colon cancer that could
benefit from new preventive and therapeutic strategies.
 
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), Cooperative Family Registry for Colon Cancer
Studies, relates 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 non-profit and
for-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.
 
MECHANISM OF SUPPORT
 
Support of this program will be through the cooperative agreement
(U01), an assistance mechanism in which substantial NCI scientific
and programmatic involvement with the recipients during performance
of the planned activity is anticipated.  Under the cooperative
agreement, the NIH intention is to support and/or stimulate the
recipient's activity by involvement in, and otherwise working jointly
with, the awardee in a partner role, but is not to assume direction,
prime responsibility, or a dominant role in the activity.  This
mechanism is appropriate because the participant organizations will
be responsible for defining their scientific objectives and
approaches.  Substantial NCI involvement is anticipated in order to
facilitate interaction between the groups, to coordinate their
efforts with other ongoing initiatives, and to promote the knowledge
and use of this resource among the scientific community.  Details of
the responsibilities, relationship and governance of the study to be
funded under cooperative agreements are discussed later in this
document under the section "Terms and Conditions of Award."
 
The total project period for applications submitted in response to
the present RFA should not exceed four years. The anticipated award
date is April 1, 1997.  Because the nature and scope of the research
proposed in response to this RFA may vary, it is anticipated that the
size of an award will vary also.  Awards and level of support depend
on the 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 pursuant to this RFA are
contingent upon the availability of funds for this purpose.
 
This RFA is a one-time solicitation.  At this time, the NCI has not
determined whether or how this solicitation will be continued beyond
the present RFA.
 
FUNDS AVAILABLE
 
Approximately $3 million in total costs per year for four years will
be committed to specifically fund applications which are submitted in
response to this RFA.  It is anticipated that two to five awards will
be made.  This funding level is dependent on the receipt of a
sufficient number of applications of high scientific merit.
 
RESEARCH OBJECTIVES
 
Background
 
Recommendations from a panel of scientists convened at the first
conference on "Genetic Epidemiology of Cancer: an Interdisciplinary
Approach", published in 1994, stated that a resource should be
created to support the identification of families with increased
occurrence of cancer with a recognized genetic component, to initiate
the coordinated collection of pertinent clinical and epidemiologic
data and biological specimens, and to establish a much needed
resource for interdisciplinary and translational studies on the
etiology of cancer.  As new knowledge about cancer molecular genetics
increases at an extremely rapid pace, these family registries would
create and preserve a resource that would otherwise be lost, provide
the infrastructure for population-based and collaborative studies
that cannot easily be supported through traditional
investigator-initiated research grants, and provide the opportunity
to design appropriate intervention and therapeutic approaches for the
high-risk populations so identified, as well as developing
appropriate genetic counseling strategies for this at-risk
population.
 
This proposed cooperative agreement, responding to the above and to
further specific recommendations from a recent workshop on "Genetic
Screening for Colorectal Cancer", is intended to complement and
expand previous family registry initiatives by creating a Cooperative
Family Registry for Colorectal Cancer Studies (CFRCCS).
 
Colorectal cancer is the third most common malignancy in the world.
In the U.S. over 157,000 people are diagnosed with colorectal cancer
each year, and 60,500 die of this disease annually.  Mortality from
colorectal cancer has changed very little in the last 50 years, and
early detection is one of the most important factors for a good
prognosis.  It is estimated that approximately 10 to 15 percent of
colorectal cancer is familial, and that one person in 200 may carry
high-risk alleles of the genes causing inherited colorectal cancer.
It is also estimated that the same genes may be involved in as much
as 13 percent of sporadic tumors.
 
Currently, germline mutations of several identified genes have been
shown to be responsible for hereditary forms of colorectal cancer.
Familial adenomatous polyposis (FAP) is a rare inherited condition
leading to colorectal cancer.  Even though the clinical
characteristics of this disease were first described more than one
hundred years ago, its molecular bases are only now being elucidated.
Germline mutations of the APC gene seem to be responsible for this
condition.  The APC gene was mapped to the long arm of chromosome 5
in 1991.  The APC gene is involved as well in the etiology of Gardner
syndrome, a variant of familial polyposis in which desmoid tumors,
osteomas, and other neoplasms occur together with multiple adenomas
of the colon and rectum.
 
Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most
common cancer susceptibility syndromes.  It is characterized by
dominant transmission and high penetrance.  Families with HNPCC are
delineated as having at least three relatives in two generations with
colorectal cancer, with one diagnosed before age 50. These families
also have elevated incidence of cancers of the endometrium, stomach,
urinary tract, and other sites. Four different mismatch repair genes
have been implicated recently in the etiology of HNPCC.  Mutations in
hMSH2, mapping to chromosome 2 and to the gene that encodes a human
homologue of the E.coli mismatch repair protein mutS, account for the
majority of cases of HNPCC. Mutations in hMLH1, homologue of the
bacterial repair gene mutL, map to chromosome 3 and are also found in
families with HNPCC.  Mutations in hPMS1 and hPMS2, encoding
homologues of the bacterial MutL and yeast PMS1, are thought to
account for a minor fraction of HNPCC.  In families with HNPCC a
mutation of one gene copy is inherited, and a somatic mutation in the
second copy is associated with a particular form of genetic
instability termed microsatellite instability or replication error
(RER).
 
Microsatellite instability is caused by slippage of one strand
relative to the other, and consequent increases of oligonucleotides
containing repetitive sequences.  Such defects are usually repaired
by mismatch repair genes. The implication of this observation is that
lack of mismatch repair causes the accumulation of mutations at
increased rate in key oncogenes or tumor suppressor genes, thus
speeding the development of malignancy.  In addition, the observation
of microsatellite instability in a variety of sporadic tumors seen in
the syndrome suggests that somatic mutations, or low penetrance
germline mutations causing mismatch repair defects, may be the cause
of a significant portion of many types of cancers seen in the general
population.  The ongoing identification of additional susceptibility
genes for colorectal cancer will soon make it possible to fully
characterize hereditary cancer patients and high-risk relatives and
provide them with an assessment of their cancer risk using molecular
techniques.  However, much knowledge needs still to be acquired and a
higher grade of technical development achieved, before this strategy
becomes applicable to the general population.
 
It is an NCI commitment to reduce morbidity and mortality from
malignancies, and a currently pressing issue is how the recent
advances in colon cancer genetics and genetic epidemiology can be
translated into public health strategies aimed at early detection.
An important strategy is predictive testing through the use of
molecular genetic assays to detect inherited cancer-predisposing
mutations in clinically healthy individuals. Appropriate and timely
translation of discoveries in molecular genetics into the reduction
of morbidity and mortality for inherited forms of cancer through
predictive testing will entail seeking the answer to a series of
immediate and specific scientific questions which are beyond the
laborious task of gene identification.
 
The CFRCCS will facilitate high-priority multidisciplinary
investigations necessary to complete the translational research
process that will lead to the application of predictive testing for
colorectal cancer susceptibility in high-risk populations, and to the
design of effective prevention and therapeutic approaches.  Such
investigations may include, but are not limited to: mutational
analysis to determine the spectrum of significant mutations versus
rare polymorphisms; the study of the penetrance of these inherited
mutations (age-dependent risk of being affected in mutation
carriers), their expressivity (organ and tissue affected) and the
clinical consequences (natural history of the disease); the study of
gene penetrance, gene-gene interaction, and the interaction with
factors influenced by lifestyle, such as dietary, and reproductive
and hormonal factors; and the study of the ethical, legal, and social
implication of genetic testing for colorectal cancer and associated
syndromes.
 
Research Goals and Scope
 
The purpose of this RFA is to stimulate a collaborative effort for
the establishment of a cooperative family registry for epidemiologic
and interdisciplinary studies of individuals at high risk for
colorectal cancer.  A population-based approach, utilizing resources
such as the SEER registries, or other cancer registries, is strongly
encouraged.  Limited funding will be available for pilot or
feasibility studies using the family registry resources, to provide
preliminary data for the subsequent submission of regular research
grant applications in epidemiologic, prevention or basic biological
research.
 
Many different approaches to colon cancer research will be able to
take advantage of family registry resources, as new knowledge and
molecular tools become available.  The existence of the CFRCCS would
enhance the cost-effectiveness of:  (1) the identification and
follow-up of high-, intermediate-, and low-risk individuals for the
purpose of preventive intervention; (2) the evaluation of the
effectiveness of optional treatment strategies as they become
available; (3) molecular epidemiology studies generating and testing
etiologic hypotheses; and (4) the integration of laboratory studies
on cancerogenic mechanisms with epidemiologic and genetic data for
colorectal cancer.
 
