Full Text CA-94-013

CHEMOPREVENTION CLINICAL TRIALS INVOLVING MODULATION/FUNCTION OF GENES
AND/OR GENE PRODUCTS

NIH GUIDE, Volume 23, Number 27, July 22, 1994

RFA:  CA-94-013

P.T. 34

Keywords: 
  Chemoprevention 
  0765014 
  Growth Factors 
  Chemotherapeutic Agents 


Letter of Intent Receipt Date:  October 15, 1994
Application Receipt Date:  November 23, 1994

PURPOSE

The Chemoprevention Branch, Division of Cancer Prevention and Control
(DCPC), National Cancer Institute (NCI), invites applications for
cooperative agreements to encourage coordinated submissions of projects
from investigators dedicated to chemoprevention clinical trials of
agents that may effect gene expression and cellular growth.

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 Applications (RFA), Chemoprevention Clinical Trials Involving
Modulation/Function of Genes and/or Gene Products, is related to the
priority area of chemoprevention.  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 and women investigators are encouraged.

Each application will be considered on its own merit as an individual
research project.  Applicants for "Chemoprevention Clinical Trials
Involving Modulation/Function of Genes and/or Gene Products" MAY NOT
concurrently submit R01 applications that represent significant
duplication of efforts.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) mechanism.  The
cooperative agreement is an assistance mechanism in which substantial
NCI programmatic involvement with the recipient during performance of
the planned activity is anticipated.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that of
the applicant/awardee.

Details of the responsibilities, relationships and governance of the
study to be funded under cooperative agreement(s) are discussed later
in this document under the section, "Terms and Conditions of Awards."

The total project period for an application submitted in response to
the present RFA may not exceed five years.  The anticipated award date
is July 1, 1995.  Because the nature and scope of the research proposed
in response to this RFA may vary, it is anticipated that the sizes of
awards will vary also.

This RFA is a one-time solicitation for applications for new awards.
Future unsolicited competitive 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 (DRG),
NIH. However, if it is determined that there is a sufficient continuing
need, the NCI will invite recipients of awards made in FY '95 under
this RFA to submit competitive continuation applications for review
according to procedures described below under APPLICATION PROCEDURES
and REVIEW CONSIDERATIONS.

FUNDS AVAILABLE

Approximately $2.0 million in total costs per year for five years will
be committed to specifically fund applications that are submitted in
response to RFA.  It is anticipated that three to six awards will be
made.  This number of awards is dependent on the receipt of a
sufficient number of applications of high scientific merit.  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

A.  Background

Evolving understanding of molecular mechanisms brings unprecedented
opportunities for advances in the prevention of cancer based especially
on the identification of specific gene products and the modulation of
their effects at the molecular level with chemopreventive agents.  New
developments in the understanding of cellular function and cellular
metabolites are occurring that provide information on cell growth,
proliferation, differentiation and neoplastic transformation.  In
vitro, in vivo, and animal model systems and the chemoprevention
decision network have identified a number of potential chemopreventive
agents and have resulted in a rational approach to cancer preventive
agent development and testing.

The endpoints for cancer treatment trials are usually a measured
reduction in tumor size or statistically measured survival in a
population whose survival is limited.  For chemopreventive
interventions, no such easily measured endpoints exist.  For a clinical
endpoint, the primary endpoint is incidence reduction, which occurs
years later.  Complex biostatistical and epidemiological strategies are
necessary in measuring study populations in order to prove efficacy.
Another approach is to develop surrogate endpoints to measure effect
and for the study of the carcinogenesis process in humans.

Inhibition of the post initiation phases of carcinogenesis is an
emerging strategy for the prevention of cancer.  Recent understanding
of the role of oncogenes and tumor suppressor genes in cancer
development suggests several strategies.  Specifically, gene products
appear to act at various points in the intracellular pathway utilized
by growth factors, cell surface receptors, GTP-binding proteins,
protein kinases, and transcription factors in stimulating cell
proliferation.  A common characteristic of these genes is that they
encode components of the signal transduction system.  This system
refers to the biochemical mechanisms that permit complex changes in the
cytoplasm and in gene expression in the nucleus which are often
controlled by extracellular ligands that act through receptors, second
messenger molecules and protein kinases.  Clinical trials of agents
effecting gene expression or gene products are being sought.

Initially, knowledge of genes involved in carcinogenesis will provide
tools for screening and diagnosis.  The challenge will be to move as
rapidly as possible from structural defects evident in disease alleles
to improved methods of compensation for these defects.  This will
involve the development of pharmaceuticals that will inhibit the
function of these altered gene products in the carcinogenesis process.

