Subject: RFACA-91-08 2/l5/9l NIH Guide
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 14 Feb 91 14:52 EST

Hi Pual,
 Please post to the NIH Listserver as: RFACA-91-08.910215
                Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR COOPERATIVE AGREEMENT APPLICATIONS
 
RFA:  CA-91-08
 
PREVENTION CLINICAL TRIALS UTILIZING INTERMEDIATE ENDPOINTS
AND THEIR MODULATION BY CHEMOPREVENTIVE AGENTS
 
P.T. 34; K.W. 0755015, 0740018, 0715035, 0710095
 
National Cancer Institute
 
Letter of Intent Receipt Date:  April 1, 1991
Application Receipt Date:  May 24, 1991
 
I.   INTRODUCTION
 
The Division of Cancer Prevention and Control (DCPC), National
Cancer Institute (NCI), invites applications for cooperative
agreements to support clinical trials directed toward examining
the role of various chemopreventive agents and/or diet in the
prevention of cancer.  This is a follow-up to earlier Requests
for Applications (RFAs) that had requested grant applications,
and then later, cooperative agreement applications in this area.
 
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, Cooperative Agreements for
Prevention Clinical Trials Utilizing Intermediate Endpoints
and Their Modulation for Chemopreventive Agents, is related
to the priority area of cancer.
 
The primary objective of this solicitation is to encourage
cancer chemoprevention clinical trials that utilize
biochemical and biological markers to identify populations
at risk and/or to provide intermediate endpoints that may
predict later reduction in cancer incidence rates.
 
These studies may be developed in phases, including a pilot
phase, that could later proceed to a full-scale
intervention.  The main emphasis should be on small,
efficient studies aimed at improving future research designs
of chemoprevention trials, providing further biologic
understanding of the trial results, or providing better,
more quantitative and more efficient endpoints for these
trials.  After successful completion of the pilot phase
(i.e., demonstrated modulation of marker endpoints by the
intervention), subsequent studies can include Phase III
clinical trials involving the designated agent, the
utilization of the monitoring test system, and a cancer
incidence or mortality endpoint.
 
Investigators may apply at this time for the pilot phase or
submit an application for both phases.  However, if the
application is for the pilot phase only, it must include a
description of its relevance to a broad clinical application
including the chemopreventive agent, marker test system, and
study population that would be the subject of a full-scale,
randomized, cancer risk reduction clinical trial.
 
Applicants funded under this RFA will be supported through
the cooperative agreement mechanism.  An assistance
relationship will exist between NCI and the awardees to
accomplish the purpose of the activity.  As more fully
described later in this announcement, the recipients will
have primary responsibility for the development and
performance of the activity.  However, there will be
government involvement 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, (3)
monitoring of safety and toxicity, and (4) quality assurance
of the clinical chemistry aspects of the study.  Awards will
not be made until all arrangements for obtaining the IND and
the agent are completed.  Final awards will also consider
not only the cost of the clinical trial but also the cost of
the agent and, if necessary, its formulation.
 
This RFA solicitation represents a single competition with
a specified deadline, May 24, 1991, for receipt of
applications.  All applications received in response to the
RFA will be reviewed by the same NCI
Initial Review Group.
 
Applications should be prepared and submitted in accordance
with the aims and requirements described in the following
sections:
 
II.  BACKGROUND INFORMATION
 
A number of compounds and/or dietary components have been
associated with the inhibition of carcinogenesis in animal
models, in vitro systems, and/or epidemiologic
investigations.  Results from these studies suggest that
chemopreventive agents, including dietary components, affect
the later stages of carcinogenesis.  The best approach to
confidently address the efficacy and safety, as well as the
applicability and effectiveness, for these agents is through
the conduct of clinical trials.
 
A variety of parameters have become available and may be
used to identify or evaluate risk modulation in selected
target populations by chemopreventive agents.  Examples
include reversal of abnormal cytology, prevention or
reversal of nuclear aberrations (micronuclei), ornithine
decarboxylase and/or prostaglandin synthetase inhibition,
DNA ploidy alterations, changes in colonic mucosal
proliferation (histology, tritiated thymidine labelling
indices), decreases in fecal mutagens, and oncogene
suppression tests.  Markers of precancerous lesions may also
be useful to define populations that may benefit from
chemoprevention trials; however, more information is
required concerning the ability of such markers to predict
and/or modulate cancer incidence.  The development of
sensitive and accurate intermediate endpoints should greatly
enhance the ability to design effective cancer risk
reduction trials.
 
