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Full Text CA-92-28
CLINICAL TRIALS OF CANCER THERAPY WITH BIOLOGICAL RESPONSE MODIFIERS
NIH GUIDE, Volume 21, Number 36, October 9, 1992
RFA: CA-92-28
P.T. 34
Keywords:
Clinical Trial
Cancer/Carcinogenesis
Biological Response Modifiers
National Cancer Institute
Letter of Intent Receipt Date: October 30, 1992
Application Receipt Date: December 22, 1992
PURPOSE
The Division of Cancer Treatment (DCT), National Cancer Institute
(NCI) invites applications to establish cooperative agreements for
Clinical Trials of Cancer Therapy with Biological Response Modifiers
(CATBRMs), for the development of novel approaches to such therapy.
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), Clinical Trials of Cancer Therapy With
Biological Response Modifiers (CATBRMs), 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
Groups constituted according to the guidelines outlined in the
RESEARCH OBJECTIVES, Section C are eligible to apply. Applying
groups may include members from academic, non-profit and for-profit
institutions. Involvement of intramural NIH personnel is limited as
described under the RESEARCH OBJECTIVES, Section C, Composition of a
CATBRM Group. Domestic and foreign organizations and institutions
(non-profit or for-profit) are eligible. Governments and their
agencies are also eligible. Applications from women and members of
minority groups are encouraged.
MECHANISM OF SUPPORT
Support of this program will be through the Cooperative Agreement
(U01), an assistance mechanism in which substantial NCI programmatic
involvement with the recipient during performance of the planned
activity is anticipated. The nature of NCI staff involvement is
described in the section entitled SPECIAL REQUIREMENTS, A. Terms of
Cooperation. Applicants will be responsible for the planning,
direction, and execution of the proposed project. There is no
intent, real or implied, for NCI staff to direct CATBRM activities or
to limit the freedom of investigators. In addition to the
requirements stated in this RFA, awards will be administered under
PHS grants policy as stated in the Public Health Service Grants
Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised
October 1, 1990.
This RFA is a reissuance of RFA CA-92-01. Applicants who did not
apply to the first announcement, or who applied but did not receive
an award, are encouraged to respond to this RFA. However, this
reissued RFA is a one-time solicitation. Generally, future
unsolicited competing renewal applications will compete as research
project applications with all other investigator-initiated
applications. However, should the NCI determine that there is
sufficient continuing program need, the NCI will invite recipients of
awards under this RFA to submit competitive continuation cooperative
agreement applications for review.
Each award will be made to the institution designated in the
application as the applicant institution. All CATBRM study group
activities will be coordinated through the Principal Investigator.
Under the Cooperative Agreement, a relationship exists between the
recipient of the award and the NCI, in which the CATBRM group is
responsive to the requirements and conditions set forth in the RFA.
Specifically, the Principal Investigator defines the details for the
project within the guidelines of the RFA, retains primary
responsibility for the performance of the activity, and agrees to
accept close coordination, cooperation, and assistance of the NCI
extramural staff (through the NCI Program Director) in all aspects of
scientific and technical management of the project in accordance with
the Terms of Cooperation.
FUNDS AVAILABLE
The NCI plans to make up to six awards for project periods up to four
years, and has set aside $1.5 million total costs for the initial
year's funding. The total funding level and number of awards to be
made 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 National Cancer Institute,
awards pursuant to this RFA are contingent upon continuing
availability of funds.
Applicants may request no more than four years of support. The
earliest possible starting date for the initial annual period will be
July 1, 1993.
RESEARCH OBJECTIVES
A. Background/Summary
The clinical successes of biological response modifiers (BRMs) in
cancer treatment are well known (e.g., single-agent `-interferon for
hairy-cell leukemia; and the responses to IL-2 based therapy in renal
cell carcinoma). These limited successes suggest a future role for
BRMs in clinical oncology. Rapid developments in molecular biology,
hybridoma technology, protein engineering, and other areas are
providing new opportunities and challenges to investigators
attempting to define this role. At an accelerating rate, new BRMs--
e.g., growth and differentiation factors; cytokines and
colony-stimulating factors; murine, chimeric, and human monoclonal
antibodies; and targeting agents such as immunotoxins, fusion
proteins, and antibody fragments--have become available for clinical
trials, and other agents now under preclinical study may be of
interest as BRMs. New technologies, such as the use of
gene-transfected cells and new methods of vaccine design, have led to
novel approaches to such previously studied strategies as adoptive
immunotherapy and active specific immunotherapy. Insights into
possible combination regimens employing BRMs are also being made. At
the same time, it is clear that much remains to be learned about the
relationship between clinical and other biological effects of BRMs--
e.g., potential mechanisms of action, appropriate parameters for
monitoring of patients, and development of endpoints which may
predict clinical benefit.
The NCI seeks, with this RFA, to foster innovative clinical trials of
BRMs by peer-reviewed groups of highly experienced clinical and
preclinical investigators who have the unique technical capabilities
to study new agents in early clinical trials and to address
hypothesis-driven issues of mechanisms of action. This initiative
will establish Clinical Study Groups for Cancer Therapy with
Biological Response Modifiers (CATBRMs), for the design and execution
of novel clinical trials with BRMs. The Research Goals and Scope of
this RFA will require a novel plan for clinical study of a given new
agent or agents, adequately supported by prior preclinical, and if
available, clinical, results. The application must describe how its
objectives are in accord with the applicant's own interests and
experience. The applicant must provide evidence of access to the
agent(s) proposed for study. A detailed protocol for an initial
clinical trial must also be included. The NCI will facilitate the
institution of a peer-reviewed, investigator-initiated trial,
participating as outlined in the section entitled SPECIAL
REQUIREMENTS, A. Terms of Cooperation.
Each CATBRM study group will be composed of: a Principal
Investigator; one or more laboratory programs, each headed by a
Program Leader, with the demonstrated expertise to design and carry
out assays for the appropriate monitoring of patients on the study;
one or more clinical programs, each headed by a Program Leader, with
demonstrated expertise in conducting clinical trials of BRMs; and the
NCI Program Director. The application may include investigators from
one or more domestic or foreign academic, non-profit, and/or
commercial institutions. Application under this RFA may also be a
logical step to develop agents arising in National Cooperative Drug
Discovery Groups (NCDDGs), P01s, or R01s.
For this RFA, a BRM is defined as: "An agent or approach intended to
modify the relationship between tumor and host by modifying a host's
biological response to tumor cells, with resultant therapeutic
benefit. This includes: agents or approaches which utilize or
modify immunological mechanisms; naturally occurring or recombinantly
produced regulatory molecules (e.g., cytokines, growth or
differentiation factors); and monoclonal antibodies and their
derivatives." (See B. Definitions, below) In responding to this
RFA, applicants should propose clinical trials of BRM agents or
strategies as so defined, where the focus of study is the testing of
a biologic hypothesis. Generally, it is envisioned that this will be
done in the context of small pilot clinical trials. Prospective
applicants who plan to study agents which are not BRMs as defined,
who plan large randomized clinical trials, or who plan trials solely
to study issues of safety and efficacy apart from any other biologic
hypothesis, will be referred to other NCI programs supporting
clinical trials for cancer therapy.