The identification of oncogenes and tumor suppressor genes opens up a
number of opportunities or targets for their study in precancers and
will result in improved capabilities for drug screening and rationale
drug design.  The major types of cancer appear to be polygenic.  This
means that transformation is not due to a single mutation, but from
multiple mutations and can result from a composite number of different
mutagenic events.  Although this has many disadvantages, it also has
the advantage that there may be many targets for chemopreventive
activity.  Currently, there is no method to rationalize these events or
to predict them a priori.  By correlating differences in responses to
various inhibitors with variations at the DNA level, investigators may
be able to develop a predictive ability for assessing risk and its
modulation by using a battery of DNA based tests.  What is the most
promising is a possibility for the utilization of a number of different
preventive agents utilized in combinations.  At the preclinical level,
the screening of agents with transgenic mice with gene knockouts will
be helpful.  The prospect of collecting and understanding
responsiveness to various agents is likely to be a major aspect of
future cancer prevention research.

Oncogene abnormalities might be used as markers for the detection of
high risk groups, and markers for the study and evaluation of precancer
progression.  Mutant oncogene products could be utilized as major
targets for the development of new molecular forms designed to
specifically inhibit to alter the function of effected pathways.

At this time, targeting gene products and their function is a most
advantageous strategy for chemopreventive interventions.  For example,
the technology might be used with extracellular molecules such as
surface receptors which would not require the compound to enter the
cells.  Failure to permeate cells might also reduce the potential side
effects.

Several examples of types of studies that might be considered are as
follows:

Ras oncogenes have been detected in 90 percent of human pancreatic
cancers, 50 percent of colorectal tumors, 30 percent of lung cancers,
and 10 to 40 percent of numerous other cancers, making them the most
prevalent oncogenes in human cancer.  It has been known that ras
proteins interact with the inner surface of the plasma membrane, where
they play a role in signal transduction.  In cancer cells, a single
mutation in the ras oncogene impairs the ability of the ras protein to
turn off the signal and continues to stimulate the cell to grow.  GTP
binding is one of the two requirements that the ras protein must meet
to be active.  The other is that the protein must be anchored to the
cell membrane.  This involves binding to farnesyl pyrophosphate.
Blocking farnesylation with chemopreventive agents might block the ras
protein attachment and, therefore, its activity.  Isoprenylation of the
protein can be blocked by intermediates in the cholesterol biosynthesis
pathway.  For example, a compound L731,735 has been developed by Merck
which inhibits one of the enzymes, farnesyl transferase, in the
cholesterol biosynthesis pathway.

A number of other inhibitors of farnesyl protein transferase have been
identified.  These include the monoterpene, limonene, a major
constituent of orange peel oil.  The mechanism of action appears
related to inhibition of isoprenylation of a 21-26 Kda protein, which
is associated with cell growth.  Lovastatin, a cholesterol biosynthetic
inhibitor has been shown to be effective earlier in the pathway.  This
compound may be a model for less toxic derivatives that may be equally
effective in inhibiting ras activation.  The compound, Riverstatin, has
inhibited the pathway with a 100-fold greater potency than Lovastatin.
Other potential compounds are available and could be evaluated in
clinical trials.

A widely accepted general model for colorectal tumorigenesis suggests
that an early and critical step in carcinogenesis is the development of
altered DNA methylation, the most common form of which is global
hypomethylation.  This is frequently accompanied by over-expression of
the c-myc proto-oncogene, as well as by genomic mutations in other
proto-oncogenes and anti-oncogenes such as K-ras and p53, DCC (deleted
in colon cancer), and MCC (mutated in colon cancer), respectively.
Because strong associations exist between DNA hypomethylation,
mutations in the above mentioned oncogenes and the evolution of colonic
adenomas, these biochemical indices are considered to be excellent
candidates for intermediary markers of colonic carcinogenesis.

Folate is an essential cofactor in the production of
S-adenosylmethionine (SAM), the primary methyl donor in the body.  The
SAM dependent methylation of specific DNA cytosine bases to form 5
methylcytosine may block ras gene expression and abnormalities in DNA
methylation.  Its deficiency may contribute to the loss of normal
control of proto-oncogene expression.  In rats, a chronic dietary
deficiency of methyl donors (i.e., choline and methionine) and methyl
transfer factors (i.e., folate and vitamin B12) lowers the
concentration of SAM, increases DNA methyltransferase activity, and
reduces methylation of DNA cytosine and increases the incidence of
liver cancer.