Chemoprevention clinical trials involve a spectrum of
subjects in various categories of risk.  These might involve
normal human subjects, subjects at high risk due to prior
exposure to carcinogens, subjects with precancerous lesions,
patients having been treated for a primary cancer now free
of disease, and patients treated for primary cancer with
alkylating agents or radiation who are at high risk for
developing second cancers.  Methods for identification of
populations at risk and assessment of their risk of
developing cancer is, therefore, a major goal of the
chemoprevention program.  These studies are expected to
augment the efficient experimental design of clinical trials
leading to lesser number of subjects required to achieve
adequate statistical power.
 
The tests used for risk identification are also of value
because of the multi-step nature of cancer induction and the
different mechanisms by which chemopreventive agents are
known to inhibit the carcinogenic process.  Thus, it is
useful to have tests that measure genotoxic exposure as well
as tests that indicate when subjects are in the later (e.g.,
promotional, progressional) phase of the carcinogenic
process.  It should be emphasized that protocols
proposing use of assays/methods for risk identification must
also include assays that measure biochemical or biological
intermediate markers of cancer endpoints (in the pilot
phase) or measurement of the intermediate endpoints
themselves (in the later Phase III trials).
 
III. RESEARCH GOALS AND SCOPE
 
The purpose of this RFA is to solicit applications from
qualified investigators interested in developing and
implementing cancer prevention clinical trials using
biological markers.  These trials, which may be designed in
two phases, will examine the role of chemopreventive agents
alone, diet modification alone, or a combination of these
interventions.
 
A.   STUDIES OF SPECIAL INTEREST
 
Short-term chemoprevention clinical trials that evaluate the
effect of innovative biomedical monitoring tests in high-
risk populations are sought.  These tests might be useful to
determine an intermediate endpoint, serve as a basis to
assess cancer risk status or to assess response to a
chemopreventive agent.  The modulation of effects by a
chemopreventive agent on tests that are indicative of
neoplastic progression may be an early indicator of its
efficacy.  Examples of such tests might include classical
cytological techniques and suppression of oncogene protein
products.  Modulation of a biological marker by a
chemopreventive agent might be highly significant in
relation to ultimate cancer prevention.  A series of one or
more tests would be included in the chemoprevention
intervention clinical trial, initially to determine baseline
parameters and later as a followup after administration of
the chemopreventive agent.  Biological fluids, including
urine, blood, and sputum, would need to be obtained from
participants for analysis.  Priority would be given for
studies with biological monitoring procedures that do not
overlap or duplicate currently funded projects.
 
The pilot phase should attempt to detect the clinical
activity of the chemopreventive agent rapidly, efficiently,
and in reasonably accurate fashion with a relatively small
number of subjects or in an in vivo or in vitro assay.  The
pilot phase is not expected to give a definite answer to the
ultimate value of the chemopreventive agent.  That is the
purpose of a larger Phase III study.  It is expected,
however, that upon completion of a pilot study, it should be
possible to make a judgement regarding the effectiveness of
the agent to modulate the marker test system (which will be
correlated with modulation of the cancer endpoint in the
Phase III studies).  Additionally, the pilot phase is
expected to give an indication of the nature of any short-
term adverse effects related to the particular dose
schedule, information on patient compliance, ability to
measure the agent in body fluids, and any other factors
related to the subsequent clinical trial.  These factors may
provide further clarification on the need for a large, full-
scale study.
 
Intervention populations of interest might include:
individuals at high risk at selected cancer sites,
individuals with precancerous lesions, and individuals
presently free of cancer but at risk for second cancers.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION
OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES
IN CLINICAL RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA
clinical research grants and cooperative agreements will be
required to include minorities and women in study
populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need
for inclusion of minorities and women in studies of
diseases, disorders and conditions which disproportionately
affect them.  This policy is intended to apply to males and
females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly
in proposed population-based studies, a clear compelling
rationale should be provided.
 