B. Definitions
COOPERATIVE AGREEMENT--An assistance mechanism in which substantial
NIH programmatic involvement with the recipient during performance of
the planned activity is anticipated.
STUDY GROUP FOR CLINICAL TRIALS OF CANCER THERAPY WITH BIOLOGICAL
RESPONSE MODIFIERS (CATBRM STUDY GROUP)--A group consisting of a
single Principal Investigator (who may also be a Program Leader); one
or more laboratory programs, each headed by a Program Leader, with
the demonstrated expertise to design and carry out assays for the
appropriate monitoring of clinical trial subjects; one or more
clinical programs, each headed by a Program Leader, with demonstrated
expertise in conducting clinical trials of BRMs, and the NCI Program
Director. Working under the guidance and direction of the Principal
Investigator, the CATBRM study group (also referred to simply as a
"study group" or a "group" in this RFA) pursues the common goal of
the novel clinical development of new agents, regimens, or strategies
for therapy of cancer with BRMs. Coordinated through the Principal
Investigator, the CATBRM study group will employ a research plan and
budget that clearly delineate the clinical and laboratory components
of both the plan and the budget.
CLINICAL PROGRAM--A research component of the overall group, with the
expertise and experience to conduct clinical trials of BRMs based on
the latest scientific developments.
LABORATORY PROGRAM--A research component of the overall group, with
the expertise and experience to carry out assays designed to
investigate mechanisms of action of clinical BRM regimens.
APPLICANT INSTITUTION--The institution, designated in the
application, that assumes legal and fiscal accountability for the
disposition of funds awarded.
PARTICIPATING INSTITUTION--One or more investigators from a single
institution who, together, participate in one of a group's clinical
or laboratory programs.
BIOLOGICAL RESPONSE MODIFIER--An agent or approach intended to modify
the relationship between tumor and host by modifying a host's
biological response to tumor cells, with resultant therapeutic
benefit. This includes: agents or approaches which utilize or
modify immunological mechanisms; naturally occurring or recombinantly
produced regulatory molecules (e.g., cytokines, growth or
differentiation factors); and monoclonal antibodies and their
derivatives.
PRINCIPAL INVESTIGATOR--By definition in Federal regulations, "a
single individual designated by the grantee in the grant application
and approved by the Secretary, who is responsible for the scientific
and technical direction of the project" (42 CFR Part 52). The
Principal Investigator is the person who assembles the CATBRM,
submits the single application in response to this RFA, and is
responsible for performance of the group as a whole and of each
Program Leader. The Principal Investigator may be an M.D., D.O., or
Ph.D., and may lead one of the Clinical or Laboratory Programs of the
group. The Principal Investigator will also coordinate group
activities. If the Principal Investigator is a Ph.D., a Clinical
Investigations Leader who is an M.D. or D.O. will be designated on
the initial group application. The Clinical Investigations Leader
will, in such a case, lead the design and conduct of the clinical
trial(s) conducted by the group.
CLINICAL INVESTIGATIONS LEADER--An M.D. or D.O., designated on the
initial grant application, who leads the design and conduct of the
clinical trial(s) conducted by the group. The Principal
Investigator, if an M.D. or D.O., may also be the Clinical
Investigations Leader.
PROGRAM LEADER--The director of one of the Clinical or Laboratory
Programs of the group.
NCI PROGRAM DIRECTOR--The extramural Program Director (cited in
INQUIRIES) of the Biological Resources Branch, Biological Response
Modifiers Program (BRMP), Division of Cancer Treatment (DCT), NCI,
designated by the NCI, who provides guidance for the overall CATBRM
program within the NCI, and who acts as NCI Coordinator for each
CATBRM group, facilitating the role of the NCI in the group.
PATENTABLE INVENTION--Any new and useful process, machine,
manufacture or composition of matter, or any new and useful
improvements thereof, as defined under the U.S. Patent Statute (35
USC 101).
C. Composition of a CATBRM Group
1. The composition of a CATBRM group is envisioned as follows:
a. A Principal Investigator, and if necessary as outlined above, a
Clinical Investigations Leader;
b. One or more Clinical Programs, each headed by a Program Leader,
each experienced in clinical oncology, clinical immunology, and the
conduct of clinical trials of BRMs for the treatment of human cancer;
c. One or more Laboratory Programs, each headed by a Program Leader,
each with demonstrated expertise in scientific disciplines necessary
to design and conduct the laboratory assays for the appropriate
monitoring of patients on the group's clinical trial;
d. The NCI Program Director, who coordinates NCI involvement in the
study group.
2. The Principal Investigator, in addition to providing scientific
and administrative leadership, may also be a Program Leader. All
Program Leaders will be directly responsible to the Principal
Investigator. The formation of the group, the application in
response to this RFA, the overall management of the group, and the
allocation of funds to the various Clinical and Laboratory Programs
based on performance and overall group needs at any given time will
be the responsibility of the Principal Investigator and the applicant
institution in accordance with PHS policies.
3. The specific makeup of the group's Clinical and Laboratory
Programs, and the specific disciplines represented, should depend on
the talents required to accomplish its scientific and technical
objectives as perceived by the Principal Investigator and Program
Leaders. The major consideration in structuring a CATBRM group
should be the full mobilization of the expertise necessary to
accomplish the group's research goals. While the specific makeup of
different groups may vary, each group's Clinical and Laboratory
Programs, when taken together, must include all necessary expertise
for the achievement of its research goals.
4. An individual scientist or clinician may be proposed as a
Principal Investigator or a Program Leader in more than one
application. If so, the Principal Investigator must demonstrate in
the application that there is no scientific or budgetary overlap or
proprietary conflict with each individual's proposed activities.
Likewise, individuals currently receiving funding via contracts,
grants, or cooperative agreements may be funded under this RFA if
there is no scientific or budgetary overlap or proprietary conflict
in funded activities. An NIH intramural scientist may participate in
a CATBRM group as a collaborator or consultant, but may not be a
Program Leader or receive salary, equipment, supplies, or other
remuneration from this program. The intramural scientist must
provide a letter of commitment and a current curriculum vitae, and
obtain appropriate NIH clearances prior to submission of the
application. The Principal Investigator must incorporate into the
application, in the usual grant format, a full description of the
collaborative project, including technical details and methodology.