Several clinical reports point to the possibility that diminished
folate status might also result in altered cell proliferation and
neoplasia.  The colonic epithelium is among the list of epithelia where
epidemiological studies have established an association between
diminished folate status and an enhanced risk of dysplasia and cancer.
Epidemiologically, this principle applies to individuals who have an
underlying predisposition to colonic dysplasia as well as to the
general population.  It has recently been observed that among
individuals with ulcerative colitis, the prevalence of colonic
dysplasia in those receiving folate supplements was about on-half that
of these receiving no supplements.  Two epidemiologic studies in the
general population have established a significant association between
diminished dietary folate intake and an enhanced risk of colon and/or
rectal cancer.

Adenomatous polyps, especially those that are multiple, greater than 1
cm. in diameter, and/or have villous or tubule-villous components, are
widely regarded as early neoplastic lesions that will progress to frank
invasive cancer if left untreated.  They also serve as markers to
identify individuals who are at increased risk of developing invasive
colon cancer.  Such patients receive regular screening colonoscopy and
are an ideal target group for chemoprevention studies with folate or
SAM that would include studies to evaluate the modulation of gene
expression.  Studies to evaluate aberrant methylation (both hypt and
hyper) in oncogene activation or tumor suppressor gene inactivation
might be considered.

With recent results from human clinical trials, it is of interest to
examine whether the effects of Sulindac and aspirin occur as a result
of alterations of gene expression.  It is believed that aspirin reduces
DNA transcription primarily through acetylation of the serine residue
of cyclooxygenase.  An appropriate panel of genes implicated in colonic
carcinogenesis has been identified.  The rationale for the selection of
biological markers, the various agents associated with colorectal
cancer and adenomas and the agents that might effect the prostaglandin
pathway are known. Specifically, measuring the steady state levels of
RNA transcribed from adenomatous polyposis coli (APC), deleted in colon
cancer (DCC), mutated in colon cancer (MCC), ras, and ornithine
decarboxylase (OPC) genes in response to chemopreventive agents is
possible.  In addition, examining the inhibition of cyclic AMP second
messenger systems which might effect the expression of colon genes
could be undertaken.  These types of experiments may provide further
understanding of the role of NSAID drugs in the inhibition of colon
neoplasia.

Such projects are timely and studies of the effects of chemopreventive
agents on gene expression and function are of intense interest.

B.  Scope and Objectives

The emphasis is on the development of short-term clinical trials that
will evaluate the modulation/function of genes or gene products by
chemopreventive agents.  The studies should be developed in phases that
may include a pilot phase in humans that could later proceed to a
full-scale intervention.  One or more biomarkers endpoints might be
initially evaluated to determine baseline parameters and, subsequently,
to serve as a follow-up after the administration of the prevention
measure or the chemopreventive agents in vivo and/or in vitro.  The
main emphasis should be on small, efficient studies aimed at improving
future research designs, providing a molecular basis for the action of
the chemopreventive agent(s), or providing improved intermediate
endpoint biomarkers.  After successful completion of the pilot phase
(i.e., demonstrated modulation of endpoint biomarkers), subsequent
studies could include a clinical trial monitoring the test system, a
cancer incidence or mortality endpoint, and a designated agent.
Studies that develop and evaluate biotechnologies for the
identification of new genes, gene products and DNA probes to identify
human disease or to identify individuals at high risk or predisposition
to cancer are also encouraged.

For the initial human phase, the proposed study might describe the
relevance of the marker test system to clinical or public health cancer
prevention, the rationale for the selection of the study population,
and the potential intervention agent or procedure.  The project could
result later in the markers and agent being evaluated in a full-scale,
double-blind, randomized, risk reduction clinical trial.

SPECIAL REQUIREMENTS

The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator, as well as the
institutional official at the time of award.

Terms and Conditions of Award

These special Terms and Conditions of Award are, in addition to, and
not in lieu of, otherwise applicable OMB administrative guidelines
Federal grant administration policy statements and regulations.

A.  Awardee Rights and Responsibilities

The administrative and funding instrument used for this program is a
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism) in which substantial NCI scientific and/or
programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the
NCI's purpose is to support and/or stimulate the recipient's activity
by involvement in and, otherwise, working jointly with the award
recipient in a partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity.  Consistent with
this concept, the dominant role and prime responsibility for the
activity resides with the awardee(s) for the project as a whole,
although specific tasks and activities in carrying out the studies will
be shared among the awardee(s) and the NCI Program Director.

1.  Safety and Toxicity Review

Each awardee institution and principal investigator agree to comply
with the recommendations of the safety and protocol review conducted by
the Program Director to assure that all FDA requirements are satisfied.