Current epidemiologic studies of familial colorectal cancer are
limited by the feasibility and expense of collecting a sufficient
number of high- and intermediate-risk families to define the genetic
heterogeneity of the familial disorder.  Moreover, as new statistical
approaches become available to explore the interaction between
genetic and environmental factors in the etiology of colorectal
cancer, the collection of appropriate epidemiologic data on exposure
to potential risk factors in high-risk families becomes extremely
important.  Other limitations are the lack of archival or
fresh-frozen tissue specimens and blood samples, and the difficulty
in collecting and validating clinical and epidemiologic data, and the
lack of population-based controls.
 
The CFRCCS will enable participant organizations to: identify
individuals with a family history of colorectal cancer and various
familial syndromes that include colorectal cancer and propose the
best sampling design to this end; collect and define the related
pedigrees; and collect clinical (tumor type, stage at diagnosis,
hormonal evaluation, etc), epidemiologic (age at diagnosis,
sociodemographic status, risk factors, etc.), and other relevant
baseline and follow-up data (such as treatment history) to correlate
with pedigree information.  Support for collection of
population-based controls may be included.  Support for the
collection, processing, and storage of related biological specimens,
including at a minimum blood samples and paraffin blocks, must be
included.  Support for molecular genetic analyses of participants may
be included.  The CFRCCS is intended to assist investigators funded
through other sources by providing data and biological specimens to
be used for multidisciplinary and translational studies on the
etiology of colorectal cancer and associated syndromes, and to
identify a population at high-risk that could be prospectively
followed for the purpose of prevention and treatment-oriented
research.
 
The applicants should demonstrate the capability and willingness to
develop common protocols during the first six months of the award,
including but not limited to:
 
o ascertainment of colorectal cancer patients and families
o epidemiologic, family history, and clinical data collection.
validation, and management (statistical support)
o collection and banking of biological specimens
o follow-up for outcomes, recurrence, and mortality
o appropriate genetic counseling of patients and family members
 
The awardees should demonstrate capability and willingness to provide
the data so collected to a central NCI coordinating database.  The
awardees will provide to the research community at large pedigree
information, epidemiological data, and biological specimens for high-
priority research studies.  It is anticipated that prioritization of
the research study proposals requesting access to the CFRCCS'
resources will be made by an Advisory Committee (AC), and will be
based on scientific validity criteria established by the Steering
Committee (SC) as described below:  The NCI will help to coordinate
and promote this process through the Program Coordinator's membership
in these committees.
 
SPECIAL REQUIREMENTS
 
A number of issues need to be discussed by the applicants to promote
the development of a CFRCCS site.
 
Applicants are encouraged to submit and describe their own ideas on
the best scientific approach to meet the goals of this RFA.
Applicants must propose detailed plans for how to organize the CFRCCS
in the most cost- effective and scientifically sound manner, as well
as their plans for establishing collaborations.  Advantages and
disadvantages of the proposed approaches should be discussed.  Plans
should describe resources, including the availability of probands and
a reasonable estimate of the expected availability and quality of
pedigree information and related epidemiological data and biological
specimens.
 
Each application must have an Operation Core for statistical and
logistic support, capable of providing the necessary coordination for
specimen and data collection, and functioning as a central facility
at the applicant's institution for management and storage of data and
specimens.  Appropriate data retrieval and data management procedures
and quality control methods for the epidemiological and clinical
data.  Procedures for quality control for specimen collection and
storage and pathology review should be described.  Applicants must
address coordination of quality control among awardees with regard to
collection and storage of data and specimens and state their
willingness to cooperate with other awardees in developing policies
for quality control and to share data and protocols with other
awardees, as well as providing the collected data to a central NCI
coordinating database.  The Operation Core should be adequately
described, including the facilities for data collection and storage
and specimen storage, as well as the investigators' experience in
this area.  The applicants must provide details on appropriate
facilities and biohazard precautions and comply with the applicable
Federal, State, and Local regulations, laws and finances in the
operation of the Registry.
 
Information on the nature of the data collected at baseline and
follow-up should be provided.  Examples of data forms, epidemiologic
questionnaire, medical records and abstracting procedures, and
software that may be appropriate for the use of the CFRCCS should be
included in the appendix.  Methods should be proposed to retrieve and
establish an inventory of biological specimens, such as blood,
fresh-frozen tissue, tissue blocks and slides. Procedures for quality
control of specimens, storage and pathology review should be
described.
 
Applicants should discuss their rationale for the selection of
families and controls to be included in the CFRCCS site, should
document their ability to recruit a sufficient number of
participants, must be able and willing to interact effectively with
each other, and should state their willingness to follow the common
"core" protocols that will be developed and agreed upon during the
first six months of the registry.
 