The composition of the proposed study population must be
described in terms of gender and racial/ethnic group.  In
addition, gender and racial/ethnic issues should be
addressed in developing a research dosing and sample size
appropriate for the scientific objectives of the study.
This information should be included in the form PHS 398 in
Section 2, A-D of the Research Plan AND summarized in
Section 2, E, Human Subjects.  Applicants/offerors are urged
to assess carefully the feasibility of including the
broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or
appropriate in all research projects to include
representation of the full array of United States
racial/ethnic minority populations (i.e., Native Americans
(including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).
 
The rationale for studies on single minority population
groups should be provided.
 
For the purpose of this policy, clinical research includes
human biomedical and behavioral studies of etiology,
epidemiology, prevention (and preventive strategies),
diagnosis, or treatment of diseases, disorders or
conditions, including but not limited to clinical trials.
 
The usual NIH policies concerning research on human subjects
also apply.  Basic research or clinical studies in which
human tissues cannot be identified or linked to individuals
are excluded.  However, every effort should be made to
include human tissue from women and racial/ethnic minorities
when it is important to apply the results of the study
broadly, and this should be addressed by applicants.
 
For foreign awards, the policy on inclusion of women applies
fully; since the definition of minority differs in other
countries, the applicant must discuss the relevance of
research involving foreign population groups to the United
States' populations, including minorities.
 
If the required information is not contained within the
application, the application will be returned.
 
Peer reviewers will address specifically whether the
research plan in the application conforms to these policies.
If the representation of women or minorities in a study
design is inadequate to answer the scientific question(s)
addressed AND the justification for the selected study
population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be
reflected in assigning the priority score to the
application.
 
All applications for clinical research submitted to NIH are
required to address these policies.  NIH funding components
will not award grants or cooperative agreements that do not
comply with these policies.
 
B.   PREPARATION OF THE PROPOSAL
 
The instructions
contained in the grant application form PHS
398 (revised 10/88, reprinted 9/89) are to be used in
preparing cooperative agreement applications.  Because of
the Terms of Cooperation included as Section V, it is
important that applicants indicate in the Research Plan how
they will meet the requirements stated in the RFA for staff
involvement.  To ensure that the cooperative agreement
remains the appropriate instrument, awardees submitting
competing continuation and supplemental applications must
describe how they have met the established terms and
conditions.
 
The following items apply to new as well as to competing
continuing proposals:
 
1.   The study must clearly address Phase I, and optionally
II.  Phase I must involve the application of a biological
and/or biochemical marker and its modulation by the study
agent.  Phase II involves the implementation of a full-scale
randomized, double-blind, risk reduction, prevention
clinical trial.  For applicants seeking to conduct only
Phase I, the study must describe relevance to a clinical
trial application including a marker, agent, and target group
that might be appropriate for a full-scale intervention
after completion of the pilot study.
 
2.   The applicant should provide a rationale for selection
of the biological or biochemical marker, its relevance to
risk identification or modulation, and its relevance to the
intervention agent and the target population.
 
3.   The applicant should provide the rationale for
selection of the proposed intervention agent.  This should
include relevant epidemiologic and laboratory data.
Preclinical and clinical data on any potential untoward
effects of the intervention agent should also be presented.
In circumstances where there might be some doubt as to the
availability or the safety of the agent, the applicant may
wish to consult with the pharmaceutical company and the NCI
Program Director prior to preparing the application.  The
applicant should thus present a reasonable case for the
"readiness" of the proposed intervention agent for a
clinical trial.
 
4.   The applicant should provide a rationale for selection
of a specific target group and provide an estimate of the
number of participants required for the completion of the
study.  Criteria and calculations used to estimate sample
size should be included.  The applicant should provide a
description of the target population or group chosen and
should justify the selection of this group.  The group
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 to its possible prevention by the
designated inhibitor(s).  The 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.   The applicant should clearly indicate the clinical
chemistry and biologic aspects of the study to include
collection, storage, handling, analysis, and quality control
of biological or biochemical samples.  The methods and
equipment to be used and the technical qualifications and
experience of the personnel involved must be addressed.  If
these aspects of the study 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.   The applicant should elucidate any known or potential
safety or toxicity considerations, the techniques and
procedures to monitor and report any adverse health effects,
and appropriate dose modifications based on toxicity
monitoring.
 
