Full Text CA-96-001

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

NIH GUIDE, Volume 24, Number 37, October 20, 1995

RFA:  CA-96-001

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Clinical Trial 
  Chemopreventive Agents 


National Cancer Institute

Letter of Intent Receipt Date:  November 21, 1995
Application Receipt Date:  January 18, 1996

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 RFAs that requested grant
applications, and then later, applications for cooperative agreements
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 Request
for Application (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 Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
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

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.2.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the
applicant/awardee.

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.  If an investigator anticipates
requiring considerable assistance in obtaining the chemopreventive
agent and/or in securing an IND permit from the FDA, such assistance
must be sought, in writing, from the Program Director, and assistance
approved by the Program Director, prior to submitting the
application.  Awards will not be made until all arrangements for
obtaining the IND and the agent are completed.  Final awards will
also consider the cost of the clinical trial, and the cost of the
agent and, if necessary, its formulation.

This RFA will be reissued annually for two 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, should
the NCI determine that there is a sufficient continuing program need,
NCI may invite all funded recipients to submit competing continuation
applications.

FUNDS AVAILABLE

Approximately $1.5 million in total costs for the first year will be
committed to specifically fund applications 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 an application submitted in response to the
present RFA may not exceed five years.  The earliest feasible start
date for the initial awards will be September 30, 1996.  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 which would be the subject of a full scale,
randomized, cancer risk reduction clinical trial.

Applications should 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 which 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 which 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

Under the cooperative agreement, a partnership will exist between the
recipient of the award and NCI, with assistance from NCI in carrying
out the planned activity.  The following terms and conditions
pertaining to the scope and nature of the interaction between NCI and
the investigators will be incorporated in the Notice of Award.  These
terms will be in addition to the customary programmatic and financial
negotiations which occur in the administration of cooperative
agreements.  The "Terms and Conditions of Award" described in this
section are in addition to, and not in lieu of, otherwise applicable
OMB administrative guidelines; DHHS grant administration regulations
45 CFR 74 and 92; other DHHS, PHS, and NIH grant administration
policy statements; and other NCI administrative terms of award.

1. Awardee Rights and Responsibilities

a. Safety and Toxicity Review

Each awardee institution and principal investigator agree to comply
with the recommendations of the safety and protocol review to assure
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 (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 Director 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.

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:

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.

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.

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:

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

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

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.

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.

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.

Grantees are responsible for initialing corrective plans if the
progress of studies reported in non-competing renewal applications
indicate that patients are not being accrued as originally proposed.
Grants can be terminated for failure to accrue adequate numbers of
both genders.

Each progress report must describe accrual by gender and
racial/ethnic group.

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.

2.  NCI Staff Responsibilities

a.  Study/Protocol Plan

The NCI Program Director 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 which are ultimately funded.  Such a
review is legally required by the Food and Drug Administration to
assure that all safety, toxicity, monitoring, and reporting issues
are in conformance with Investigational New Drug 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 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

If an investigator anticipates requiring considerable assistance in
obtaining the chemopreventive agent and/or in securing an
Investigational New Drug (IND) permit from the Food and Drug
Administration (FDA), such assistance must be sought in writing to
the Program Director, and assistance approved by the Program
Director, prior to submitting the application.  Awards will not be
made until 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 below.  In addition,
the NCI may withdraw funding for such a protocol if the grounds for
termination are patient safety and toxicity.

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 Food and Drug
Administration (FDA) regulations.

j. The awardees will retain custody of and primary rights to their
data.

k. 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.

3. Arbitration Mechanism

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the
NCI, may be brought to arbitration.  An arbitration panel will be
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.

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 subpopulations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This 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 Population, 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 was reprinted in the Federal
Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting
errors in the earlier publication, and reprinted in the NIH GUIDE FOR
GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed under INQUIRIES.  Program
staff may also provide additional relevant information concerning the
policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by November 21, 1995, a
letter of intent that includes a descriptive title of the proposed
research, name, address, and telephone number of the Principal
Investigator, identities of other key personnel and participating
institutions, and 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:

Marjorie Perloff, M.D.
Division of Cancer Prevention and Control
National Cancer Institute
Executive Plaza North, Suite 218
Bethesda, MD  20892
Telephone:  (301) 496-4664
FAX:  (301) 402-0553

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these cooperative agreements.  These forms are
available at most institutional offices of sponsored researcher; from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, 6701 Rockledge Drive, Room 3032, MSC
7762, Bethesda, MD 20892-7762, telephone (301) 435-0714, email:
dirg@drgpo.drg.nih.gov, and from the NCI Program Director listed
under INQUIRIES.

The RFA label available in the PHS 398 application form 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 RFA title, "Prevention Clinical Trials Utilizing Intermediate
Endpoints and Their Modulation by Chemopreventive Agents," and the
RFA number, CA-96-001, 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 three signed, exact, clear and single sided
photocopies, in one package to:

DIVISION OF RESEARCH GRANTS
National Institutes of Health
6701 Rockledge Drive, Room 1040 MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for courier/overnight service)

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

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard, MSC 7405
Rockville, MD  20852 (if hand-delivered or delivery service)
Bethesda, MD  20892 (if using U.S. Postal Service)

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 for preparing applications contained in the
grant application form PHS 398 (rev. 5/95) are to be used in
preparing Cooperative Agreement applications.  Because of the award
terms and conditions included in the section under SPECIAL
REQUIREMENTS, 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 as well as to 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 must 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 must 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 must 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 must be included.  The
applicant must provide a description of the target population or
group chosen and must 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 must 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.  Each project in
a multiproject application must have individual budgets for the first
budget period and a summary budget for all years.

5. The applicant must 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 must 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 must 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

Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, it will be returned without
review.

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 with the review
criteria stated below.  As part of the initial merit review, all
applications will receive a written critique and may undergo a
process in which only those applications deemed to have the highest
scientific merit will be discussed, assigned a priority score, and
receive a second level review by the National Cancer Advisory Board.

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 plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.

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 an award will be September 30,
1996.  In addition to scientific and technical merit as determined by
peer review, availability of funds, and programmatic priorities,
funding decisions will also consider not only the cost of the
clinical trial but also the cost of the agent and, if necessary, its
formulation.  Funding priority will 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.  Funding
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.

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 to:

Marjorie Perloff, M.D.
Division of Cancer Prevention and Control
National Cancer Institute
Executive Plaza North, Suite 218
Bethesda, MD  20892-4200
Telephone:  (301)496-4664
FAX:  (301) 402-0553
Email:  perloffm@dcpcepn.nci.nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Robert Hawkins
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800 Ext. 213

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 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  and
Federal regulations 42 CFR Part 52 and PHS grant policies 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.

The PHS strongly encourages all grant recipients to provide a
smoke-free workplace and promote the non-use of 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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