Full Text CA-93-029

CLINICAL STUDIES OF SYSTEMIC THERAPIES

NIH GUIDE, Volume 22, Number 21, June 11, 1993

RFA:  CA-93-029

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Clinical Medicine, General 
  Treatment, Medical+ 


National Cancer Institute

Letter of Intent Receipt Date:  October 22, 1993
Application Receipt Date:  December 7, 1993

PURPOSE

The Cancer Therapy Evaluation Program of the Division of Cancer
Treatment at the National Cancer Institute (NCI) invites Interactive
Research Project Grant (IRPG) applications to perform research
projects designed to conduct clinical studies of innovative systemic
therapies investigating promising therapeutic approaches in a single
tumor type or focused on a single class of novel compounds or a
mechanism of action.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Clinical Studies of Systemic Therapies, 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

Domestic and foreign for-profit and non-profit organizations,
governments and their agencies are eligible to apply.  Applications
can be from single institutions and multiple institutions
(collaborating institutions, consortia, cooperative groups).  New and
experienced investigators are encouraged to apply.  Applications from
minority individuals and women are encouraged.

For the purpose of this RFA (CA-93-029), each IRPG must consist of a
minimum of three investigator-initiated research grant applications
(R01s).

Amended applications from CA-92-25 are encouraged.  An IRPG that
received funding for one or more, but not all, of the applications in
the original package may submit revised applications for those that
were unfunded.  IRPGs submitted under CA-92-25 can be submitted with
less than three required independent R01s under CA-93-029.  However,
the number of applications currently funded under CA-92-25 plus
revised applications submitted under CA-93-029 must be three or more
R01s.

MECHANISM OF SUPPORT

Support of this program will be by the traditional research project
grant (R01) through the use of the IRPG program (see Background,
RESEARCH OBJECTIVES).  Except as otherwise stated in this RFA, awards
will be administered under PHS grants policy as stated in the Public
Health Service Grants Policy Statement, DHHS Publication No. (OASH)
90-50,000, revised October 1, 1990.

The total cost for each IRPG (consisting of three or more R01s) is
limited to $750,000 per year.  The average amount of direct cost per
year for each R01 will range from $140,000 to $180,000.  The total
project period for applications submitted in response to the RFA may
not exceed four years.  The earliest feasible start date for the
initial awards will be August 1994.

This RFA is a one-time solicitation.  If it is determined that there
is a sufficient continuing program need, the NCI will invite
recipients of awards under this RFA to submit competitive
continuation applications for review according to the procedures
described below.

FUNDS AVAILABLE

Approximately $2,000,000 in total costs per year for four years will
be committed to fund applications submitted in response to this RFA.
It is anticipated that three IRPGs will be funded in FY 94.  This
funding level is dependent on the receipt of a sufficient number of
applications of high scientific merit.  Although this program is
provided for in the financial plans of the NCI, the award of R01
grants pursuant to this RFA is also contingent upon the availability
of funds for this purpose.

RESEARCH OBJECTIVES

Background

Investigator initiated grant support is by far the largest single
entity in the National Cancer Institute (NCI) research budget. The
NCI utilizes a range of funding mechanisms to support clinical
research efforts of differing scale and scope.  For the conduct of
large scale, multi-institutional clinical trials, the Cancer Therapy
Evaluation Program has established a program of integrated national
networks of clinical investigators and institutions (Clinical Trials
Cooperative Groups).  The primary responsibility of the cooperative
groups is to perform definitive evaluation of clinical treatment
programs.  These groups have limited involvement with pilot studies
and ancillary laboratory studies, which bridge the gap between the
laboratory and the clinic.  Currently, translational research and
preliminary clinical studies are supported by grants (R01, P01 and
U01 awards) under the Research Project Grant category.  This smaller
scale clinical research is usually done within single institutions or
in small consortia of institutions interested in a particular area of
therapeutic investigation.  These investigator initiated mechanisms
support early clinical development of new therapeutic agents and
treatment modalities.  They support pharmacokinetics studies, studies
of mechanisms of action and resistance of therapeutic agents, and all
types of clinical correlative studies.  This effort is the essence of
translational research, which brings the basic science to the bedside
and provides leads for definitive treatment trials.