7.   The applicant should specify the methods to be used to
document nutrient intake, if indicated, and adherence to the
prescribed intervention during the course of the trial.
 
8.   The applicant must indicate a willingness to work
cooperatively with the assistance of the Program Director in
the implementation and conduct of the study.
 
IV.  MECHANISM OF SUPPORT
 
This RFA will use the cooperative agreement mechanism.  The
cooperative agreement is an assistance mechanism in which
limited NIH programmatic involvement with the recipient
during performance of the planned activity is defined.
The nature of Program Director's involvement is described in
Section V.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the
applicant/awardee.  Except as otherwise stated in this RFA,
awards will be administered under PHS grants policy as
stated in the Public Health Service Grants Policy Statement,
DHHS Publication No. (OASH) 90-50,000, revised October 1,
1990.
 
This RFA will be issued annually for three years.  However,
should the NCI determine that there is a sufficient
continuing program need, NCI may invite all funded
recipients to submit competing continuation applications.
 
Approximately $1 million in total costs per year for 3 to 5
years will be committed to specifically fund applications
that are submitted in response to this RFA.  It is
anticipated that 3 to 5 awards will be made annually.  This
funding level is dependent on the receipt of a sufficient
number of applications of high scientific merit.  The total
project period for applications submitted in response to the
present RFA should not exceed 5 years.  The earliest
feasible start date for the initial awards will be December
1, 1991.  Although this program is provided for in the
financial plans of the NCI,
awards made pursuant to this RFA will be contingent upon the
continued availability of funds for this purpose.
Non-profit and for-profit institutions are eligible to
apply.  Foreign as well as domestic institutions are
eligible.
 
V.   TERMS OF AWARD
 
These special terms of award are in addition to, and not in
lieu of, otherwise applicable OMB administrative guidelines,
HHS grant regulations 45 CFR 74 and other Health and Human
Services, Public Health Service, and NIH grants
administration policy.
 
The NCI will provide appropriate assistance, advice, and
guidance as described below.  The role of the NCI will be to
facilitate, not to direct.
 
A.   PROGRAM STAFF INVOLVEMENT
 
1.   STUDY/PROTOCOL PLAN
 
Dr. Marjorie Perloff, Program Director, Chemoprevention
Branch, DCPC, NCI, may assist the awardee in the study and
protocol design by providing information regarding:  a) the
nature of concurrent studies in the area of research,
pointing out possible duplication of effort; b) safety and
toxicity of proposed regimens; and c) the availability of
necessary drugs.  The NCI Program Director may also offer
advice regarding the scientific rationale, priority, design,
and implementation of the proposed studies.  A safety and
protocol review will be undertaken on all clinical trials
from applications that are ultimately funded.  Such a review
is legally required by the FDA to
assure that all safety, toxicity, monitoring, and reporting
issues conform with Investigational New Drug
guidelines.  The awardee institution and Principal
Investigator must agree to comply with the recommendations
of the review.
 
2.   DATA ACCESS
 
The Program Director will have access to the data to review
toxicity and safety aspects of the project, prepare IND
applications, and monitor any trial aspects required by other
federal agencies.  This information is necessary to satisfy
FDA regulations with regard to Code of Federal Regulations
(CFR) 21.  Data generated, however, are the property of the
awardee institution.  The Program Director may encourage and
facilitate sharing of data between investigators when this
is in the mutual interest of the investigators and the NCI.
 
3.   INVESTIGATIONAL NEW DRUG (IND)
 
The NCI will have the option to cross file or independently
file an IND on investigational drugs evaluated in trials
supported under the cooperative agreements.
 
The NCI will advise investigators of specific requirements
and changes in requirements concerning investigational drug
management for compliance with NCI and the FDA guidelines
and regulations.  Investigators conducting trials under
cooperative agreements will be expected, in cooperation with
the NCI, to comply with all FDA monitoring and reporting
requirements for investigational agents, for reporting
adverse reactions, and for maintaining necessary records of
drug receipt and distribution.
 