The participation of an intramural scientist is independent of and
unrelated to the role of the NCI Program Director as described in the
SPECIAL REQUIREMENTS, A. Terms of Cooperation, 2.a.
5. A CATBRM group may include members from a single institution or a
number of institutions, depending on the specific goals of the group.
6. Although a minimum of one Clinical and one Laboratory Program per
group is necessary, no limit on the number of Programs per group is
stipulated. In preparing applications, however, prospective
Principal Investigators should keep in mind that effective, efficient
cooperation can be difficult in groups with more than a few Clinical
and Laboratory Programs. In addition, very large groups may require
budgets large enough to be a limiting factor in funding decisions.
7. A CATBRM group may include one or more foreign members, or may
consist entirely of investigators or programs located outside the
United States.
8. Under the provisions of assistance through Cooperative Agreement,
the NCI Program Director will participate as a member of the group in
a manner specified in the Section SPECIAL REQUIREMENTS, A. Terms of
Cooperation. The NCI Program Director will not conduct Clinical or
Laboratory Programs.
D. Research Goals and Scope
1. The goals of this RFA are:
a. The development of novel approaches to the treatment of human
cancer with BRMs, employing new agents, concepts, or treatment
strategies. Applications must clearly seek new knowledge in this
field.
b. The clinical testing of such approaches by the conduct of one or
more related, well-designed clinical trials with BRMs. A detailed
clinical protocol must be submitted with the application (see
APPLICATION PROCEDURES, below) and must describe the subsequent
clinical trials envisioned by the applicant group. A central, common
theme should be the focus of these protocols and the CATBRM group's
efforts overall.
c. Exploration of mechanisms of antitumor effect and resistance, and
of the effects of modifications designed to alter these to clinical
and biologic advantage. This includes concurrent laboratory studies
which are designed to (a) elucidate observations or test hypotheses
arising from the clinical trial(s), or (b) refine the clinical
approaches used. Such studies may include in vitro or in vivo
experiments, theoretical modelling, development of surrogate
endpoints, or other studies as appropriate for the scientific goals
of the application.
d. Monitoring of specific immunomodulatory or other parameters, as
appropriate for the scientific goals of the application.
e. Observation of clinical effects (e.g., tumor responses, toxic
side-effects) of the treatment regimen, and, if appropriate,
correlation of these with other biologic endpoints.
SPECIAL REQUIREMENTS
A. Terms of Cooperation
1. Responsibilities of Awardees
It is the responsibility of the CATBRM study group to develop the
details of its research design; define its objectives and approaches;
plan and conduct the research; analyze and interpret the data
obtained; and publish the results. The NCI anticipates that
decisions in all activities will be reached by group consensus under
the leadership of the Principal Investigator, and that the NCI
Program Director will have the opportunity to offer input to this
process.
a. Membership in the Group
Group membership includes the Principal Investigator, the Clinical
Investigations Leader, the Program Leaders, and the NCI Program
Director.
In no case will changes of Principal Investigator, Program Leaders,
Clinical or Laboratory Programs, or participating institutions be
made without prior approval from the NCI. Such approval may be sought
either in the application for continuation grant (PHS 2590 (rev.
9/91)) or during the course of the budget period. In the latter
case, the procedure for requesting prior approval is described in the
"Methods for Grantees to Request Approvals," PHS Grants Policy
Statement, page 8-5.
b. Protocol Development
As for all group activities, it is anticipated that decisions
regarding protocol development will be reached by consensus of the
group, under the leadership of the Principal Investigator. The
Principal Investigator (or, if required, the Clinical Investigations
Leader) shall designate a single Protocol Chairperson for each
proposed clinical trial. The Principal Investigator will be
responsible for communication with NCI, through the NCI Program
Director.
c. Protocol Submission
The Principal Investigator will submit all group protocols to the NCI
Program Director for review and approval. The NCI Program Director
will coordinate any required NCI review (e.g., review by the Cancer
Therapy Evaluation Program (CTEP) if the protocol is to be conducted
under an NCI-held IND), and assure that the results of such review
are communicated to the Principal Investigator. The Principal
Investigator will be responsible for communicating the results of the
protocol review to the group's Program Leaders and participating
institutions.
Disagreements arising from NCI protocol review that cannot be
resolved by mutual discussion will be resolved by an arbitration
panel. The panel will consist of one CATBRM group nominee, one NCI
nominee, and a third member, chosen by the other two, with expertise
in clinical trials of BRMs. The panel will review the NCI decision
and recommend an appropriate course of action to the Director, DCT.
These special arbitration procedures in no way affect the awardee's
right to appeal an adverse determination in accordance with PHS
regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45
CFR Part 16. The CATBRM group will not expend NCI funds to conduct
any part of any NCI- disapproved CATBRM study unless the NCI
disapproval has been modified by this arbitration process.
d. Quality Control
The awardee institution is responsible for ensuring that the group
establishes mechanisms for quality control of therapeutic and
diagnostic modalities employed in its trials.
e. Study Monitoring
The group will establish mechanisms for study monitoring. The
awardee institution is responsible for assuring the group maintains
accurate and timely knowledge of the progress of each study through:
o Establishing procedures for assigning each new patient to a
treatment group at the time of entry to the study;
o Assuring that each Clinical and Laboratory Program is maintaining
verifiable data, conducting studies in compliance with the approved
clinical protocols, and complying with regulatory requirements for
the protection of human subjects and investigational agent
accountability;
o Tracking and reporting of patient accrual and adherence to defined
accrual goals;
o Ongoing assessment of case eligibility and evaluability;
o Timely medical review and assessment of patient data;
o Rapid reporting of treatment-related morbidity (adverse drug
reactions), in accordance with regulatory requirements, and measures
to ensure communication of this information to all parties; and
o Timely communication of results of studies.
f. Data Management and Analysis
The awardee institution is responsible for ensuring that the group
develops procedures to ensure that data collection and management
are: (1) adequate for quality control and analysis; (2) as simple as
appropriate in order to encourage maximum participation of physicians
entering patients and to avoid unnecessary expense; and (3)
sufficiently uniform across the participating institutions.
Data from protocols conducted under NCI-held INDs must also be
available for external monitoring, in accordance with an agreement
between the NCI and the FDA governing the NCIs responsibilities as a
drug monitor.
g. Compliance with Federally Mandated Regulatory Requirements
The awardee institution retains the primary responsibility for
establishing procedures for all participating institutions to comply
with Food and Drug Administration (FDA) regulatory requirements for
studies involving investigational agents, and Office of Protection
from Research Risks (OPRR) requirements for the protection of human
subjects. These procedures are:
(1) Methods for assuring that each institution at which investigators
are conducting group trials has a current, approved assurance on file
with the OPRR.