2.  Quality Assurance and Adverse Reaction Reporting

(a) 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.

(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 for this award.

(c) The awardee is required to adhere to NCI guidelines for the use of
investigational drugs, including investigator registration (FDA Form
1573), and maintaining a record of drug receipt.  Adverse drug
reactions, whether 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.  Data Management and Reporting Requirements

Data acquisition and analysis is the responsibility of the
investigator.  Each awardee institution will retain custody of and have
primary rights to the data developed under these awards, subject to
government rights of access consistent with current HHS, PHS and NIH
policies.

Investigators will be required to submit semi-annual and annual reports
to NCI using the following schedule and format as required by FDA
Investigational Drug Regulations.

(1) Semi-Annual Reports

Semi-annual scientific reports should report on the progress of the
project during the previous six months and the cumulative progress of
the study.

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

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

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

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

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

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

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

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

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

o  A list of 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 trial protocol modifications made
during the previous year and not previously reported to the FDA 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.  The Grants
Administration Branch will not issue an award that fails to meet this
criterion.

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.

Due Dates for Reports

January 1 and July 1 for the semi-annual report.

(f) 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.

B.  NCI Staff Responsibilities

1.  Study/Protocol Plan

The NCI Program Director (see INQUIRIES) will assist the awardees 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, and (b) availability of necessary
pharmacological agents.  The NCI Program Director will 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 (IND) guidelines.  The awardee institutions
and principal investigator must agree to comply with the
recommendations of the review.

2.  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 the
Code of Federal Regulations (CFR) 21.  The awardees, however, will
retain custody of, and primary rights to, their data.  The NCI Program
Director may encourage and facilitate sharing of data between
investigators when this is in the mutual interest of the investigators
and the NCI.

3.  Investigational New Drug (IND)

The NCI will have the option to cross-file or independently file an IND
on investigational drugs evaluated in trials supported under this
cooperative agreement.

The NCI will advise investigators of specific requirements and changes
in requirements concerning investigational drug management for
compliance with NCI and the FDA guidelines and regulations.
Investigators conducting trials under cooperative agreements will be
expected, in cooperation with the NCI, to comply with all FDA
monitoring and reporting requirements for investigational agents, for
reporting adverse reactions, and for maintaining necessary records of
drug receipt and distribution.

4.  Assistance with Obtaining or Purchasing Investigational Drugs

If an investigator anticipates requesting considerable assistance in
obtaining the chemopreventive agents and in securing the
Investigational New Drug (IND) permit from the Food and Drug
Administration (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 agent
are complete.  Final awards by the NCI will also consider not only the
cost of the trial, but also the cost of the agent, including its
formulation, encapsulation and packaging, if these costs are to be
borne by the Government.

5.  Protocol Modification

No protocol modifications shall be implemented without approval from
the NCI Program Director, consistent with FDA requirements.

6.  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.  The Arbitration Mechanism
is described in C. below.

7.  Clinical Trials Progress Review

Progress will be evaluated semi-annually by the NCI Program Director
from material presented in the awardee's semi-annual report (as
described above).  Recommendations of the NCI Program Director will be
communicated by letter to the investigator to which he/she is expected
to respond.

8.  Quality Assurance

(1) The NCI has established a clinical chemistry quality assurance
program with the National Institute of Standards and Technology,
Gaithersburg, Maryland, which may provide chemical standards for some
of the agents being used and assayed in clinical trials.  These
standards will contribute to the quality control of selected laboratory
determinations.  If available, 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 mechanisms must conform with Food and Drug Administration (FDA)
regulations.

9.  Other Terms

No patients may be enrolled in this study without the prior written
approval of the NCI 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.

C.  Arbitration

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 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 10-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women 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 subject 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 October 15, 1994, a
letter of intent that includes a descriptive title of the proposed
research, the name, address and telephone number of the principal
investigator, the names of other key personnel, the participating
institutions, and the number and title of the RFA in response to which
the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, it is requested
in order to provide an indication of the number and scope of
applications and to avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. Winfred F. Malone at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The regular research grant application form PHS 398 (rev. 9/91) is to
be used in applying for cooperative agreements.  These forms are
available at most institutional offices of sponsored research, from the
Office of Grants Information, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892,
telephone 301/435-0714, and from the NCI Program Director listed under
INQUIRIES.

The RFA label available in form PHS 398 (rev. 9/91) 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, "Chemoprevention Clinical Trials Involving
Modulation/Function of Genes and/or Gene Products," and the RFA number,
CA-94-013, must be typed in line 2a of the face page of the application
form and the YES box must be marked.

