Full Text CA-92-06

INTERMEDIATE ENDPOINTS AND THEIR MODULATION BY CHEMOPREVENTIVE AGENTS

NIH GUIDE, Volume 21, Number 7, February 21, 1992

RFA:  CA-92-06

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Chemopreventive Agents 
  Biochemical Markers 
  Biological Markers 


National Cancer Institute

Letter of Intent Receipt Date:  March 25, 1992
Application Receipt Date:  May 19, 1992

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.

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,
Intermediate Endpoints and Their Modulation for 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,
colleges, hospitals, laboratories, units of State or local governments,
and eligible agencies of the Federal Government.  Applications from
minority individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) mechanism.  The
cooperative agreement is an assistance mechanism in which substantial
programmatic involvement of the awarding component with the recipient
during performance of the planned activity is anticipated as described
under SPECIAL REQUIREMENTS.  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 five years.  However, if the NCI
determines that there is a sufficient continuing program need, NCI may
invite all funded recipients to submit competing continuation
applications. Competing continuation applications will not compete with
new applications for funding.

The cooperative agreement mechanism is an assistance mechanism in which
a relationship exists between the awarding component and the awardees
to accomplish the objectives of the activity.  The recipients will have
primary responsibility for the development and performance of the
activity as described under SPECIAL REQUIREMENTS.  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.

FUNDS AVAILABLE

Approximately $1.5 million in total costs per year for five years will
be committed to fund applications that are submitted in response to
this RFA.  It is anticipated that three to five awards will be made
each year for five years.  This number of awards is dependent on the
receipt of a sufficient number of applications of high scientific merit
and the availability of funds.  The total project period for
applications submitted in response to the RFA may not exceed five
years.  The earliest feasible start date for the initial awards will be
April 1, 1993.

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 for cancer 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 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 may
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.

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.  Clinical trials
are the best approach to address the efficacy, safety and
applicability, and effectiveness of these agents in humans.

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, such as 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 the risk of developing cancer is, therefore, a major goal
of the chemoprevention program.  These studies are expected to improve
the efficiency of the experimental design of clinical trials so that
fewer subjects are needed 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 and tests that 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 Phase III 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, 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 follow-up
after administration of the chemopreventive agent.  Biological fluids,
including urine, blood, and sputum would have to be obtained from
participants for analysis.

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 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
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 for particular types of cancer, individuals with precancerous
lesions, or individuals presently free of cancer but at risk for second
cancers.

SPECIAL REQUIREMENTS

A.  Program Staff Involvement

1.  Study/Protocol Plan

The NCI Program Director 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 and 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 on all clinical trials that are 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.

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 aspects of the trial 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 rights to their data.  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

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 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 and Purchasing Investigational Drugs

The NCI may assist the investigator in obtaining the agent to be used
in the proposed study.  The NCI Program Director may begin discussions
with the Principal Investigator and the pharmaceutical industry with
regard to obtaining the drug after the application has been recommended
for funding by the initial review group, the NCI, and the National
Cancer Advisory Board.  If a suitable agent is unavailable at no cost,
the NCI may proceed to purchase the agent through standard procurement
mechanisms.  Purchase of the agents is only undertaken after measures
to obtain the drug at no cost have been exhausted.

5.  Protocol Modification

Protocol modifications may be implemented after approval from the
Program Director and, if necessary, from the FDA.

6.  Protocol Termination

The Program Director may request that a protocol study be terminated on
the basis of (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.

7.  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, an
arbitration panel composed of one member of the award recipient group
nominated by the awardee, one NCI nominee, and a third member with
appropriate expertise chosen by the other two members will be formed to
review the NCI decisions.  These special arbitration procedures in no
way affect the right of the awardee 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.

8.  Clinical Trials Progress Review

Progress will be evaluated semi-annually by the Program Director from
material presented in the semi-annual report (as described below).
Recommendations of the Program Director will be communicated by a
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.

9.  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.

10.  Other Terms

Patient enrollment may not begin without the prior written approval of
the Program Director for this cooperative agreement.  Such approval is
contingent upon 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 quality control mechanisms.  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.  Any proposed changes in the protocol must receive the
advance permission of the NCI Program Director.

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 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.

3.  Informed Consent; Institutional Review Board Approval

a.  Approval by the Institutional Review Board (IRB) must be obtained
by awardees on all protocols.

4.  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:

a.  Semi-annual Reports

The Semi-annual Report must 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 must report the number
recruited but ineligible, the number inevaluable, and the number of
study violations.