4.   ASSISTANCE WITH OBTAINING OR PURCHASING INVESTIGATIONAL
DRUGS
 
The NCI may assist the investigator to obtain the agent to
be used in the proposed study.  Once the application is
approved by the peer review committee, the NCI, the
National Cancer Advisory Board, and the NCI Program Director may
begin discussions with the Principal Investigator and
pharmaceutical industry with regard to obtaining the drug.
In the event a suitable agent is not available at no cost,
the NCI may proceed to purchase the agent through normal
procurement mechanisms.  Purchase of the agents is only
undertaken after measures to obtain the drug at no cost have
been exhausted.  Awards will not be made until all
arrangements for obtaining the agent are complete.  Final
awards by the NCI will also consider not only the cost of
the trial but also the cost of the agent, including its
formulation, encapsulation, and packaging, if these costs are
to be borne by the Government.
 
5.   PROTOCOL DISAPPROVAL
 
Protocols may be disapproved by the NCI on the basis of
patient safety and toxicity, failure to meet FDA regulations
concerning NCI-sponsored investigational drugs, obvious
duplications, or failure to satisfy the goals of the RFA or
of the awardee applications.  The Arbitration Mechanism is
described in V-8 below.
 
6.   PROTOCOL MODIFICATION
 
No protocol modifications shall be implemented without
approval from the Program Director, and also from the FDA
if indicated.
 
7.   PROTOCOL TERMINATION
 
The Program Director may request that a protocol study be
terminated.  Reasons for this request may be:  a) insufficient
accrual, b) further accrual will not add information of
scientific value, and/or c) consideration of patient safety.
The NCI will not provide drugs or IND sponsorship for a
study after requesting termination.  Investigators who wish
to challenge protocol termination may do so according to the
arbitration process described below.  If the request to
terminate a study is upheld by the arbitration panel, but
the awardee chooses to continue the study, the results of
that study will be subject to careful monitoring through
progress reports.  In addition, the NCI may withdraw funding
for such a protocol if the grounds for termination are
patient safety and toxicity.  The Arbitration Mechanism is
described in V-8.
 
8.   DESCRIPTION OF ARBITRATION MECHANISM
 
When mutually acceptable agreements on the safety of
research protocols, protocol disapproval, or protocol
termination cannot be obtained between investigators and the
NCI staff committee, as described above, an arbitration
panel composed of one member of the grant recipient group
nominated by the grantee, one NCI nominee, and a third
member with appropriate expertise chosen by the other two
members will be formed to review NCI decisions.  These
special arbitration procedures in no way affect the
awardee's right to appeal an adverse action in accordance
with PHS regulations at 42 CFR Part 50, Subpart D, and HHS
regulations at 45 CFR Part 16.
 
9.   CLINICAL TRIALS PROGRESS REVIEW
 
Progress will be evaluated semi-annually by the Program
Director from material presented in the awardee's semi-
annual report (as described in Section V.B.4.A. below).
Recommendations of the Program Director will be communicated
by letter to the investigator to which he/she is expected to
respond.
 
Insufficient numbers of patients accrued to attain the
stated delta value (d=difference between treatments to be
detected divided by standard deviation), unsatisfactory
progress, or non-compliance with terms of award may result
in a reduction of the budget, withholding of support, or
suspension or termination of the award.
 
10.  QUALITY ASSURANCE
 
a.   The NCI has established a clinical chemistry quality
assurance program with the National Institutes of Standards
and Technology, Gaithersburg, Maryland, that will provide
chemical standards for some of the agents that will be used
and assayed in the clinical trials.  These standards
will contribute to the quality control of selected
laboratory determinations.  The awardee will participate in
the laboratory quality control activity when so notified.
 
b.   Periodically, the NCI staff will review the mechanisms
established by each awardee for quality control of clinical
studies.  These mechanism must conform with
FDA regulations.
 
11.  OTHER TERMS
 
No patients may be enrolled in this study without the prior
written approval of the Program Director for this
cooperative agreement including submission to and approval
by the FDA of an IND application and satisfactory response
to the recommendations of the safety and protocol review.
 