(2) Review and approval of each protocol by all responsible
Institutional Review Boards (IRBs) prior to patient entry; review of
each protocol at least annually by the IRB(s) so long as the protocol
is active; review and approval of protocol amendments by the IRB(s).
(3) Assurance that each patient (or each patient's legal
representative) gives written informed consent prior to entry on
study.
(4) A system for assuring timely reporting of all serious and
unexpected toxicities (adverse drug reactions, also referred to as
ADRs) to the IRB and to the drug supplier in accordance with FDA
requirements, and for informing the NCI Program Director of ADRs.
For trials conducted under NCI-held INDs, this includes reporting of
ADRs to the Investigational Drug Branch (IDB), CTEP, according to
CTEP guidelines.
(5) An on-site audit program for periodic data verification and
review of regulatory responsibilities at each participating
institution; for trials under NCI-held INDs, submission of reports of
each such audit to NCI within six weeks of the audit.
(6) For trials conducted under NCI-held INDs, a method of providing,
upon request of the NCI, quarterly summaries of toxicity, efficacy,
pharmacokinetics, and other laboratory data adequate to allow CTEP to
fulfill its responsibility closely to monitor Phase I trials which it
sponsors.
(7) For trials conducted under NCI-held INDs, bi-weekly submission of
comprehensive study data to CTEP's Clinical Trials Monitoring Service
(CTMS), according to CTMS guidelines, if CTMS monitoring is deemed
necessary by the NCI. This monitoring is necessary for the initial
trial of a new agent in humans, and may be required for additional
Phase I toxicity monitoring of trials, at the NCI's discretion.
(8) For trials conducted under NCI-held INDs, implementation of the
requirements for storage and accounting for investigational agents
(described in the DCT Investigator's Handbook, which is available
from the NCI Program Director upon request); registration of the
protocol chairperson with CTEP's Drug Management Authorization
Section for each such trial.
The NCI will not approve a request for a group to add any institution
that does not have an approved Assurance of Compliance for the
Protection of Human Subjects on file with OPRR. The awardee
institution will be responsible for assuring that no patients are
accrued to a protocol at any participating institution until the
protocol has been reviewed and approved by the IRB.
Prompt, full compliance with all FDA-mandated requirements for
investigational drug management will be required of all group
investigators. These requirements may include suspension of protocol
accrual, or changes in the conduct of a protocol (e.g., to insure
patient safety).
h. Progress Review
The group will establish a mechanism for assessing performance of its
members, with particular attention to accrual of adequate number of
eligible patients onto CATBRM trials, timely submission of required
data, conscientious observance of protocol requirements, preparation
of manuscripts for publication, and participation in group
leadership.
Should the Progress Review process indicate poor performance by a
participating institution, the awardee institution may request NCI
approval to replace the institution according to the procedures
outlined above in the SPECIAL REQUIREMENTS, A.1.a. of this RFA.
i. Protocol Closure
The NCI may request that a CATBRM protocol be closed to further
patient accrual if: (a) the protocol's accrual goal has been met,
(b) there has been an insufficient accrual rate, (c) there has been
poor protocol performance, or (d) changes in drug availability make
protocol completion unlikely. The NCI Program Director will submit
any such request for protocol closure, with the reasons for the
request, in writing to the Principal Investigator. If the group
wishes to continue patient accrual, the Principal Investigator or the
Clinical Investigations Leader must submit a written justification to
the NCI Program Director for NCI review and approval. Without NCI
approval, the group may not expend NCI funds for additional patient
accrual to the protocol proposed for closure. Unresolved
disagreements regarding the appropriateness of protocol closure for
any of the above reasons will be submitted to arbitration by the
process outlined above.
Regulatory issues, such as those affecting patient safety, may
require suspension of protocol accrual, or changes in the conduct of
a protocol. As noted in the SPECIAL REQUIREMENTS, A.1.g. Terms of
Cooperation, the group must comply fully with any suspension of
accrual or other protocol modification mandated by federal regulatory
officials. The awardee institution retains the primary
responsibility for assuring group compliance with federally-mandated
regulatory requirements.
j. Attendance at Meetings
The Principal Investigator, Program Leaders, and the NCI Program
Director will meet periodically to review progress, plan and design
research activities, and establish priorities. The Principal
Investigator will determine the frequency of meetings, and will be
responsible for scheduling the time and place of each meeting.
No NCI staff member may chair group meetings. A critical determinant
of group success will be the degree of communication among its
members. Therefore, additional informal meetings among all
participants as well as regular telephone and written communication
is encouraged.
k. Reporting Requirements
Reporting requirements will be in agreement with FDA regulations and
NCI procedures. Annual progress reports will be submitted to the
NCI, and included in the non-competing research application. The
report will include summary data on protocol performance by each
participating institution, specific data on patient accrual, detailed
reports of treatment associated morbidity, and other data deemed
relevant by the Principal Investigator. In addition, quarterly data
summaries will be provided as described above for trials of agents
for which NCI holds the IND.
l. Publication of Data
Timely publication of major findings is encouraged. Publication or
oral presentation of results obtained under this Cooperative
Agreement will require appropriate acknowledgement of the NCI
support. The Government, via the NCI Program Director, will have
access to all data generated under this Cooperative Agreement and may
periodically review the data. The awardee will retain custody of and
primary rights to the data, consistent with current HHS, PHS, and NIH
policies.
2. Nature of NCI Staff Participation
As described throughout these Terms of Cooperation, the role of the
NCI will be to assist and facilitate, not to direct, group
activities.
a. NCI Program Director
The NCI shall designate a Program Director to guide the overall
CATBRM program with the NCI. The NCI Program Director for the CATBRM
program will be an extramural program director of the Biological
Resources Branch, BRMP, DCT, NCI. The Program Director will also
coordinate and facilitate NCIs role in each group. Decisions
requiring NCI approval as outlined in these terms of cooperation will
require the written approval of the NCI Program Director. The NCI
Program Director will also insure that required approvals from other
NCI components (for example, CTEP approval of protocols conducted
under NCI-held INDs) are sought in a timely fashion and obtained.
b. NCI as a Scientific Resource for CATBRM Group Activities
The NCI Program Director will serve as a resource available to the
group for specific scientific information with respect to treatment
regimens and clinical trial design.
c. NCI Assistance in Protocol Development
While the CATBRM group's initial clinical protocol will have been
developed as part of the application submitted to peer review, it is
possible that the group will develop subsequent protocols within the
objectives approved by peer review. The NCI Program Director will
assist in developing such protocols by providing, as appropriate:
(1) information about concurrent clinical trials in the group's area
of research; (2) information about additional investigational agents
relevant to the group's research goals; (3) assistance in applying
additional government resources, as outlined below in section A.2.l.
of these Terms of Cooperation; and (4) comments on the scientific
rationale, design, statistical requirements, and implementation of
the proposed protocol. All group protocols for which government
funds from this cooperative agreement are expended will be subject to
the terms of award, including these Terms of Cooperation.
d. NCI Review of Proposed Protocols
Awardees will conduct clinical protocols in accordance with the
research objectives and methods approved by peer review. All
protocols and protocol amendments must be submitted to the NCI
Program Director for NCI review and approval. Awardees' initial
protocols will have been scientifically approved by peer review. NCI
will review subsequent protocols to insure they are within the scope
of peer review. NCI will also review all protocols for safety
considerations, as required by federal regulatory requirements. The
NCI Program Director will coordinate and facilitate the review and
approval process.