The applicants should demonstrate the capability for developing
common protocols including, but not limited to:
 
o ascertainment of colorectal cancer families;
 
o epidemiologic and clinical data collection, validation and
management (statistical support);
 
o collection and banking of biological specimens (blood and tissues);
 
o follow-up for cancer treatment, recurrence, mortality, and core
epidemiologic data;
 
o counseling of family members on risk and possible preventive or
therapeutic interventions.
 
The applicants must state a willingness and should discuss their
approach to cooperate with the SC and the AC in evaluating research
proposals utilizing the CFRCCS resources, and to abide by the
decisions of the AC in prioritizing such proposals, after final
approval by the SC based on data and specimen availability.
 
The applicant should provide the name and qualifications for the
second investigator from his/her Institution to be designated as a
member of the SC.  As the principal investigators of the funded
applications and one designee will be members of a SC which will meet
three times in the first year and twice in each subsequent year,
travel funds for these meetings should be set aside as a budget item.
As the AC will meet with the SC once a year, funds should also be
included to support travel by one member of the AC to one SC meeting
once a year, plus any additional travel anticipated for AC members.
 
Study Organization and Function
 
The overall structure of the CFRCCS will consist of two to five
funded Institutions (awardees) that are governed and coordinated
through the SC.  Each awardee unit will be composed of one funded
site, an Operation Core at the funded site, and a P.I. providing the
scientific and administrative leadership for the unit and serving as
the Head of the Operation Core.
 
The overall function of the CFRCCS is to promote multidisciplinary
and translational research in the framework of studies in the genetic
epidemiology of colorectal cancer, by serving as a national resource
to the research community at large.  Requests for specimen and data
from the awardees and their collaborators will be reviewed,
prioritized by the AC, and approved by the SC along with all other
requests from investigators in the research community at-large.
 
The Terms and Conditions of Award, below, will be included in all
awards issued as a result of this RFA. It is critical that each
applicant include specific plans for responding to these terms.
 
Terms and Conditions of Award
 
These special Terms of Award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS Grant
Administration regulations at 45 CFR part 74 and 92, and other HHS,
PHS, and NIH Grant Administration policy statements.
 
The administrative and funding instrument used for this program is a
cooperative agreement (UO1), an assistance mechanism (rather than an
acquisition mechanism) in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the
NIH purpose is to support and/or stimulate the recipient's activity
by involvement in and otherwise working jointly with the award
recipient in a partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity. Consistent with
this concept, the dominant role and prime responsibility for the
activity resides with the awardee(s) for the project as a whole,
although specific tasks and activities in carrying out the studies
will be shared among the awardees and the NCI Program Coordinator.
 
1.  Awardee Rights and Responsibilities
 
Awardees will have primary rights and responsibilities to define
projects and approaches and to plan and conduct the project,
including:
 
o  The Awardee's PI will participate as a permanent member of the SC
and designate a second investigator from his/her institution to be a
permanent member of such committee;
 
o  The Awardee will work together with the other Awardees through the
SC to establish the CFRCCS operating policies, uniform core
protocols, and quality control procedures for specimens and data.
The Awardee will be required to accept and implement the common
policies and procedures approved by the SC;
 
o  The Awardee must agree to provide access to both specimens and
data to investigators both within and outside the awardee's
institutions, based on the prioritization of the research proposals
set by the AC and final approval by the SC.  The Awardee will abide
by the decisions of the SC based on recommendations from the AC;
 
o  The Awardee will retain custody of, and have primary rights to,
the data developed under this awards, subject to the Government
rights of access consistent with current HHS, PHS, and NIH policies;
 
o  Each awardee will need to implement and comply with the common
study protocols as established by the SC, and in compliance with the
agreed upon timetable, but additional elements could be appended by
individual institutions to address issues of unique interest or
capabilities in each center;
 
o  The Awardee must provide a semi-annual progress report to the EPB,
DCEG, NCI, and a copy to the chairperson of the SC, in a format that
is compatible with the annual progress report of the other awardees.
Information on the operation of the CFRCCS site as well as
performance and progress on pilot studies are to be included;
 
o  Collaboration among awardees in the reporting of findings
originated from this initiative is encouraged. Collaborative
publications among awardees and NCI are anticipated;
 
Immediately after the notification of award, the successful applicant
should also provide the name of one scientist not affiliated with
his/her Institution as a potential member of the SC.  In addition,
each applicant should provide the names and qualifications of two
scientists not affiliated with his/her Institutions as potential
members of the AC.  Letters of commitment and CV's from the potential
members of the AC and SC should be attached.
 
