Full Text CA-93-021

PREVENTION CLINICAL TRIALS UTILIZING INTERMEDIATE ENDPOINTS AND THEIR
MODULATION BY CHEMOPREVENTIVE AGENTS

NIH Guide, Volume 22, Number 18, May 7, 1993

RFA:  CA-93-021

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Clinical Trial 
  Nutrition/Dietetics 
  Chemopreventive Agents 


National Cancer Institute

Letter of Intent Receipt Date:  May 28, 1993
Application Receipt Date:  August 12, 1993

PURPOSE

The Division of Cancer Prevention and Control (DCPC), National Cancer
Institute (NCI), invites applications for cooperative agreements to
support clinical trials that are 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 grants, and then later, cooperative agreement
applications in this area.

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,
Prevention Clinical Trials Utilizing Intermediate Endpoints and Their
Modulation by Chemopreventive Agents, 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 "Healthy People
2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Applications from
minority and women investigators are encouraged.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement mechanism (U01).  The
cooperative agreement is an assistance mechanism in which substantial
NIH programmatic involvement with the recipient during performance of
the planned activity is anticipated.  The nature of the Program
Director's involvement is described in the section on SPECIAL
REQUIREMENTS, A.1.  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.  Future unsolicited
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.  However, if the NCI
determines that there is a sufficient continuing program need, the NCI
may invite all funded recipients to submit competing continuation
applications.

Applicants funded under this RFA will be supported through the
cooperative agreement mechanism (U01).  An assistance relationship will
exist between the 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.  The anticipated direct costs per award
will be in the range of $300,000 to $500,000 for the first year.

FUNDS AVAILABLE

Approximately $1.5 million in total costs for the first year will be
committed to specifically fund applications which are submitted in
response to this RFA.  It is anticipated that three to five awards will
be made annually.  This number of awards 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 may not exceed five years.  The earliest feasible start
date for the initial awards will be April 1, 1994.  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.

RESEARCH OBJECTIVES

Background

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,
which could later proceed to a full scale intervention.  The main
emphasis should be on small, efficient intervention 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 could include a definitive clinical trial monitoring
the test system, a cancer incidence or mortality endpoint, and a
designated agent.

Investigators may apply at this time for the pilot phase, or submit an
application for both the pilot and definitive trial studies.  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.

Applications must be prepared and submitted in accordance with the aims
and requirements described in the following sections:

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 which indicate that subjects are in the later
(e.g. promotional, progressional) phase of the carcinogenic process.
It should be emphasized that protocols that propose 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 definitive trials).

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, suppression
of oncogene protein products, etc.  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 follow-up after
administration of the chemopreventive agent.  Biological fluids
including urine, blood, sputum, etc., would have 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.  In vivo or in
vitro assays are acceptable if of particular and direct relevance to
clinical trials.  The pilot phase is not expected to give a definite
answer to the ultimate value of the chemopreventive agent, which 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 definitive trials).  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,
or individuals presently free of cancer but at risk for second cancers.
Intermediate marker studies of breast cancer chemoprevention are
especially encouraged.

SPECIAL REQUIREMENTS

A.  Terms and Conditions of Award

The special terms and conditions as described in section 1 and 2 below
will be incorporated in the Notice of Grant Award and are in addition
to, and not in lieu of otherwise applicable HHS Administrative
Regulations at 45 CFR 74; other DHHS, PHS, and NIH Grant Administration
Policy Statements and other NCI administrative terms of award.

1.  Program Staff Involvement

a.  Study/Protocol Plan

The NCI Program Director (listed under LETTER OF INTENT) will 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) 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 by the NCI Program
Director on all clinical trials from proposals that are ultimately
funded.  Such a review is legally required by the FDA to assure that
all safety, toxicity, monitoring, and reporting issues are in
conformance with IND guidelines.  The awardee institution and Principal
Investigator must agree to comply with the recommendations of the
review.

b.  Data Access

The NCI 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.  The awardees, however, will retain
custody of and primary rights to their data.  The NCI Program Director
may encourage and facilitate sharing of data between investigators when
this is in the mutual interest of the investigators and the NCI.

