Full Text CA-95-017

CANCER THERAPY WITH BIOLOGICAL RESPONSE MODIFIERS

NIH GUIDE, Volume 24, Number 33, September 22, 1995

RFA:  CA-95-017

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Biological Response Modifiers 


National Cancer Institute

Letter of Intent Receipt Date:  October 30, 1995
Application Receipt Date:  January 4, 1996

PURPOSE

The Division of Cancer Treatment (DCT), National Cancer Institute
(NCI), invites applications to establish cooperative agreements for
Cancer Therapy with Biological Response Modifiers (CATBRMs), to
translate promising preclinical results into innovative clinical
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), 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 Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone (202) 512-
1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Involvement of intramural NIH personnel is limited as described under
the "RESEARCH OBJECTIVES," C, Composition of a CATBRM Group.  Women,
members of racial/ethnic minority groups and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an "assistance" mechanism
(rather than an "acquisition" mechanism) in which substantial NIH
scientific and/or programmatic involvement with the awardee is
anticipated during performance of the activity.  Under the
cooperative agreement, the NIH purpose is to support and/or stimulate
the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the
activity.  Details of the responsibilities, relationships and
governance of the study to be funded under cooperative agreement(s)
are discussed later in this document under the section "Terms and
Conditions of Award."

This RFA is a reissuance of RFAs CA-92-01 and CA-92-28, which were
issued under the title, "Clinical Trials of Cancer Therapy with
Biological Response Modifiers (CATBRMs)."  Applicants who did not
apply under the previous RFAs, who applied but did not receive an
award, and those who have received an award, are encouraged to
respond to this RFA.  However, this reissued RFA is a one-time
solicitation.  Future unsolicited competing renewal applications will
compete as research project applications with all other
investigator-initiated applications.  Applicants who are past
recipients of CATBRM awards must include results of the work
supported by those awards, including scientific progress, and how the
awardees have met the Terms and Conditions of Award.

FUNDS AVAILABLE

The NCI plans to make up to four awards for project periods up to
four years, and has set aside 1.0 million dollars 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 NCI, awards pursuant to
this RFA are contingent upon continuing availability of funds.  The
earliest possible starting date for the initial annual period will be
July 1, 1996.

RESEARCH OBJECTIVES

Background

Success with biological response modifier (BRM) therapy of cancer has
been limited, and the NCI seeks to foster new approaches.  Many 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.  Other agents now under preclinical study may be of interest
as BRMs.  Development of new technologies (such as gene transfer),
and identification of tumor antigens, have led to a resurgent
interest in cancer vaccines.  Discoveries in cellular immunology are
also prompting new approaches to adoptive immunotherapy and bone
marrow transplantation, in an attempt to improve the antitumor
effects of cytotoxic cells.  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 that may predict clinical benefit.

Frequently, attempts to translate promising scientific developments
into early clinical trials encounter one or more common obstacles,
including lack of availability of clinical-grade agents, difficulties
in completing IND-directed studies or preparing an IND, and others.
With this RFA, the NCI seeks to assist BRM translational research by
teams of clinical and preclinical investigators with the unique
technical capabilities to study new agents in innovative clinical
trials and to address hypothesis-driven issues of mechanisms of
action.  The "Research Goals and Scope" of this RFA 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 that the investigational agent(s) proposed for study
are available for development to a clinical trial.  A statement of
the type of assistance sought from the NCI and a detailed outline of,
or a full 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
and Conditions of Award.

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 patient monitoring and other
associated preclinical studies; 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, nonprofit, and/or commercial institutions.  Awards
under this RFA may also be a way to support the development of agents
that have arisen from research supported by the National Cooperative
Drug Discovery Groups (NCDDGs), P01s, R01s, R29s, R03s, or other
grant mechanisms.

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 that 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 below, Definitions.)  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 that 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.

Definitions

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 which clearly delineates 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, and other
related preclinical studies appropriate to the group's overall
scientific plan.

PARTICIPATING INSTITUTION (PARTICIPANT)- All institutions and/or
individual investigators, both funded and unfunded, who participate
in the work of the CATBRM group or collaborate with the group.

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.

CLINICAL INVESTIGATIONS LEADER - An M.D. or D.O., designated on the
initial 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.  The Principal Investigator may also be a
Program Leader.

NCI PROGRAM DIRECTOR - An extramural Program Director of the
Biological Resources Branch, Biological Response Modifiers Program
(BRMP), Division of Cancer Treatment (DCT), NCI, designated by 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 NCI in the group.

Composition of a CATBRM Group

A Principal Investigator and, if necessary as outlined above, a
Clinical Investigations Leader;

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;

One or more Laboratory Programs, each headed by a Program Leader,
each with demonstrated expertise in scientific disciplines necessary
to design and conduct laboratory monitoring assays and other related
preclinical investigations; and

The NCI Program Director, who coordinates NCI involvement in the
study group.

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.

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.

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 as long as 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 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 under
"SPECIAL REQUIREMENTS," Terms and Conditions of Award.

A CATBRM group may include members from a single institution or a
number of institutions, depending on the specific goals of the group.
While a minimum of one Clinical and one Laboratory Program per group
is necessary, there are no limits on the number of Programs in a
group.  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.