2.  National Cancer Institute Staff Responsibilities
 
The NCI Program Coordinator will be designated by the Chief,
Extramural Programs Branch, EBP, DCEG, NCI. He/she will have
substantial scientific-programmatic involvement during conduct of
this activity through participation in the SC and AC activities.  The
Program Coordinator will provide technical assistance, advice and
coordination, assure that the SC and the AC follow the NIH guidelines
on conflict of interest issues, and play a critical role in promoting
the availability and use of the registry.  The role of the Program
Coordinator is to assist and facilitate, but not to direct, the
activities supported by the CFRCCS.
 
The NCI Program Coordinator will:
 
o  Lend his/her expertise and overall knowledge of the NCI- and
NIH-sponsored colorectal cancer research to facilitate the selection
of scientists non-affiliated with the awardees institutions who are
to serve in the AC and SC;
 
o  Serve as liaison, helping to coordinate activities among the
awardees; act as a liaison to the NCI, and as an information resource
about extramural multidisciplinary cancer research activities in the
area of genetics and molecular epidemiology of colorectal cancer;
 
o  Attend the SC meetings as a voting member, assist in developing
operating guidelines, quality control procedures, and consistent
policies for dealing with recurrent situations that require
coordinated action;
 
o  Serve as liaison between the SC and the AC, attending AC meetings
in a non-voting liaison member role, and lending a degree of
continuity between AC and SC, as the ad-hoc AC composition may change
depending on the expertise required to review the submitted research
proposals;
 
o  Serve on subcommittees of the SC and the AC as required;
 
o  Assist in the monitoring of field data collection, helping to
ensure standardization in methods across study centers; and assist in
the interpretation and reporting of the collected information.  This
will be necessary because of the complexity of this multisite
structure, requiring an high degree of coordination and program
involvement to achieve adequate standardization of procedures;
 
o  Assist by providing advice in the management and technical
performance of the investigation.  The Program Coordinator will serve
as scientific liaison between the awardees and other program staff at
NCI who have previous experience in the establishment of cancer
registries and tumor bank;
 
o  Assist in promoting the availability of the CFRCCS resources to
the scientific community at large, for use in translational and
prevention-oriented colorectal cancer research, as stated in this RFA
goals.
 
The NCI reserves the right to reduce the budget, to withhold support,
and to suspend, terminate or curtail a study or an award in the event
of substantial shortfall in specimen accrual, data reporting,
inadequate quality control in specimens or clinical data collection,
non-adherence to biohazard precautions, refusal to carry out the
recommendations of the SC and AC, or substantial failure to comply
with the terms of the award.
 
3. Collaborative Responsibilities
 
a.  Steering Committee
 
The SC will serve as the main governing board of the CFRCCS (see
"Terms and Conditions of Award").  The SC membership includes the NCI
Coordinator, the P.I., one other investigator from each awarded
cooperative agreement, and one research scientist with expertise in
the field of multidisciplinary and translational colorectal cancer
research who is not affiliated with any of the awardees institutions.
This last member will be appointed by mutual agreement of the NCI
Coordinator and the PI's.  Additional members can be added by action
of the SC.  Other appropriate NCI staff may need to attend the SC
meetings if their expertise is required, to participate in specific
discussions.
 
The SC will be responsible for reviewing the plans for development of
the CFRCCS proposed in the individual applications of the awardees.
This Committee will develop uniform procedures for data collection
and management, tissue collection, processing and distribution, and
quality control.  The SC will develop the criteria for review and
prioritization of research proposals requiring the use of the
CFRCCS's resources. The NCI Program Coordinator will assist the other
members of the SC in all these tasks.  Furthermore, the NCI Program
Coordinator will serve as the scientific liaison between the awardees
and the other program staff of NCI who have previous experience in
the establishment of family cancer registries.  Awardees will be
required to accept and implement the common guidelines and procedures
approved by the SC.
 
The first meeting of the SC will be called by the NCI Program
Coordinator shortly after award of the cooperative agreements.  At
this initial meeting, the Committee will elect a Chairperson (someone
other than the Program Coordinator).  The Chair of the SC is
responsible for coordinating the Committee's activities, for
preparing meeting agendas, and for scheduling and chairing meetings.
The Program Coordinator attends and participates in all meetings of
the SC, and should be informed of any major interactions.  Subsequent
meetings will be planned and scheduled at this meeting.  Two
additional meetings will be held during the first year of operation,
and there two meetings a year thereafter, one of which with the AC.
The meetings will be held in Bethesda or at another convenient
location.  Accordingly, respondents must request sufficient funds
within the submitted budgets to accommodate travel expenses for the
P.I. and his designee.  Subcommittees will be established by the SC
as it deems appropriate.
 