An unprecedented number of new therapeutic agents are ready for
evaluation in pilot clinical studies.  In addition, insights into the
biologic function and clinical relevance of growth factors, genes
that promote and suppress neoplasia, mechanisms of treatment
sensitivity and resistance, and function of the immune system provide
important new clinical research opportunities for investigators.  The
NCI is interested in expanding support for clinical research.  Under
this IRPG RFA, the NCI encourages the coordinated submission of
related research project grant applications from investigators who
want to collaborate on a common cancer research theme, but do not
require extensive shared physical resources or multiple core
functions.  This mechanism is not meant to replace the program
project (P01) mechanism but to support a level of collaboration
between that of the P01 and that available through an individual R01.

The IRPG is defined in PA-93-078 (NIH Guide for Grants and Contracts,
Vol. 22, No. 16, April 23, 1993) as two or more investigator
initiated research grant proposals that are reviewed for independent
merit but that share a theme and resource(s), and that require
concurrent funding to maximize the effectiveness of the resource or
to allow maximal creative interaction between researchers.
Applicants will benefit from use of the IRPG mechanism by
establishing a larger framework of reference for the proposed work,
facilitating formal collaborations tailored to achieving research
objectives, providing a record of independently acquired awards
credited to each funded investigator, and allowing retention of
research autonomy by the named Principal Investigator on each of the
interactive grants.

Research Goals And Scope

This RFA is soliciting applications to perform IRPGs with the goal of
developing new clinical studies involving systemic therapies with a
therapeutic intent.  The IRPGs may have as their key focus either:
(1) clinical studies investigating promising therapeutic approaches
in a single tumor type or (2) the development of new clinical
treatment strategies focused on a single class of novel compounds or
mechanism of action.  Each project supported in the IRPG is expected
to contribute to and be directly related to the common theme of the
IRPG application.  The application must clearly explain how the
projected integrated R01 research grants can be expected to
accomplish the stated goal more efficiently and effectively than they
could without the anticipated interactions.  At least one clinical
trial protocol must be proposed in one of the grant applications.
The clinical trials should be well integrated with the laboratory
studies proposed within the same R01 grant or in separate R01 grants.

Support will be provided to institutions with established clinical,
laboratory and statistical resources.  Some examples of research
areas that individual R01 grant applications would focus on include:
(1) pre-clinical drug development studies, utilizing in vitro or in
vivo models, leading to new clinical trials; (2) studies to elucidate
or exploit the mechanism of action or resistance of therapeutic
agents; (3) pharmacokinetics and pharmacodynamic studies of new
agents or in combination; (4) clinical correlative studies designed
to improve therapeutic approaches; (5) clinical trials of new
systemic therapies utilizing therapeutic agents alone or in
combination with other modalities.  Investigators are not limited to
the above examples of potential studies.  The NCI encourages
investigators to propose other scientific approaches that suit the
interactive R01 mechanism and the requirements of this RFA.

The aims of this RFA are two-fold:  (1) to provide support for
translational research that brings innovative basic research findings
into the clinic and (2) to foster the development of interactions
between basic science laboratories of different disciplines and
clinicians performing clinical trials to advance therapeutic clinical
research.

Special Requirements

Definitions

Principal Investigator (PI) - The person who submits the single R01
grant application in response to this RFA and who is responsible to
the applicant/awardee institution for the scientific and
administrative direction and proper conduct of all aspects of the R01
grant.

Project Coordinator -  The person designated by the PIs of the
interactive R01 grants who is responsible for the overall
coordination of the scientific direction of the interactive R01
grants.