(b) Interim analyses of results, if appropriate.

(c)  Toxicities, graded as to severity.

(3) Explanation of any of the following situations:  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, biochemical monitoring of study
compliance.

(5) A list of all publications resulting from work under this
cooperative agreement, including manuscripts in press and submitted.
Submit two copies of each reprint.

(6) Curriculum vitae of new project investigators.

b.  Final Study Report

The final report of a completed study shall consist of detailed
analyses of the results, plans for publications, a comprehensive list
of all previous publications resulting from 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 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 NIH policy as defined in the HHS Regulations for the Protection of
Human Subjects 45 CFR 46 also applies.  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 March 25, 1992, 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 an 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.
Chemoprevention Branch
National Cancer Institute
Executive Plaza North, Suite 201
9000 Rockville Pike
Bethesda, MD  20892-4200
Telephone:  (301)496-8563
FAX:  (301) 402-0553

APPLICATION PROCEDURES

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 business offices; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Room 449, Westwood Building, 5333 Westbard Avenue Bethesda, MD
20892, telephone 301/496-7441; or from the NCI Program Director named
below.

The RFA label available in the  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-92-06, 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 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 additional copies of the
application must also be sent to:

REFERRAL OFFICER
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 848
5333 Westbard Avenue
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, 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 the preparation of an application
contained in the Grant Application Form PHS 398 are to be used in
preparing Cooperative Agreement applications.  Applicants must indicate
in the Research Plan a plan to meet the requirements for NCI staff
involvement as stated under SPECIAL REQUIREMENTS.  To ensure that the
cooperative agreement remains the appropriate instrument, awardees
submitting competing continuation and supplemental applications must
describe how the established terms and conditions have been met.

The following items apply to new and to competing continuation
applications:

1.  The study must clearly address Phase I, and optionally Phase 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 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 must include relevant epidemiologic
and laboratory data.  Preclinical and clinical data on any potential
untoward effects of the intervention agent must also be presented.  In
circumstances in which there might be some doubt about 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 must 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 must 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).  An estimated accrual rate must be included.  If more
than one institution is involved, the application must include
verification of the co-investigators' willingness to participate and
pertinent additional information regarding the staff qualifications of
the cooperating institutions, resources, research plans, patient
availability, and data flow, and corresponding budget requirements.

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 outside the
applicant's institution, a letter from the cooperating institutions
indicating their willingness to participate must be included.

6.  The applicant must elucidate any known and 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 NCI 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.  In such a case, a letter of agreement from either the GCRC
program director or Principal Investigator must be included with the
application.

REVIEW CONSIDERATIONS

A.  Review Procedures

Upon receipt, applications will be reviewed by the Division of Research
Grants (DRG) for completeness. 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 responsiveness to 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 as
an investigator-initiated grant application at the next receipt date.
Questions concerning the relevance of proposed research to the RFA may
be directed to the Program Director as described in 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
(triage) to identify those applications that are clearly not
competitive for awards.  Applications determined to be non-competitive
will be returned to the applicant.

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 will be by the National Cancer Advisory Board.

B.  Review Criteria

The following factors will be considered in evaluating the scientific
merit:

o  Scientific merit of the study objective(s), design, and methodology
to include considerations of toxicity, safety, and quality assurance.

o  Basic and clinical scientific significance and originality of the
proposed research.

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

o  Adequacy of time (effort) that the Principal Investigator and staff
will devote to conduct the proposed studies.

o  Relevancy and appropriateness of the specific target population and
assurance of accessibility.

o  Identity of sources of data, tissues, fluids, and other specimens,
procedures for collection and analysis, and assurances of
accessibility.

o  Availability of the chemopreventive agents or dietary factors.  If
an IND is held for the agent, that information must be furnished with
the application when submitted.  If the NCI is to assist in obtaining
the IND, that information must be furnished.

o  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.

AWARD CRITERIA

The earliest feasible start date for the initial awards will be April
1, 1993.  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.  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 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.  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 to:

Marjorie Perloff, M.D.
Chemoprevention Branch
National Cancer Institute
Executive Plaza North, Suite 201
9000 Rockville Pike
Bethesda, MD  20892-4200
Telephone:  (301) 496-8563
FAX:  (301) 402-0553

Direct inquiries regarding fiscal matters to:

Ms. Eileen Natoli
Team Leader, DCPC
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
9000 Rockville Pike
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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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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