c.  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.

d.  Assistance with Obtaining or Purchasing Investigational Drugs

The NCI Program Director will assist the investigator to obtain the
agent to be used in the proposed study.  Once the application is
recommended for funding by the peer review committee, the NCI, and the
National Cancer Advisory Board, 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.

e.  Protocol Modification

No protocol modifications may be implemented without approval from the
NCI Program Director, and also from the FDA, if indicated.

f.  Protocol Termination

The NCI 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 in g 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.

g.  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 Program Director, as
described above, an arbitration panel will be formed composed of one
award recipient designee, one NCI designee, and a third designee with
appropriate expertise chosen by the other two members of the panel.
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.

h.  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, suspension or termination of the award.

i.  Quality Assurance

(1) The NCI has established a clinical chemistry quality assurance
program with the National Institutes of Standards and Technology,
Gaithersburg, Maryland which will provide chemical standards for some
of the agents that will be used and assayed for 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.

(2) Periodically, the NCI Program Director will review the mechanisms
established by each awardee for quality control of clinical studies.
These mechanism must conform with FDA regulations.

j.  Other Terms

Patient enrollment may not begin without the prior written approval of
the NCI 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.

2.  Responsibilities of Awardees

a.  Safety and Toxicity Review

Each awardee institution and Principal Investigator agree to comply
with the recommendations of the safety and protocol review to ensure
that all FDA requirements are satisfied.

b.  Quality Control and Adverse Reaction Reporting

(1) The awardee will be required by the NCI Program Director 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.

(2) The awardee agrees to perform the study according to the approved
protocol.  Any proposed changes in the protocol must receive the
advance permission of the NCI Program Director for this award.

(3)  The awardee is required to conform to NCI guidelines for the use
of investigational drugs, including investigator registration (form FDA
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 Director shown on the Notice of Grant 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.

c.  Informed Consent; IRB Approval

Approval by the Institutional Review Board (IRB) must be obtained by
awardees on all protocols because of the involvement of human subjects.

d.  Data Management and Reporting Requirements

Data acquisition and analysis is the responsibility of the
investigator.

Investigators will be required to submit reports to NCI using the
following schedule and format:

(1) 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.

(a) Individual Study Information. The summary is required to include
the following information for each study:

o  The title of the study (with any appropriate study identifiers such
as protocol number), its purpose, a brief statement identifying the
patient population and the inclusion of women and minorities, and a
statement as to whether the study is completed.

o  The total number of subjects initially planned for inclusion in the
study, the number entered into the study to date, the number whose
participation in the study was completed as planned, and the number who
dropped out of the study for any reason.

o  If the study has been completed, or if interim results are known, a
brief description of the study results.

(b) Summary Information. Information obtained during the previous six
months' clinical and nonclinical investigations, including:

o  A narrative or tabular summary showing the most frequent and most
serious adverse experiences by body system.

o  A list of subjects who died during participation in the
investigation, with the cause of death for each subject.

o  A list of subjects who dropped out during the course of the
investigation in association with any adverse experience, whether or
not thought to be drug related.

o  A brief description of what, if anything, was obtained that is
pertinent to an understanding of the drug's actions, including for
example, information about dose response, information from controlled
trials, and information about bioavailability.

o  A list of the preclinical studies (including animal studies)
completed or in progress during the past year and a summary of the
major preclinical findings.

(c) A description of the general investigational plan for the coming
year to replace that submitted one year earlier.

(d) A description of any significant pilot trial protocol modifications
made during the previous year and not previously reported to the IND in
a protocol amendment.

(e) A brief summary of significant foreign marketing developments with
the drug during the past year, such as approval of marketing in any
country or withdrawal or suspension from marketing in any country.

Due Dates for Reports

January 1 and July 1 for the semiannual report.

