Full Text CA-94-026

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

NIH GUIDE, Volume 23, Number 26, July 15, 1994

RFA:  CA-94-026

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Chemoprevention 
  Chemopreventive Agents 
  Clinical Trial 


National Cancer Institute

Letter of Intent Receipt Date:  August 25, 1994
Application Receipt Date:  October 13, 1994

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 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 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 "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 Program Director's
involvement is described in the section SPECIAL REQUIREMENTS.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant/awardee.

This RFA will be issued annually for two years.  Future unsolicited
competing continuation applications will compete with all other
investigator-initiated (R01) research applications and be peer reviewed
by a study section in the DRG.  However, should the NCI determine
subsequently that there is a sufficient continuing program need, NCI
may reissue a new RFA and invite all funded recipients to submit
competing continuation applications.  In the latter case, competing
continuation applications will not compete with new applications for
funding.

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
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 all
arrangements for obtaining the IND and the agent are completed.  Final
award decisions will consider not only the cost of the clinical trial,
but also the cost of the agent and, if necessary, its formulation.

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 applications submitted in response to the present
RFA may not exceed five years.  The earliest feasible start date for
the initial awards will be July 1, 1995.  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 RFA 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
CRF 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.

The NCI Executive Committee states that there must be gender equality
in all NCI funded clinical trials absent scientific justification for
gender underrepresentation of a single sex study.  An award that fails
to meet this criterion will not be issued.

Program staff are responsible for reviewing actual accrual reported on
non-competing renewal applications.  Investigators will be required to
initiate corrective plans if studies are not accruing as originally
proposed.

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

Grants can be terminated for failure to accrue adequate numbers of both
genders.

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
above).  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, and/or 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

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.

STUDY POPULATIONS

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 involvinghuman 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 below.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by August 25, 1994, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the principal investigator, the names
and telephone numbers 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 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 researcher; from
the Office of Grants Information, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892,
telephone 301/710-0267; and from the NCI Program Director listed under
INQUIRIES.

The RFA label available in the application 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 RFA title,
"Prevention Clinical Trials Utilizing Intermediate Endpoints and Their
Modulation by Chemopreventive Agents", and the RFA number, CA-94-026,
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
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 providing for the preparation of the
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, 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

A.  Review Procedure

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 NCI staff find that
the application is not responsive to the RFA, it will be returned
without further consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NCI in accordance with the review criteria
stated below.  As part of the initial merit review, a process (triage)
may be used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response to
the RFA.  Applications judged to be competitive will be discussed and
be assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
principal investigator/program director and the official signing for
the applicant organization will be promptly notified.

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) that 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 an award will be July, 1995.
Funding discussions 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.  In setting
funding priorities, the NCI will 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 and address the letter
of intent 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

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
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  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 Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

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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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