The NCI will not provide investigational drugs or permit expenditure
of NCI funds for a protocol that has not been approved according to
the above procedures. The NCI Program Director will assist the group
in developing any protocol revisions necessary to permit NCI approval
of the protocol. Unresolved disagreements regarding NCI protocol
review will be submitted to the same arbitration process outlined
above.
e. NCI Review of Quality Control and Study Monitoring
For protocols involving NCI-held INDs, the NCI Program Director will
coordinate any necessary NCI review and approval of quality control
and study monitoring mechanisms to insure that FDA and OPRR-mandated
regulatory requirements are met. The awardee institution will be
responsible for insuring the group meets all federally-mandated
regulatory requirements, as noted elsewhere in these Terms of
Cooperation.
f. NCI Review of Data Management and Analysis
The NCI Program Director will review the group's mechanisms for data
management and analysis (see above, A.l. Responsibilities of
Awardees). Such mechanisms must be in place before NCI funds may be
expended for any group clinical trial. Any disagreements between the
NCI and the group relating to data management and analysis that
cannot be resolved by bilateral discussions will be submitted to the
same arbitration process previously outlined.
g. Access to Data
The Government, via the NCI Program Director, will have access to
data generated under this Cooperative Agreement and may periodically
review the data. However, the awardee will retain custody of and
primary rights to the data, and timely publication of major findings
by the group members is encouraged. Publications or oral
presentation of work done under this agreement will require
appropriate acknowledgement of the NCI support.
Data from protocols conducted under NCI-held INDs must also be
available for external monitoring, in accordance with an agreement
between the NCI and the FDA governing the NCI's responsibilities as a
drug monitor.
h. NCI Involvement in Investigational Drug Management
INDs for group trials may be held by the NCI, by a member of the
group, or by an appropriate third party (such as the drug
manufacturer, if not a member of the group). The proposed IND
arrangements will be included in the initial application.
The NCI must approve in advance any redistribution, outside the
group, of biological and chemical materials received from the
Government; and any dissemination of research findings resulting from
the use of such materials so redistributed. The NCI Program Director
will, in such instances, be responsible for assuring that any
required approvals from other NCI officials are obtained.
When the NCI is to file the initial IND or cross-file on an existing
IND for an agent to be studied by a group, the NCI Program Director
will coordinate NCI assistance (e.g., facilitating the completion of
any necessary agreements between drug suppliers and NCI, or advising
the Principal Investigator of FDA-mandated specific requirements and
changes in requirements concerning investigational drug management).
Investigators performing trials under Cooperative Agreements will be
expected to comply with all FDA monitoring and reporting requirements
for investigational agents.
i. NCI Review of Mechanisms for Meeting Federally Mandated
Regulatory Requirements
The NCI Program Director will review the study group's mechanisms for
meeting FDA regulatory requirements for investigational agents, and
OPRR requirements for the protection of human subjects, and will
determine whether review and approval by the NCI regulatory affairs
officials is also required (specifically for studies under NCI-held
INDs). If so, the NCI Program Director will facilitate that review
and approval.
j. NCI Review of Progress
Performance of the group will be reviewed at least annually by the
NCI Program Director on the basis of the group's annual reports and
quarterly data summaries (described above under Responsibilities of
Awardees). In addition, periodic accrual information may be
requested from the group by the NCI Program Director for all active
protocols when deemed appropriate.
Insufficient patient accrual, progress, or noncompliance with the
Terms of Award, including these Terms of Cooperation, may result in a
reduction in budget, withholding of support, suspension, or
termination of award.
k. NCI Involvement in Protocol Closure
The NCI may request that a CATBRM protocol be closed to further
patient accrual if: (a) the protocol's accrual goal has been met;
(b) there has been an insufficient accrual rate; (c) there has been
poor protocol performance; or (d) changes in drug availability make
protocol completion unlikely. The NCI Program Director will submit
any such request for protocol closure, with the reasons for the
request, in writing to the Principal Investigator. If the group
wishes to continue patient accrual, the Principal Investigator or the
Clinical Investigations Leader must submit a written justification to
the NCI Program Director for NCI review and approval. Without NCI
approval, the group may not expend NCI funds for additional patient
accrual to the protocol proposed for closure. Unresolved
disagreements regarding the appropriateness of protocol closure for
any of the above reasons will be submitted to arbitration by the
process outlined above.
Regulatory issues, such as those affecting patient safety, may
require suspension of protocol accrual, or changes in the conduct of
a protocol. As noted in the SPECIAL REQUIREMENTS, A.1.g, the group
must comply fully with any suspension of accrual or other protocol
modification mandated by federal regulatory officials. The awardee
institution retains the primary responsibility for assuring group
compliance with federally-mandated regulatory requirements.
l. Use of Other NCI Resources in Support of Group Activities
Upon recommendation of the NCI Program Director, the NCI may make
limited use of its contract based resources in support of group
research activities. Use of such resources may be considered on an
occasional basis, at the NCI's discretion, within its budgetary and
programmatic constraints.
m. NCI Review of Changes in Group Membership
Post-award changes in a group's Principal Investigator, Program
Leaders, Clinical or Laboratory Programs, or participating
institutions will require NCI approval in accordance with the
procedures described in the "SPECIAL REQUIREMENTS" section A.1.a.
above.
Failure of the awardee institution to propose an acceptable
replacement for any of the above changes, or to demonstrate to the
satisfaction of the NCI that the group's research can be completed in
an appropriate and timely fashion, will result in withholding of
support, suspension, or termination of this award.
3. The Terms of Cooperation described in this section are in
addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS Grant Administration Regulations at 45
CFR Part 74, and other HHS, PHS, and NIH grant administration policy
statements.
B. Drug Information/IND's/Drug Supply
1. Patent status of agent(s) proposed for study.
Since applicants are likely to propose studies with agents in early
development, it is essential that each application address the patent
status of the agent(s) proposed for study.
If a patent already exists, or is pending, for an agent, the
application should so state, and identify the patent holder. A
letter, signed by the Principal Investigator and each Program Leader,
recognizing the patent holder and status, must be included with the
application prior to peer review.