Responsibilities of Each Awardee

Each awardee is responsible for his/her own proposed research
project(s) to advance the goals of the RFA and to define its
approaches to attain these goals.  It is the primary responsibility
of the PI to state clearly the objectives of the research project, to
direct the research stipulated in the application, and to ensure that
the results obtained are published in a timely manner.  It is
anticipated that decisions on the overall scientific direction of the
package of interactive R01s will be reached by consensus of the
collaborating PIs.

Responsibilities of the Project Coordinator

In addition to the responsibilities stated above for each awardee,
the Project Coordinator has the responsibility of providing
coordination of the overall scientific direction of the interactive
R01s.  He/she will accomplish this role by facilitating scientific
collaborations among the various investigators.  The Project
Coordinator will also be responsible for establishing mechanisms to
facilitate regular communication and coordination among
investigators.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF FEMALES AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
females in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and females in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If females or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 in the Research
Plan, 1-4, AND summarized in Section 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from females and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of females applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
females or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 22, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the names and addresses of the Principal Investigators, the
names of other investigators and key personnel, the participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.  Amended IRPGs should
indicate which institutions are already funded, if applicable.

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. Roy S. Wu at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The PHS 398 (rev. 9/91) research grant application form is to be used
in applying for this RFA.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Inquiries, 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 named below.

The RFA label available in the PHS 398 research application form must
be affixed to the bottom of the face page.  Failure to use this label
could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition,
the RFA number and title must be typed on line 2a of the face page of
the application form.

All the R01 applications constituting the proposed IRPG cohort must
be submitted in a single package, whether or not the applications
arise from the same institution.  Each application within the package
must be clearly identified and a cover letter must list the total
number of applications submitted for the IRPG cohort, indicating the
Principal Investigator of each.  The various applications should not
be collated into an IRPG "package."  For each application, the
original, three copies, and the appendix material must be packaged
together and clearly identified.

The IRPG package must be sent or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, send two additional copies of each
application in the form of an IRPG package to:

Ms. Toby Friedberg, Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 650
6130 Executive Boulevard
Bethesda, MD  20892

Applications must be received by December 7, 1993.  If an application
is received after that date, it will be returned without review.  If
the application submitted in response to this RFA is substantially
similar to a research grant application already submitted to the NIH
for review, but 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.  Therefore, an application cannot be
submitted in response to this RFA that is essentially identical to
one that has already been reviewed.  This does not preclude the
submission of substantial revisions of applications already reviewed,
but such applications must include an introduction addressing the
previous critique.

Special Instructions

Particular attention must be paid to completion of Section 7,
Consultants and Collaborators, for each IRPG application.  In
addition to those collaborations that would be necessary to carry out
the proposed research, whether or not the IRPG mechanism is involved,
within Section 7, each application that is a component IRPG must
provide an identical statement (titled "IRPG INTERACTIONS") regarding
the IRPG collaboration.  This section should list each application
that is part of the IRPG, including title, Principal Investigator,
and other participating scientists.  The single Project Coordinator,
responsible for coordinating the collaborative efforts among the
research projects and for promoting interaction and communication
among the Principal Investigators, should be identified here.  This
section should further discuss the intended interactions among the
components of the IRPG and the perceived benefits of supporting all
of the components of the IRPG as a combined effort.

Requests for limited shared resources, if any, should be included in
this part of Section 7.  This should include costs and full budget
justification.  To further clarify the utilization of shared
resources, additional succinct information is needed and it is
suggested that two tables be included.  Table I would be identical in
all applications of the IRPG cohort.  Table II will detail the
distribution of effort for all of that application's personnel
(professional, technical and clerical) on all shared activities
and/or resources.  A sample format for the Tables can be obtained
from the NCI Program Director listed under INQUIRIES.  The
utilization of these resources by each IRPG will be evaluated
independently by the study section and any appropriate modifications
recommended.

Special Instructions for Revised Applications from CA-92-25

All revised applications from CA-92-25 must follow instructions for
revised applications contained in the PHS 398 kit.