The SC will be responsible for confirming the availability and
accessibility of specimens and data for use by investigators
requesting the use of the registry resources for approved research
proposals.  In no circumstance will the SC overturn the
recommendation of the AC, except when specimens and/or data are not
available.
 
The SC will select members for the AC.  The SC, in the conduct of all
business matters, will pay particular attention to conflict of
interest issues, and will bring such matters to the attention of the
AC and of the NCI Program Coordinator.
 
b.  Advisory Committee
 
The AC is responsible for reviewing, evaluating and approving
research proposals submitted by investigators from the research
community at large, as well as from the awardees, for the use of the
registry resources.  A recommendation in terms of priority of the
proposed research will be provided to the SC after review of each
application.  The AC will meet with the SC at least once yearly, at
one of the two scheduled SC meetings. Accordingly, respondents must
request sufficient funds in the submitted budget to accommodate
travel expenses of the selected AC members.
 
The AC will be composed of senior scientists with expertise in
multidisciplinary and translational research in the field of
colorectal cancer, which may include epidemiologists, laboratory
researchers, clinicians, or other expertise that the SC deems needed.
The membership of the AC may vary, depending on the scientific areas
of the proposed research to be reviewed and evaluated, and temporary
"ad hoc" members can be selected if additional expertise is required
for specific applications.  All members will be selected by the SC
(two nominee per awarded site).  The tenure of the permanent AC
members will be of two years.  The Program Coordinator will function
as a non-voting liaison member between the AC and the SC, and attend
the AC meetings.
 
The members of the AC will evaluate all research proposals (those of
the awardees as well as from the research community at large)
proposing to utilize the CFRCCS resources, according to the
evaluation and review criteria provided by the SC.  The review of
proposals can be conducted either in person, by conference call or by
mail at least twice a year.  All reviews will be conducted according
to rules pertaining to the conduct of reviews for NIH grants,
contracts, and cooperative agreements and to the review criteria
developed by the SC, paying special attention to issues of conflict
of interest, whether real or apparent.  The AC will provide a
recommendation to the SC as to the priority of the proposed research.
The AC Chair will forward the final recommendation to the SC.  The AC
will provide advice to the SC on scientific matters as appropriate
and needed.
 
4.  Arbitration Procedures
 
Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between the award recipients and the
NCI may be brought to arbitration.  An arbitration panel will be
composed of three members, one selected by the SC (without the vote
of the Program Coordinator) or by the individual awardee in the event
of an individual disagreement, a second member selected by the NCI,
and the third member selected by the two prior selected members.
This special arbitration procedure in no way affects the awardee's
right to appeal an adverse action that is otherwise appealable in
accordance with the PHS regulation at 42 CFR part 50, subpart D and
HHS regulation at 45 CFR part 16."
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulation 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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
 
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 of March 28, 1994 (59 FR 14508-14513) and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23, Number 11,
March 18, 1994.
 
Investigators may obtain copies of the policy from these sources or
from the program staff or contact person listed below.  Program staff
may also provide additional relevant information concerning the
policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by August 6, 1996, a
letter of intent that includes a descriptive title of the proposed
research, the name, address and telephone number of the Principal
Investigator, the identities of other key personnel, the
participating institution(s), and the number and title of the RFA in
response to which the application may be submitted.
 
Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the
information that it contains allows NCI staff to estimate the
potential review workload and avoid conflict of interest in the
review.  The letter of intent is to be sent to Dr. Daniela Seminara,
at the address listed under INQUIRIES.
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Extramural Outreach and Information Resources, National
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD
20892-7910, telephone 301-710-0267, e-mail:
[email protected].
 
A number of issues need to be discussed by the applicants to promote
the development of a CFRCCS site.  Applicants are encouraged to
submit and describe their own ideas on the best scientific approach
to meet the goals of this RFA.  Applicants must propose detailed
plans for how to organize the CFRCCS in the most cost-effective and
scientifically sound manner, as well as their plans for establishing
collaborations.  Advantages and disadvantages of the proposed
approaches should be discussed.  Plans should describe resources,
including the availability of probands and a reasonable estimate of
the expected availability and quality of pedigree information and
related epidemiological data and biological specimens.
 