If patent coverage does not already exist for a proposed study agent,
or if new patents (e.g., use patents) are to be filed, the
application must include a detailed description of procedures for
obtaining patent coverage for each such agent. This is essential to
avoid patent disputes from delaying performance of awards by
successful applicants. Procedures must also be described for
resolution of legal problems within the group, should they arise. A
formal agreement to these procedures, signed and dated by the
organizational official authorized to enter into patent arrangements
for each group member and member institution, must be on file at the
Division of Extramural Activities, NCI prior to peer review.
The specific patenting arrangements relevant to a group's application
may vary widely depending upon the particular agent(s) proposed for
study, the clinical trial(s) proposed, and the particular composition
of a given group. Each applying group is encouraged to employ the
arrangement most appropriate to its particular circumstances.
Regardless of the arrangement used, however, its description MUST be
included as part of the application. The description should be
inserted following the overall Budget Section. Supporting documents
(e.g., letters of agreement) should be included in the Appendix to
the application.
2. IND status of agent(s) proposed for study.
Each application must address the Investigational New Drug (IND)
application status for each agent proposed for study. INDs for
CATBRM clinical trials may be held by the applicant, or by the
supplier of the agent. Alternatively, when desirable to facilitate
the conduct of the clinical trial, the NCI may hold the IND or
cross-reference an existing IND. Applicants are encouraged to
propose the IND arrangement most appropriate to the goals of their
application.
If an IND already exists for an agent, the IND number and the
identity of the IND holder should be included in the body of the
application.
For any agent for which an IND does not exist, the application must
include enough information to demonstrate that an IND will be
obtained in a timely fashion. This information should include:
o a description of currently available preclinical data for the
agent;
o a list of additional preclinical studies which remain to be done
in support of IND filing;
o the anticipated date of IND filing;
o In addition, the application should demonstrate that INDs for all
agents to be used in the initial clinical trial will be available
early enough to allow patient accrual to begin within three months of
the date of award.
o The application should also demonstrate that INDs for agents to be
used in subsequent clinical trials are expected to be available early
enough that continuous patient accrual to clinical protocols may be
expected throughout the award period.
o Applicants proposing to conduct a trial without an IND must
demonstrate that all applicable FDA requirements will be met,
consistent with the above guidelines.
Discussions of IND issues should be inserted in the body of the
application, following the overall Budget Section. Supporting
documents (e.g., letters of agreement) should be included in the
Appendix to the application.
3. Supply of agent(s) for clinical trials.
Each application must describe the steps the applying group will take
to insure adequate supplies of agents for the clinical trials
proposed. Depending upon an applicant's particular circumstances,
such information may include a discussion of mechanisms of procuring
agents, timetables for production of agents, or evidence of industry
collaboration. If possible, letters of support from pharmaceutical
companies should be included.
Discussions of drug supply issues should be inserted in the body of
the application, following the overall Budget Section. Supporting
documents (e.g, letters of agreement) should be included in the
Appendix to the application.
STUDY POPULATIONS
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them. This policy is intended to
apply to males and females of all ages. If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.
The composition of the proposed study population must be described in
terms of gender and racial/ethnic group. In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study. This information must be included in the form PHS 398 in
Sections 1-4 of the Research Plan 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 is defined as 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 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 women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.
For foreign awards, the policy on inclusion of women applies fully;
since the definition of minorities differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.
If the required information is not contained within the application,
the application will be returned.
Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.
All applications for clinical research submitted to NIH are required
to address these policies. NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.
LETTER OF INTENT
Prospective applicants are asked to submit, by October 30, 1992, a
short letter of intent that includes a descriptive title of the
proposed research, the name, address, and telephone number of the
Principal Investigator, the identities of other key personnel and
participating institutions, and the number and title of this RFA.
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of
applications. It allows ICD staff to estimate the potential review
workload and to avoid conflict of interest in the review.
Letters of intent is to be sent directly to:
Jon T. Holmlund, M.D.
Biological Resources Branch
Biological Response Modifiers Program
National Cancer Institute-FCRDC
Building 1052, Room 253
Frederick, MD 21702-1201
Telephone: (301) 846-1098
FAX: (301) 846-5429
APPLICATION PROCEDURES
A. Minimal Requirements for Application
Applications must meet the requirements listed below. Except for
item 1, each of these must be briefly addressed in the INTRODUCTORY
section of the application. The INTRODUCTORY section may reference a
fuller discussion elsewhere in the application, provided that the
location of that discussion is clearly given in the INTRODUCTORY
section.
1. The research grant application form PHS 398 (rev. 9/91) is to be
used. This form is available at most institutional business offices;
from the Office of Grants Inquiries, Division of Research Grants,
National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, MD 20892 (telephone 301/496-7441); and from the NIH Program
Administrator named below.
2. Name a single Principal Investigator, who is an M.D., Ph.D., or
D.O., who will be responsible for the application, for group research
activities, and for the dispersal of funds for the support of group
activities.
3. If the Principal Investigator is a Ph.D., name a single Clinical
Investigations Leader, who is an M.D. or a D.O., who will be
responsible for the overall conduct of the group's clinical trials.
4. Identify the applicant institution that will assume legal and
financial responsibility and accountability for the use and
disposition of funds awarded on the basis of this RFA.
5. Provide, in the body of the application, a description of the
patent status of the agent(s) to be studied, and of the group's plans
to address patent issues, as discussed above in the SPECIAL
REQUIREMENTS section B.1. of this RFA. Include supporting documents
in an Appendix.
6. Provide, in the body of the application, a description of the IND
status of the agent(s) proposed for study, including (in an Appendix)
supporting information, as discussed above in the SPECIAL
REQUIREMENTS section B.2. of this RFA.
7. State how the group plans to insure the availability of adequate
drug supplies for the clinical trial. Include supporting material
(e.g., letters of support from drug suppliers) in an Appendix.
8. Describe the group's overall goals and, in the context of these
goals, describe how the group envisions the clinical development of
the agent(s) and/or regimen(s) to be tested.
9. Include one detailed clinical protocol, for the first trial
proposed. Include Notice of IRB Approval. Provide detailed evidence
supporting the rationale for the protocol, including literature
citations, and emphasizing the results of work done by the proposed
group members. Describe any subsequent trials envisioned by the
group during the award period; it is not necessary, however, to
include additional detailed protocols.
10. Provide from the Principal Investigator and from each Program
Leader a signed statement of acceptance of the provisions outlined
under the SPECIAL REQUIREMENTS section A.1. Terms of Cooperation.
11. Provide a clear, concise plan that depicts the
interrelationships among the members of the group and the
contribution of each to fulfillment of group objectives. This plan
may be in narrative and/or diagrammatic form; use the form which most
clearly describes the group. The name, organization, and scientific
discipline of the Principal Investigator, Program Leaders, and other
key personnel should be included.