B.   RESPONSIBILITIES OF AWARDEES
 
1.   SAFETY AND TOXICITY REVIEW
 
The awardee institution and Principal Investigator agree to
comply with the recommendations of the safety and protocol
review.
 
2.   QUALITY CONTROL AND ADVERSE REACTION REPORTING
 
a.   The awardee is required to set up mechanisms for
quality control.  Some or all of the following may be
relevant:  compliance with protocol requirements for
eligibility, treatment and follow-up, laboratory data,
dietary data, pathological materials, and operative reports.
 
b.   The awardee agrees to perform the study according to
the approved protocol and consent forms.  Any proposed
changes in the protocol must receive the advance permission
of the NCI Program Official for this award.
 
c.   The awardee is required to conform to NCI guidelines
for the use of investigational drugs including investigator
registration (FDA Form 1573), maintaining a record of drug
receipt, and reporting of adverse drug reactions.  Life-
threatening or unexpected toxicity MUST be reported by the
investigator IMMEDIATELY by telephone to the NCI Program
Official shown on the Notice of Award and confirmed with
details in writing within two weeks.  The investigator will
be responsible for amending protocols and consent forms
based on new toxicity information sent to the investigators
by NCI staff.
 
3.   INFORMED CONSENT; IRB APPROVAL
 
a.   Approval by the Institutional Review Board (IRB) must
be obtained by awardees on all protocols because of the
involvement of human subjects.
 
b.   Informed consent forms must comply with HHS Regulations
and NIH guidelines and should include preclinical and
clinical toxicology information as relevant.  Changes in the
consent forms submitted by the awardee should be reported to
the NCI.
 
c.   Awardees will be responsible for amending informed
consent forms if new toxicity information becomes available.
 
4.   DATA MANAGEMENT AND REPORTING REQUIREMENTS
 
Data acquisition and analysis is the responsibility of the
investigator.  Data that must be collected are listed in
the protocol format available from the Program Director.
 
Investigators will be required to submit reports to NCI
using the following schedule and format:
 
A.   Semi-annual Reports
 
Semi-annual scientific reports should report on the progress
of the project during the previous six months and the
cumulative progress of the study.
 
The Semi-annual Report should include:
 
1.   A concise narrative progress summary covering the
previous six months (give dates of the six-month period
covered) and the cumulative progress of the study.
 
2.   Tabular display of:
 
a.   Accrual history of the project presented in six-month
periods.  In addition to total accrual, the investigator
should report the number recruited but ineligible, number
inevaluable, and number of study violations.
 
b.   Interim analyses of results, if appropriate.
 
c.   Toxicities, graded in severity.
 
3.   Explanation of the following:  increase
or decrease in accrual, any unusual or unexpected incidence
of ineligible or inevaluable participants, and any unusual or
unexpected study violations.
 
4.   Brief description of quality control measures such as
review of records,
on-site monitoring, and biochemical monitoring of study
compliance.
 
5.   A list of all publications related to work under this
cooperative agreement.  This listing should include
published references, manuscripts in press or submitted.
Submit two copies of each reprint.
 
6.   Curriculum vitae should be provided if there has been a
change in any of the project investigators.
 
B.   Final Study Report
 
The final report of a completed study shall consist of
detailed analyses of results and toxicity, plans for
publications, a comprehensive list of all previous
publications related to the project, and plans for archiving
and storing the study records.
 
VI.  REVIEW PROCEDURES AND CRITERIA
 
A.   REVIEW PROCEDURE
 
Upon receipt, applications will be reviewed (initially) by the
Division of Research Grants (DRG) for completeness.  Incomplete
applications will be returned to the applicant without further
consideration.  Evaluation for responsiveness to the RFA is an
NCI program staff function.  Applications will be judged to
determine if they meet the goals and objectives of the program as
described in the RFA.  Those that are judged non-responsive will
be returned, but may be submitted as investigator-initiated
applications at the next receipt date.  Questions concerning the
relevance of proposed research to the RFA should be directed to
the Program Director as described in section VIII.
 
In cases where the number of applications is large compared
to the number of awards to be made, the NIH may conduct a
preliminary scientific peer review to identify those which
are clearly not competitive for awards.
 