Each application must have an Operation Core for statistical and
logistic support, capable of providing the necessary coordination for
specimen and data collection, and functioning as a central facility
at the applicant's institution for data and specimens management and
storage.  Appropriate data retrieval and data management procedures
and quality control methods for the epidemiological and clinical
data.  Procedures for quality control for specimen collection and
storage and pathology review should be described.  Applicants must
address coordination of quality control among awardees with regard to
collection and storage of data and specimens, state their willingness
to cooperate with other awardees in developing policies for quality
control and to share data and protocols with other awardees, as well
as providing the collected data to a central NCI coordinating
database.  The Operation Core should be adequately described,
including the facilities for data collection and storage and specimen
storage, as well as the investigators' experience in this area.  The
applicants must provide details on appropriate facilities and
biohazard precautions and comply with the applicable Federal, State,
and Local regulations, laws and finances in the operation of the
Registry.
 
Information on the nature of the data collected at baseline and
follow-up should be provided.  Examples of data forms, epidemiologic
questionnaire, medical records and abstracting procedures, and
software that may be appropriate for the use of the CFRCCS should be
included in the appendix.  Methods should be proposed to retrieve and
establish an inventory of biological specimens, such as blood,
fresh-frozen tissue, tissue blocks and slides. Procedures for quality
control of specimens, storage and pathology review should be
described.  Applicants should discuss their rationale for the
selection of families and controls to be included in the CFRCCS site,
should document their ability to recruit a sufficient number of
participants, must be able and willing to interact effectively with
each other, and should state their willingness to follow the common
"core" protocols that will be developed and agreed upon during the
first six months of the registry.
 
The applicants should demonstrate the capability for developing
common protocols including, but not limited to: the ascertainment of
colorectal cancer families; the collection of epidemiologic, family
history and clinical data and their validation and management; the
collection and banking of biological specimens; follow-up of the
identified population for cancer treatment, recurrence, mortality,
and core epidemiologic data; and the appropriate counseling of family
members on risk and possible preventive or therapeutic interventions.
 
The applicants must state a willingness and should discuss their
approach to cooperate with the SC and the AC in evaluating research
proposals utilizing the CFRCCS resources, and to abide by the
decisions of the AC in prioritizing such proposals, after final
approval by the SC based on data and specimen availability.
 
The applicant should provide the name and qualifications for the
second investigator from his/her Institution to be designated as a
member of the SC.  As the principal investigators of the funded
applications and one designee will be members of a SC which will meet
three times in the first year and twice in each subsequent year,
travel funds for these meetings should be set aside as a budget item.
As the AC will meet with the SC once a year, funds should also be
included to support travel by one member of the AC to one SC meeting
once a year, plus any additional travel anticipated for AC members.
 
Of the funds provided by this RFA, at least 90% of the total cost
proposed in each application must be directed to the basic CFRCCS
activities (accrual of families, data and specimen collection,
management, and retrieval).  Up to 10% of the total cost, or $50,000
per year (whichever is smaller, starting from the second year of the
cooperative agreement), can be requested for pilot or feasibility
studies utilizing the family registry resources.  Applicants seeking
these funds for pilot studies utilizing the CFRCCS resources, should
document their ability to conduct colorectal cancer research and
document any of their ongoing work in this area.  The research
hypothesis, background and rationale and design of the pilot study
should be described as part of the research plan, keeping within the
allowed page limits. The SC and the AC will review the pilot studies
proposed in the application in response to this RFA even if the
studies received approval under peer review.  Moneys for pilot
studies will be restricted until the AC gives these pilot studies
high priority ratings, and the requested specimens and/or data are
available and have been released by the SC.  The review of these
pilot studies will occur along with the review and prioritization of
other requests submitted by investigators in the research community
at large.  The pilot studies will begin no sooner than year two of
the cooperative agreement. However, if the AC does not rank the pilot
project as a high priority, a new pilot study that is rated as high
priority by the AC can be substituted.
 
Pilot/feasibility studies should be designed to obtain sufficient
data to form the foundation for future RO1 research grant
applications, to help identify new areas where additional
investigations are warranted, and to promote interdisciplinary and
translational colorectal cancer research.
 
The RFA label available in the application form PHS 398 (rev. 5/95)
must be affixed to the bottom of the face page.  Failure to use this
label could result in delayed processing of the application such that
it may not reach the review committee in time for review.  In
addition, the number and title of the RFA must be typed on line 2a of
the face page of the application and YES must be checked.
 
Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies in one package to
the Division of Research Grants at the address below.  The
photocopies must be clear and single sided.
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, SUITE 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 be sent to:
 
Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD 20892
 
It is important to send these copies at the same time that the
original and three copies are sent to DRG; otherwise, the NCI cannot
guarantee that the application will be reviewed in competition with
other applications received on or before the designated receipt date.
 
Applications must be received by September 20, 1996.  If an
application is received after that date, it will be returned to the
applicant without review.  If the application submitted in response
to this RFA is substantially similar to a research grant application
already submitted to the NIH for review, but has not yet been
reviewed, the applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.  Therefore,
an application cannot be submitted in response to this RFA that is
essentially identical to one that has already been 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.
 
REVIEW CONSIDERATIONS
 
General Considerations
 
All applications will be judged on the basis of the scientific merit
of the proposed project and the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA.  Although
the technical merit of the proposed protocol is important, it will
not be the sole criterion of evaluation of a study.  Other
considerations, such as the importance and timeliness of the proposed
study, access to patients, and multidisciplinary and translational
nature of the studies, will be part of the evaluation criteria.
 
Review Method
 
Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NCI. Incomplete applications will be
returned to the applicant without further consideration.  If NCI
staff find that the application is not responsive to the RFA, it will
be returned for further consideration.
 
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NCI in accordance to the review criteria
stated below.  As part of the initial merit review, all applications
will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the National Cancer Advisory Board.
 
Review Criteria
 
Applicants are encouraged to submit and describe their own ideas
about how to best meet the goals of the cooperative study and their
specific protocols, and are expected to address issues identified
under SPECIAL REQUIREMENTS of the RFA.
 
The review group will assess the scientific merit of the protocols
and related factors, including:
 
o  extent to which the application addresses the goals and objectives
of the RFA;
 
o  adequacy of the applicant's plans for addressing the special
scientific and technical program requirements presented in the RFA;
 
o  merit of the proposed activities and organizational plans for
implementing the CFRCCS;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  time availability of the PI and staff;
 
o  availability of, and access to, a suitable patient population;
 
o  adequacy of existing physical facilities and resources of the
applicants' Institutions;
 
o  demonstrated ability and willingness to carry out common protocol;
 
o  adequacy of plans for effective cooperation and coordination among
participating awardees and the NCI Program Coordinator, as per
Special Requirements of the RFA;
 
o  adequacy of proposed number of study subjects to be recruited and
plans for inclusion of minorities;
 
o  adequacy of proposed data to be collected and procedures for data
handling, managing, and preparing for analyses;
 
o  evidence that appropriate steps have been taken to insure the
rights of human subjects;
 
o adequacy of the proposed plan to provide counseling appropriate for
the CFRCCS activities
 
o  the scientific and technical significance or originality of the
proposed pilot studies in the field of translational colorectal
cancer research.  It is to be noted that the review of this part of
the grant application will be given much less weight relative to the
review of the registry facilities, procedures and epidemiological
data base, as no more than 10 percent of the total cost, or up to $
50,000 per year for three years (whichever number is smaller,
starting the second year of the Cooperative Agreement) may be
requested for these studies.
 
The review group will also examine the proposed budget and will
recommend an appropriate budget and period of support for each
application that is recommended for further consideration.
 
The second level of review by the National Cancer Advisory Board
considers the special needs of the Institute and the priorities of
the National Cancer Program.
 
AWARD CRITERIA
 
The earliest anticipated date of award is April 1, 1997. The
following will be considered for making funding decisions:
 
o  scientific and technical merit of the proposed project as
determined by peer review;
o  adequate effort to represent the minority groups in the population
sampled;
o  availability of funds;
o  program balance among research areas.
 
INQUIRIES
 
Written and telephone inquiries concerning the RFA and the
opportunity to clarify any issues or questions from potential
applicants are welcome.
 
Direct inquiries regarding programmatic and scientific issues to:
 
Dr. Daniela Seminara
Extramural Programs Branch
National Cancer Institute
Executive Plaza North, Suite 535
6130 Executive Boulevard MSC 7395
Bethesda, MD  20892-7395
Telephone:  (301) 496-9600
Email:  [email protected]
 
Direct inquiries regarding fiscal matters to:
 
Ms. Catherine Blount
Grants Management Branch
National Cancer Institute
6120 Executive Boulevard
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 262
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.393, Cancer Cause and Prevention Research.  Awards
are made under authorization of the Public Health Service Act, Title
IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42
USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR Part 52 and 45 CFR Part 74 and 92.  This
program is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems Agency review.  Unless
otherwise noted all PHS grants policies apply.
 
The PHS strongly encourages all grant 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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