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
6130 Executive Boulevard, Room 636
Rockville, MD  20852 (if hand-delivered or delivery service)
Bethesda, MD  20892 (if using U.S. Postal Service)

Applications must be received by November 23, 1994.  No addenda or
appendix materials will be accepted after the receipt date.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) will
not accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the applicant
withdraws the pending application.  The DRG will not accept any
application that is essentially the same as one already reviewed.  This
does not preclude the submission of a substantial revision of an
application already reviewed, but such an application must include an
introduction addressing the previous critique.

Preparation of the Application

The general instructions provided for the preparation of the
applications contained in the Grant Application Form PHS-398 are to be
used in preparing Cooperative Agreement applications.  Because of the
award terms and conditions included in the section under SPECIAL
REQUIREMENTS, Terms and Conditions of Award, it is important that
applicants indicate in the Research Plan how they will meet the
requirements stated in the RFA.  To ensure that the cooperative
agreement remains the appropriate instrument, awardees submitting
competing continuation and supplemental applications must describe how
they have met the established terms and conditions.

The following items apply to all applications:

1.  The study should clearly address a pilot trial and optionally a
definitive trial.  The pilot trial must involve the application of a
biological and/or biochemical marker and its modulation by the study
agent.  The definitive trial involves the implementation of a
full-scale, randomized, double-blind, risk reduction, prevention
clinical trial.  For applicants seeking to conduct only a pilot trial,
the study must describe relevance to a clinical trial application,
including a marker, agent and target group that might be appropriate
for a full-scale intervention after completion of the pilot study.

2.  The applicant should provide a rationale for selection of the
biological or biochemical marker, its relevance to risk identification
or modulation, and its relevance to the intervention agent and the
target population.

3.  The applicant should provide the rationale for selection of the
proposed intervention agent.  This should include relevant
epidemiologic and laboratory data.  Preclinical and clinical data on
any potential untoward effects of the intervention agent should also be
presented.  In circumstances where there might be some doubt as to the
availability or the safety of the agent, the applicant may wish to
consult with the pharmaceutical company and the NCI Program Director
prior to preparing the application.  If an investigator anticipates
requiring considerable assistance in obtaining the chemopreventive
agents or in securing the Investigational New Drug (IND) permit from
the Food and Drug Administration, such assistance must be sought in
writing from the Program Director, prior to submitting the application.

4.  The applicant should provide a rationale for selection of a
specific target group and provide an estimate of the number of
participants required for the completion of the study.  Criteria and
calculations used to estimate sample size should be included.  The
applicant should provide a description of the target population or
group chosen and should justify the selection of this group.  The group
should be defined, as appropriate, by age, sex, race, dietary customs,
education, geographic location, occupational or lifestyle risk factors,
and 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 proposal should
include verification of the coinvestigators' willingness to
participate, and pertinent additional information regarding the
cooperating institutions' staff qualifications, resources, research
plans, including patient availability and data flow, as well as
corresponding budget requirements.

5.  The applicant should clearly indicate the clinical chemistry and
biologic aspects of the study to include collection, storage, handling,
analysis, and quality control of biological or biochemical samples.
The methods and equipment to be used and the technical qualifications
and experience of the personnel involved must be addressed.  If these
aspects of the study are to be conducted by groups other than at the
applicant's institution, a letter from the cooperating institutions
indicating their willingness to participate should be included.

6.  The applicant should elucidate any known or potential safety or
toxicity considerations, the techniques and procedures to monitor and
report any adverse health effects and appropriate dose modifications
based on toxicity monitoring.

7.  The applicant should specify the methods to be used to document
nutrient intake, if indicated, and adherence to the prescribed
intervention during the course of the trial.

8.  The applicant must indicate a willingness to work cooperatively
with the assistance of the 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.  If so, a letter of agreement from either the GCRC program
director or principal investigator could be included with the
application.

10.  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 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.

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, intervention agents,
etc., procedures for their collection and analysis, and assurances of
their accessibility.

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

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

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

AWARD CRITERIA

The earliest feasible start date for the initial awards will be July 1,
1995.  In addition to the technical merit of the applications, the NCI
will consider how well the applicant institutions meet the goals and
objectives of the program as described in the RFA, availability of
resources, and study populations, in making funding decisions.

INQUIRIES

Written and telephone inquiries concerning the 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:

Winfred F. Malone, Ph.D., M.P.H.
Division of Cancer Prevention and Control
National Cancer Institute
Executive Plaza North, Room 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 Federal regulations
42 CFR Part 52 and grant policies 45 CFR Part 74 and 92.  This program
is not subject to the intergovernmental review requirement 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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