Full Text CA-94-022

RESEARCH PROGRAM GRANTS IN CHEMOPREVENTION

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

RFA:  CA-94-022

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Chemoprevention 
  Biomedical Research, Multidiscipl 


National Cancer Institute

Letter of Intent Receipt Date:  September 1, 1994
Application Receipt Date:  October 20, 1994

PURPOSE

The Division of Cancer Prevention and Control (DCPC), National Cancer
Institute (NCI), invites applications to support a research and
development program of multiple projects directed towards
chemoprevention of cancer, requiring a broadly based and
multidisciplinary approach.

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), Research and Development Projects in
Chemoprevention, 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 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 (U19) mechanism.  The
cooperative agreement is an assistance mechanism in which substantial
NIH programmatic involvement with the recipient during performance of
the planned activity is anticipated.  The nature of the Program
Director's involvement is described in the section SPECIAL
REQUIREMENTS.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the
applicant/awardee.  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 continuing applications for review
according to procedures described below in the APPLICATION PROCEDURES
and REVIEW CONSIDERATIONS sections.

As more fully described later in this RFA, the recipients will have
primary responsibility for the development  and performance of the
activity.  However, there will be government involvement with regard
to:  (1) assistance in securing an Investigational New Drug (IND)
approval from the Food and Drug Administration (FDA), (2) coordination
and assistance in obtaining the chemopreventive agent, (3) monitoring
of safety and toxicity, and (4) quality assurance of the clinical
chemistry aspects of the study.  If an investigator anticipates
requiring considerable assistance in obtaining the chemopreventive
agent and/or in securing an 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
awards 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 $4.0 million in total costs for the first year for
project periods up to five years will be committed to specifically fund
applications that are submitted in response to this RFA.  It is
anticipated that four 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 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 Chemoprevention Branch invites research project cooperative
agreement applications (U19) in chemoprevention to encourage and
facilitate multidisciplinary collaborations through the coordinated
submission of related research projects that share a common research
theme in chemoprevention.

To be eligible for awards, the application must include a minimum of
three scientifically meritorious projects, one of which must involve a
clinical trial.  The theme might involve a particular agent or class of
agents (i.e., anti-initiators or antipromoters:  retinoids,
non-steroidal anti-inflammatory agents), populations (general, at-risk,
subjects with precancer or cancer patients free of disease), sites
(breast, prostate, lung, colon), or surrogate markers.  Relevant
preclinical and clinical ancillary projects might include in vitro and
in vivo (animal) efficacy studies, pharmacokinetic and pharmacological
evaluations, biomarker studies, and nested case control evaluations.
The application should include a sufficient number of scientifically
meritorious projects to promote an effective collaborative effort among
the participating investigators.

This particular type of research project cooperative agreement (U19)
builds on the leadership of a key principal investigator and the
interaction of the participating investigators in order to integrate
the individual projects in a way that accelerates the acquisition of
knowledge beyond that expected from the same projects conducted
separately, without combined leadership or a common theme.  Individual
investigators may apply their specialized research capabilities to
basic, developmental, and clinical aspects, as they relate to the
focused, central theme of the overall project.  This grant mechanism
also offers a special way to achieve an economy of effort through the
sharing of personnel, facilities, equipment, data, ideas, and concepts.

The principal investigator of the research program cooperative
agreement must be an established scientist with a strong record of
accomplishment, who is substantially committed to, and capable of,
exercising the responsibility for the scientific leadership,
integration and administration of a major effort in cancer prevention.
The component projects should be directed by investigators who are
experienced in the conduct of independent research and whose
backgrounds and interests relate sufficiently to one another in order
to allow for integrated group pursuits.

Awardees will have primary responsibility for the development and
performance of the activities.  However, there will be involvement by
the NCI Program Director with regard to (1) coordination and assistance
in obtaining the chemopreventive agent, (2) securing an IND approval
from the FDA, (3) monitoring of safety and toxicity, and (4) quality
assurance of clinical chemistry aspects of the study.

SPECIAL REQUIREMENTS

A.  General

This RFA represents a single competition, with a specified deadline,
October 20, 1994, for receipt of applications.  It is expected that
each application will describe plans for a mixture of basic,
developmental and clinical research from an investigator wanting to
focus on a particular study in cancer chemoprevention.  Each
application should have a general focus on study outcomes, and on the
application of basic research and development to human subjects and
populations.

B.  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

Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant/awardee.  The
awardees will retain custody of and have primary rights to their data.

a.  Safety and Toxicity Review

Each awardee institution and principal investigator agrees 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.  Data Management and Reporting Requirements

Data acquisition and analysis is the responsibility of the
investigator.  Each awardee institution will retain custody and primary
rights to their data developed under these cooperative agreements.

Investigators will be required to submit reports to NCI using the
following schedule and format as required by FDA Investigational Drug
Regulations, Code of Federal Regulations (CFR) 21, par. 312.23.

(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 non-clinical investigations, including:

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

A list of subjects who dropped out during the course of the
investigation, with the cause of death for each subject.

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 will not be
issued 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.

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

Due Dates for Reports

(1) January 1 and July 1 for the semi-annual 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 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 drugs.  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 applications which are
ultimately funded.  Such a review is legally required by the FDA to
ensure that all safety toxicity, monitoring, and reporting issues are
in conformance with IND guidelines.  The awardee institutions 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 IND permit
from the FDA, such assistance must be sought in writing from the
Program Director, and assistance approved by the Program Director,
prior to submitting the application.  Awards will not be made until all
arrangements for obtaining the 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 shall be implemented without approval from
the NCI Program Director, consistent with FDA requirements.

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.  The Arbitration Mechanism
is described below.

g.  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 below).  Recommendations of the NCI Program Director will be
communicated by letter to the investigator to which he/she is expected
to respond.

Insufficient numbers of patients accrued to attain the stated delta
value (d=difference between treatments to be detected divided by
standard deviation), unsatisfactory progress, or non-compliance with
terms of award may result in a reduction of the budget, withholding of
support, suspension or termination of the award.

h.  Quality Assurance

(1) The NCI has established a clinical chemistry quality assurance
program with the National Institutes of Standards and Technology
(NIST), 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) The NCI Program Director will review the mechanism established by
each awardee for quality control of clinical studies.  These mechanisms
must conform with FDA regulations.

i.  Non-compliance with Terms of Award

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.

j.  Other Terms

(1) Patient enrollment in a study may not be initiated 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.

3.  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 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 September 1, 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 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 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 brochure, Guidelines for the Program Project Grant of
the National Cancer Institute, should also be consulted.

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,
"Research Project Grants in Chemoprevention" and the RFA number,
CA-94-022, 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
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636A
6130 Executive Boulevard
Rockville, MD  20852  (If hand-delivered)
Bethesda, MD  20892 (If using U.S. Postal Service)

It is important to send these copies at the same time that the original
and three copies are sent to DRG; otherwise, the NCI cannot guarantee
that the applications will be reviewed in competition with other
applications received by the designated receipt date.  Revised or
additional information may not be submitted after the receipt date
unless specifically requested by NCI staff.

The general instructions for 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 submitting competing continuation and
supplemental applications must describe how they have met the
established terms and conditions.

REVIEW CONSIDERATIONS

A.  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 the initial awards will be July
1995.  In addition to the technical merit of the applications, NCI will
consider how well the applicant institutions meet the goals and
objectives of the program as described in the RFA, the availability of
NCI funds, and the applicability of proposed study populations.

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, requests for the program
project guidelines, 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 93.999, 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 PHS grant policies CFR Parts 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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