12. Provide a plan to assure the maintenance of close collaboration
and effective communication among members of the group which will
include letters of commitment to this plan by all Program Leaders.
Include plans for scheduling group meetings, notifying group members
(including the NCI), and documenting and disseminating group meeting
proceedings.
13. Demonstrate that the Principal Investigator and the Program
Leaders possess the necessary scientific skills and leadership
qualities to conduct the proposed research successfully; include
relevant research programs, experience, unique competencies, and
pertinent publications.
14. Demonstrate the competence of the Principal Investigator to
manage comprehensive research projects, and to coordinate and
integrate research activities of diverse Clinical and Laboratory
Programs.
15. Demonstrate that each component Clinical and Laboratory Program
is required for the attainment of the group's objectives and that
each has available the professional and technical personnel to permit
efficient and successful conduct of the proposed research. Show that
total personnel of the group are sufficient in quality and quantity
to assure successful conduct of the proposed research.
16. Demonstrate for all key personnel the time available for this
project and show for all key professional personnel: (1) title,
identifying number, percentage of effort devoted to the project,
direct costs, and project period of all awarded and pending grants,
Cooperative Agreements, contracts, and industrial commitments
regardless of source of funding; and (2) identify and explain areas
of potential scientific and/or budgetary overlap with active and
pending grants, contracts, and Cooperative Agreements and what
support would be relinquished if this Cooperative Agreement award is
made. Describe the steps that will be taken to insure successful
completion of the group's research should a key member leave the
group.
17. Demonstrate that each component Laboratory Program and the group
as a whole have available the facilities required for conduct of the
proposed research. Funds will not be provided for alteration or
renovation of facilities under this Cooperative Agreement.
18. Demonstrate that the group may expect sufficient patient accrual
to complete the clinical trial in a timely fashion.
19. Describe the quality control measures that will be used by the
group, as required under the "SPECIAL REQUIREMENTS" section A.1.,
Terms of Cooperation.
20. Demonstrate the capability to conduct study monitoring, and data
management and analysis, as required under the "SPECIAL REQUIREMENTS"
section A.1., Terms of Cooperation.
21. Describe how the group will comply with federally mandated
regulatory requirements, as outlined under the "SPECIAL REQUIREMENTS"
section A.1., Terms of Cooperation, and demonstrate that each
institution conducting group trials has a current, approved assurance
on file with OPRR.
22. Describe how the group will comply with the NIH policies
concerning inclusion of women and minorities in clinical research
study populations ("STUDY POPULATIONS" section of this RFA).
B. Method of Applying
1. Receipt Date
The deadline for receipt of applications is December 22, 1992.
Applications received after this date will be returned to the
applicant without review.
2. General
a. Submit a signed, typewritten original of the application,
including a single Checklist, and three signed, exact single-sided
photocopies in one package to:
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
At the same time of submission, two additional exact, single-sided
copies of the application must also be sent to:
Referral Officer
National Cancer Institute
Westwood Building, Room 848
Bethesda, MD 20892
Telephone: (301) 496-3428
The NCI-FCRDC address under INQUIRIES is sufficient for express mail
or courier service to that location.
b. To expedite the review of your application, and to assure its
identification with this RFA:
(1) The application form must have "CLINICAL STUDY GROUPS FOR CANCER
THERAPY WITH BIOLOGICAL RESPONSE MODIFIERS (CATBRMs) (RFA CA-92-28)
on line 2a of the face page of the application form; personalized
titles more fitting for your application should be listed on line 1
and not on line 2. The YES box on the face page must be marked.
(2) The RFA label available in the application 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 your application
such that it may not reach the review committee in time for review.
(3) Applicants from institutions that have a General Clinical
Research Center (GCRC) funded by the NIH National Center for Research
Resources are requested to identify the GCRC as a resource for
conducting the proposed research.
3. Organization of Application and Suggested Modifications of Form
PHS 398
This RFA requires the submission of a single application for the
proposed CATBRM study group. 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.
Because of the possible multi-institutional nature of a group, and
the special requirements in this RFA, additional suggestions
regarding format and some modifications seem desirable to provide a
comprehensive yet readily reviewable application.
a. Each application should clearly identify the CLINICAL and
LABORATORY programs proposed, the proposed costs attributable to
each, and the relationship among the various programs. If it is not
possible to do this using a single form PHS 398 (rev. 9/91), separate
forms PHS 398 (rev. 9/91) may be used to describe the various
programs. If this is done, the application must have one
INTRODUCTION SECTION and consecutively numbered sections for each of
the CLINICAL PROGRAMS and each of the LABORATORY PROGRAMS including
the Clinical or Laboratory Program of the proposed Principal
Investigator. Use form PHS 398 (rev. 9/91) for each CLINICAL PROGRAM
and each LABORATORY PROGRAM, but omit the face page for the
individual program. A single face page should apply to the entire
application. Insert the INTRODUCTION after the Table of Contents.
It is suggested that the title "Principal Investigator" for the
section describing the Clinical or Laboratory Program of the
Principal Investigator) be substituted for "Principal
Investigator/Program Director" and that the Description" (grant
application form, page 2) for each of the Clinical or Laboratory
Program, in addition to describing the work proposed, provide a
statement of relevance to the overall objectives of the proposed
group. A single checklist should be provided for the overall
application. Do not include a checklist for each Clinical or
Laboratory Program. The 25-page limitation stipulated in the PHS-398
kit applies to each of the individual Clinical or Laboratory
Programs. The overall Introductory Section should also be limited to
25 pages.
All "Minimal Requirements for Application" must be discussed in the
INTRODUCTORY section (or in the body of the application if only one
Form PHS-398 (rev. 9/91) is used. As noted elsewhere in this RFA,
include supporting documents in an Appendix.
Sections pertaining to Clinical or Laboratory Programs should
provide, for each program, a Detailed Budget for the First 12- Month
Budget Period INCLUDING APPLICABLE INDIRECT COSTS FOR CONSORTIUM
INSTITUTIONS and a Budget for the Entire Proposed Project Period.
JUSTIFY BUDGET REQUESTS according to the guidelines in Form PHS-398.
The formal clinical protocol submitted with the application should be
in an APPENDIX to the application.