Those applications judged to be both competitive and
responsive will be further evaluated, using the review
criteria shown below, for scientific and technical merit by
an appropriate peer review group convened by the Division of
Extramural Activities, NCI.  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.
 
B.   REVIEW CRITERIA
 
The following factors will be considered in evaluating the
scientific merit of each response to the RFA:
 
1.   Extent of relevance to the overall goals and objectives
of the RFA.
 
2.   Scientific merit of the study objective(s), design, and
methodology to include considerations of toxicity, safety,
and quality assurance.
 
3.   Basic and clinical scientific significance as well as
originality of the proposed research.
 
4.   Research experience and/or competence of the Principal
Investigator and other key personnel to conduct the proposed
studies.
 
5.   Adequacy of time (effort) that the Principal
Investigator and staff would devote to conduct the proposed
studies.
 
6.   Relevancy and appropriateness of the specific target
population along with assurance as to its accessibility.
 
7.   Identity of sources of data, tissues, fluids;
procedures for their collection and analysis; and assurances
as to their accessibility.
 
8.   Availability of the chemopreventive agents or dietary
factors.  If an IND is held for the agent, that information
should be furnished at the time of application submission.  If
the NCI is to assist in obtaining the IND, that information
should be furnished.
 
9.   Adequacy of plans for NCI program staff involvement
with the proposed studies.
 
The review group will critically examine the submitted
budget and will recommend an appropriate budget and period
of support for each approved application.
 
VII. METHOD OF APPLYING
 
The research grant application form PHS 398 (revised
10/88, reprinted 9/89) must be used in applying for these
grants.  These forms are available at most institutional
business offices; from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health,
Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda,
Maryland 20892; and from the NCI Program Director named
below.
 
The RFA label available in the revision of application form
PHS 398 must be affixed to the bottom of the face page.  Failure
to use this label may result in delayed processing of your
application such that it may not reach the review committee
in time for review.  In addition, the title of the
application, "Prevention Clinical Trials Utilizing
Intermediate Endpoints and Their Modulation by
Chemopreventive Agents", and the RFA number, CA-91-08,
must be typed in block 2 of the face page of the
application form.
 
Submit a signed, typewritten original of the application,
including the Checklist, and four (4) 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
Westwood Building, Room 240
Bethesda, MD  20892**
 
At time of submission, two (2) additional copies of the
application should also be sent to:
 
REFERRAL OFFICER
Division of Extramural Activities
National Cancer Institute
Room 848, Westwood Building
5333 Westbard Avenue
Bethesda, MD  20892
 
Applications must be received by May 24, 1991.  If an
application is received after that date, it will not be
accepted and will be returned.
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.
 
VIII. LETTER OF INTENT
 
Prospective applicants are asked to submit, by April 1,
1991, a letter of intent that includes a descriptive title
of the proposed research, the name and address of the
Principal Investigator, the names of other key personnel,
the participating institutions, and the number and title of
the RFA in response to which the application is being
submitted.
 
Although a letter of intent is not required, is not binding,
and does not enter into the review of subsequent
applications, it is requested in order to provide an
indication of the number and scope of applications to be
reviewed.
 
The letter of intent must be sent to:
 
Marjorie Perloff, M.D.
Chemoprevention Branch
Executive Plaza North, Suite 201
National Institutes of Health
9000 Rockville Pike
Bethesda, MD  20892-4200
Telephone:  (301) 496-8563
 
IX.  INQUIRIES
 
Written and telephone inquiries concerning the objectives and
scope of this RFA and inquiries about whether or not specific
proposed research would be responsive are encouraged and
must be directed to the Program Director, Marjorie
Perloff, M.D. at the above address.  She welcomes the
opportunity to clarify any issues or questions from
potential applicants.
 
This program is described in the Catalog of Federal Domestic
Assistance Number 93.399, Cancer Control.  Awards will be
made under the authority of the Public Health Service Act,
Title IV, Section 301 (Public Law 78-410,; 42 U.S.C. 241,
and Section 412, as amended by Public Law 99-158, 42 U.S.C.
258a-1); and administered under PHS grant policies and
Federal regulations 42 CFR Part 52 and 45 CRF Part 74.  This
program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems
Agency review.