(2) 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.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH 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
design and sample size appropriate for the scientific objectives of the
study. This information must be included in the form PHS 398 in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.  Applicants 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 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 28, 1993, 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 may be 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 is to be sent to Dr. Marjorie Perloff at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The receipt date for applications is August 12, 1993. The research
grant application form PHS 398 (rev. 9/91) is to be used in applying
for these cooperative agreements.  These forms are available at most
institutional offices of sponsored research; from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of Health,
Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/594-
7248; and from the NCI Program Director listed under INQUIRIES.

The RFA label available in the form PHS 398 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 title of the
application, "Prevention Clinical Trials Utilizing Intermediate
Endpoints and Their Modulation by Chemopreventive Agents", and the RFA
number, CA-93-021, must be typed in block 2a of the face page of the
application form.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed, exact, clear, and single-sided
photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional copies of the application must
also be sent to:

Ms. Toby Friedberg, Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892

If the application submitted in response to this RFA is substantially
similar to a research grant application already submitted to the NIH
for review, and has been or 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.  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 for the preparation of applications
contained in the grant application form PHS 398 (rev. 9/91) are to be
used in preparing cooperative agreement applications.  Because of the
award terms and conditions included in the Section under SPECIAL
REQUIREMENTS, A. Terms and Conditions of Award, 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
who are invited by the NCI to submit competing continuation and
supplemental applications must describe how they have met the
established terms and conditions.

The following items apply to new and competing continuation
applications:

1.  The study must clearly address a pilot trial and optionally a
definitive trial.  The pilot trial must involve the application of a
biological and/or biochemical marker and its modulation by the study
agent.  The definitive trial involves the implementation of a full
scale randomized, double-blind, risk reduction, prevention clinical
trial.  For applicants seeking to conduct only a pilot trial, 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 life style risk
factors, and relevancy 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 application
should include verification of the coinvestigators' 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.

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.

10.  The applicant should indicate the availability of the
chemopreventive agents or dietary factors.

REVIEW CONSIDERATIONS

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.
Applications that are judged non-responsive will be returned, but may
be submitted for investigator initiated grant competition at the next
receipt date.  Questions concerning the relevance of proposed research
to the RFA may be directed to the NCI Program Director listed under
INQUIRIES.

If the number of applications is large compared to the number of awards
to be made, the NCI 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.  Scientific merit of the study objective(s), design, and methodology
to include considerations of toxicity, safety and quality assurance.

2.  Basic and clinical scientific significance as well as originality
of the proposed research.

3.  Research experience and/or competence of the Principal Investigator
and other key personnel to conduct the proposed studies.

4.  Adequacy of time (effort) which the Principal Investigator and
staff would devote to conduct the proposed studies.

5.  Relevancy and appropriateness of the specific target population
along with assurance as to its accessibility.

6.  Identity of sources of data, tissues, fluids, etc., procedures for
their collection and analysis, and assurances as to their
accessibility.

7.  Adequacy of plans for NCI program staff involvement with the
proposed studies.

8.  Adequacy of plan for inclusion of women and minorities.

The review group will critically examine the submitted budget and will
recommend an appropriate budget and period of support for each
meritorious application.

AWARD CRITERIA

The earliest feasible start date for the initial awards will be April
1, 1994.  Priority would be given for studies with biological
monitoring procedures that do not overlap or duplicate projects
currently funded by the NCI.  Awards will not be made until all
arrangements for obtaining the agent are complete.  Final awards by the
NCI will consider not only the cost of the clinical trial, but also the
cost of the agent, including its formulation, encapsulation and
packaging, if these costs are to be borne by the Government.  In making
funding decisions the National Cancer Advisory Board considers the
special needs of the Institute and the priorities of the National
Cancer Program.

INQUIRIES

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

Direct inquiries regarding programmatic issues and address the letter
of intent to:

Marjorie Perloff, M.D.
Chemoprevention Branch
National Cancer Institute
Executive Plaza North, Suite 201
Bethesda, MD  20892-4200
Telephone:  (301)496-8563
FAX:  (301) 402-0553

Direct inquiries regarding fiscal matters to:

Ms. Eileen Natoli
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800 Ext. 56

AUTHORITY AND REGULATIONS

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 grants policies
and Federal regulations 42 CFR Part 52 and 45 CFR Part 74.  This
program is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.

.

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