For those revised applications that are composed of IRPGs that
received funding for one or more, but not all of the applications in
the original response to CA-92-25, an expanded section 7 is
recommended.  In addition to the information requested above, the
applicant(s) should provide the title, the name and institution of
the Principal Investigator, the abstract and the specific aims of the
funded components of the IRPG.  A special effort should be made to
describe and justify the nature of the interaction with the funded
grant(s).  The total costs for the funded grant(s) and the revised
application(s) cannot exceed the $750,000 total cost limit set forth
under MECHANISM OF SUPPORT.

REVIEW CONSIDERATIONS

Review Procedure

Upon receipt, applications will be reviewed by the Division of
Research Grants (DRG) for completeness.  Incomplete applications will
be returned to the applicant without further consideration.
Evaluation for responsiveness to the program requirements and
criteria stated in the RFA is an NCI program staff function.
Applications that are judged non-responsive will be returned to the
applicant.  An application judged to be non-responsive to this RFA
may be submitted as an investigator initiated IRPG at the next
receipt date for unsolicited applications.  Questions concerning the
responsiveness of proposed research to the RFA are to be directed to
program staff listed under INQUIRIES.

If the number of applications submitted is large compared to the
number of awards to be made, the NCI may conduct a preliminary
scientific peer review to eliminate those that are clearly not
competitive.  The NCI will remove from competition those applications
judged to be noncompetitive for award and notify the applicant and
institutional business official.

Those applications judged to be both responsive and competitive will
be further evaluated according to the review criteria stated below
for scientific and technical merit by an appropriate peer review
group convened by the Division of Extramural Activities, NCI.  The
second level of review by the National Cancer Advisory Board
considers the special needs of the Institute and the priorities of
the National Cancer Program.

Review Criteria

The factors considered in evaluating the scientific merit of each
application will be:

o  Extent to which the proposed research addresses the goals of the
RFA

o  Scientific, technical, or medical significance and originality of
proposed research within each R01 application;

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  Research or clinical experience, training, time availability, and
qualifications of the investigators involved;

o  Adequacy of plans for effective collaboration among laboratory,
clinical, and statistical investigators within
   each R01;

o  Adequacy of the available resources and environment (e.g.
facilities, equipment, statistical resources; patient population)

o  Adequacy of the mechanisms for quality control, study monitoring,
data management and reporting, and data analysis;

o  Adequacy of provisions for the protection of human subjects;

o  Adequacy of the plans for inclusion of females and minorities.

The reviewers will also judge the appropriateness of the proposed
budget and duration in relation to the proposed research.  For each
application that is given a priority score, the review group will
assign an adjectival descriptor that reflects the extent and
effectiveness of its collaboration(s) with other applications
included in the IRPG.  This assessment will be documented in a brief
administrative note in the summary statement to assist the NCI in
making final decisions on each application in the context of the
overall IRPG.

AWARD CRITERIA

The anticipated date of award is August 1, 1994.  In addition to the
technical merit of the application, the NCI will consider how well
the applicant institution meets the goals and objectives of the
program as described in the RFA, availability of resources, and study
populations.  Those applications involving breast cancer research
will have priority.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope
of this RFA and inquiries about whether or not specific proposed
research would be responsive are encouraged.  The NCI Program
Directors welcome the opportunity to clarify any issues or questions
from potential applicants.

Direct inquiries regarding programmatic issues and address the letter
of intent to:

Dr. Roy S. Wu
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663

Direct inquires regarding fiscal matters to:

Ms. Jennifer Edwards
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 57
FAX:  (301) 496-8601

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No 93.395, Cancer Treatment Research.  Awards are made
under the authorization of the Public Health Service Act, Title IV
Sections 301, 410, and 411, Part A (Public Law 78-410, 42 USC 241 as
amended, Public Law 99-158, 42 USC 285a) and administered under PHS
grants policies and Federal Regulations at 42 CFR Part 52 and 45 CFR
Part 74.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.

.

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