Often the various research objectives necessary to reach the group's
goals may need to be phased in, at least in part, in sequential
fashion. In such cases, the budgets for the individual Clinical and
Laboratory Programs should, logically, reflect an appropriate change
in relative emphasis among objectives until an operational steady
state situation is attained. Justification for phase-in budgets
should also be provided.
b. The application should begin with an INTRODUCTORY SECTION bearing
the title CLINICAL STUDY GROUP FOR CANCER THERAPY WITH BIOLOGICAL
RESPONSE MODIFIERS (CATBRM), and the phrase, "Prepared in Response to
RFA No. CA-92-28." Form PHS 398 is to be used for this Introductory
Section and must describe the proposed CATBRM group as a whole with
respect to goals, objectives, and overall research plan. In this
Introductory Section, list the Program Leaders as "Key Personnel
Engaged on Project." Other key personnel must be listed in the
proposed research plan for each individual Clinical or Laboratory
Program. It is important to discuss any prior collaborative efforts
among investigators in the group as well as advantages expected from
the group effort, e.g., how the projects are mutually reinforcing,
how collectively they will further the goals of the proposed
research, etc.
In the Introductory Section, a summary budget should reflect the
consolidated TOTAL DIRECT COSTS of the entire proposed group. This
should include the direct costs at the applicant institution and both
direct and indirect costs at participating institutions. The
Introductory Section should also provide, from the applicant
institution, a Detailed Budget for the First 12-Month Period and a
Budget for the Entire Proposed Project Period for Direct Costs for
each of the following:
(1) The Principal Investigator's Clinical or Laboratory Program; and
(2) Management and coordination of group activities.
Inasmuch as the Principal Investigator may also function as a Program
Leader for his/her Laboratory Program, parts of form PHS 398 that
duplicate information provided in the section describing the
Principal Investigator's work need not be included in the
Introductory Section. The Introductory Section should, however,
contain any additional information about the proposed Principal
Investigator or his/her institution as evidence of capability to
carry out the scientific and administrative duties required in this
RFA.
c. The application will be reviewed as a whole as well as program by
program. Therefore, prepare a detailed Table of Contents that will
enable reviewers to find specific information readily and number all
pages consecutively after the face page, which is page 1. Complete
all items on the face page of the application (only one per
application) as in a regular research grant proposal. Identify
projects by number, title and Program Leader. Identify cores by
letter, title and Program Leader.
d. In order to facilitate project by project review, a complete PHS
398 form (rev. 9/91)--exclusive of face page and checklist--should be
used for each program. This specifically includes project budgets
and curriculum vitae. The C.V. of the Principal Investigator should
be included in the INTRODUCTORY SECTION and in their individual
Clinical or Laboratory Programs (if any); the C.V.s of all other
personnel should appear only in the Clinical or Laboratory Programs
or Cores with which they are affiliated; the INTRODUCTORY SECTION
should use only brief textual descriptions of those personnel who
appear elsewhere in the application. Such descriptions should be
cross-referenced to the appropriate Program.
REVIEW CONSIDERATIONS
A. Review Procedure
Upon receipt, applications will be reviewed by the DRG for
completeness and responsiveness. Incomplete applications will be
returned to the applicant without further consideration. Evaluation
for responsiveness to this RFA is an NCI program staff function.
Applications will be judged to determine whether or not they meet the
goals and objectives of the program as described in the RFA. If an
application is not responsive to the RFA, it will be returned to the
applicant and the proposed Principal Investigator will be contacted
to determine whether submission for review in competition with
unsolicited applications at the next review cycle is desirable to the
applicant. If an application is judged non-responsive to this RFA,
any of its constituent Clinical or Laboratory Programs may be
submitted as an investigator-initiated regular research grant (R01)
at the next receipt date. Alternatively, the consortium of Clinical
Programs, Laboratory Programs, or some combination of Clinical and
Laboratory Programs could seek funding as a program project grant
(P01). In either event, the application would require modification
in accordance with either the R01 or P01 guidelines. Such new
application would not be considered an application for a Cooperative
Agreement, nor would it be considered a response to an RFA. Questions
concerning the relevance of proposed research to the RFA may be
directed to program staff listed under INQUIRIES.
If the number of applications received 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 for award. The NCI will remove from further competition
those applications judged to be noncompetitive and notify the
Principal Investigator and institution official.
Those applications judged to be both competitive and responsive will
be further evaluated, using the review criteria shown below, for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI. Following
peer review, the applications will receive a second-level review by
the National Cancer Advisory Board, which considers the special needs
of the Institute and the priorities of the National Cancer Program.
B. Peer Review Criteria
1. Extent of relevance of applicant's objectives to the clinical
development of novel approaches to the treatment of cancer with
BRM's.
2. Scientific merit and originality of proposed research.
3. Specific scientific and clinical merit of the proposed clinical
trial.
4. Quality of data supporting the proposed clinical trial.
5. Scientific and technical merit of the proposed laboratory
studies.
6. Evidence that the Principal Investigator and the Program Leaders
possess the scientific skills and leadership qualities needed to
conduct the proposed research successfully; experience, competence,
commitment, and time availability of Principal Investigator, Program
Leaders, and other key personnel.
7. Evidence that each component Clinical and Laboratory Program is
required for the attainment of the group's objectives, and that each
has available the professional and technical personnel to permit
efficient and successful conduct of the proposed research.
8. Competence of Principal Investigator to develop, implement, and
manage comprehensive research programs, and to coordinate and
integrate research activities of diverse clinical and laboratory
programs.
9. Adequacy of plans for effective intra-group communication and for
assuring group cohesiveness.
10. Adequacy of existing physical facilities and resources of the
Principal Investigator and Program Leaders.
11. Evidence that Clinical Programs are capable of completing the
clinical trial in a timely fashion, including evidence of adequate
patient accrual.
12. Evidence of approval and commitment of institutions represented
by group members to group goals.
13. Commitment to accept provisions outlined under the "SPECIAL
REQUIREMENTS" section A.1., Terms of Cooperation.
14. Evidence that appropriate steps have been taken to insure the
protection of human subjects.
15. Evidence that the applicant is in compliance with NIH policies
regarding the inclusion of women and minorities in clinical research
study populations ("STUDY POPULATIONS" section of this RFA).
The review group will critically examine the submitted budget and
will recommend an appropriate budget and period of support for each
approved application.
AWARD CRITERIA
The anticipated date of award is June 30, 1993. In addition to
technical merit, availability of resources (including drug supplies
for the proposed clinical trials) and overlap with existing studies
sponsored by the Biological Response Modifiers Program will be
considered in making awards.
INQUIRIES
Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues and questions from potential
applicants is welcome.
Direct inquiries regarding programmatic issues to:
Jon Holmlund, M.D.
Program Director, Biological Resources Branch
Biological Response Modifiers Program
National Cancer Institute-FCRDC
Building 1052, Room 253
Frederick, MD 21701-1201
Telephone: (301) 846-1098
FAX: (301) 846-5429
Direct inquiries regarding fiscal matters to:
Ms. Katharine Schulze
Grants Management Specialist
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
6120 Executive Boulevard
Bethesda, MD 20892
Telephone: (301) 496-7800, Ext. 16
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 authorization of the Public Health Service Act, Title, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal
Regulations 42 CFR 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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