A CATBRM group may include one or more foreign members or may consist
entirely of investigators or programs located outside the United
States.

Research Goals and Scope

The development of novel approaches to the treatment of human cancer
with BRMs, employing new agents, concepts, or treatment strategies.

The clinical testing of such approaches by the conduct of one or more
related, well-designed clinical trials with BRMs.

Exploration of mechanisms of antitumor effect and resistance, and of
the effects of modifications designed to alter these to clinical and
biologic advantage.

Observation of clinical effects (e.g., tumor responses) of the
treatment regimen, and, where appropriate, correlation of these with
other biologic endpoints.

SPECIAL REQUIREMENTS

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

Terms and Conditions of Award

These special Terms of Award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Parts 74 and 92, and other HHS,
PHS, and NIH Grant Administration policy statements.

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

A.  Awardee Rights and Responsibilities

1.  Protocol Development

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.

Group protocols using investigational agents sponsored (i.e., for
which the IND is held) by the Division of Cancer Treatment (DCT), NCI
must be developed in accordance with the instructions in the NCI
INVESTIGATOR'S HANDBOOK.  The INVESTIGATOR'S HANDBOOK (available
directly from the Cancer Therapy Evaluation Program [CTEP] or through
the NCI Coordinator) describes, in accordance with agreements between
NCI and the Food and Drug Administration (FDA):

o  Requirements for Protocol Development and Submission
o  Ordering Investigational Drugs from NCI
o  Responsibility for Reporting of Results to NCI
o  Adverse Event Procedures
o  Accountability and Storage of Investigational Agents
o  Monitoring and Quality Assurance

2.  Coordination of Group Activities

The Principal Investigator is responsible for coordinating all group
activities, and for communication with the NCI Coordinator.

3.  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 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.

4.  Group Compliance with Federally Mandated Regulatory Requirements

The awardee institution retains the primary responsibility for
ensuring that the group is in compliance with all Food and Drug
Administration (FDA) regulatory requirements for studies involving
investigational agents and NIH policies applying to the conduct of
research involving human subjects.  Participants are required to
follow group procedures for complying with the federally mandated
regulations.

a.  The group must be able to demonstrate that each participating
institution has a current, approved assurance number on file with the
NIH Office of Protection from Research Risks (OPRR).

b.  The group must be able to demonstrate that each protocol and
informed consent is approved by the responsible Institutional Review
Board(s) (IRBs) prior to patient entry, that each ongoing protocol is
reviewed by the IRB(s) at least annually, and that each amendment of
a protocol or informed consent is approved by the IRB(s).

c.  The group must be able to demonstrate that each clinical
investigator has provided the IND sponsor with a current FDA form
1572 and a copy of the investigator's current curriculum vitae.

d.  The group must be able to demonstrate that each patient (or each
patient's legal representative) gives written informed consent prior
to entry on study.

e.  The group must assure timely reporting of all serious and
unexpected toxicities (adverse drug reactions, also referred to as
ADRs) 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.

f.  For trials conducted under NCI-held INDs, the group must have a
method of providing, upon request of the NCI, summaries of toxicity,
efficacy, pharmacokinetic, and other laboratory data for inclusion in
DCT's annual report to the FDA for each investigational agent it
sponsors.

g.  For trials conducted under NCI-held INDs, the group must have a
method for submitting comprehensive study data to CTEP's Clinical
Trials Monitoring Service (CTMS) every two weeks, according to CTMS
guidelines.  The decision to use CTMS monitoring will be NCI's.

h.  For trials conducted under NCI-held INDs, the group must
implement the NCI requirements for storage and accounting for
investigational agents.

6.  Quality Control and Study Monitoring

a.  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.  Participants are
required to follow group procedures for quality control.  These
procedures must be reviewed by the NCI Coordinator prior to
initiation of clinical trials by the group.

b.  Study Monitoring

The group will establish mechanisms for study monitoring.
Participants are required to follow group procedures 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.

c.  Quality Assurance and Quality Control of Data

The awardee must assure that each Clinical and Laboratory Program
maintains accurate, verifiable data.  If there is any indication of a
pattern of non-compliance with protocol or regulatory requirements,
or a finding of possible alteration of data, these findings must be
reported immediately by telephone, and before close of business the
next business day by FAX, to the NCI Coordinator.

7.  Data Management and Analysis

The group must establish and implement mechanisms for data management
and analysis that 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.
Participants are required to follow group procedures for data
management and analysis.

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.

8.  Protocol Closure

If the group wishes to close accrual to a study prior to meeting the
initial accrual goal, the Principal Investigator must submit
available results and other documentation to the NCI Coordinator for
review and concurrence.

The NCI Program Director shall submit any NCI request for protocol
closure (according to the guidelines given below, under "NCI Staff
Responsibilities"), 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.

Regulatory issues, such as those affecting patient safety, may
require suspension of protocol accrual, or changes in the conduct of
a protocol.  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.

9.  Protocol/Progress Reporting Requirements

Reporting requirements will be in agreement with FDA regulations and
NCI procedures.  Annual progress reports shall 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.  The report must also
document the number of women and ethnic minority patients enrolled on
the group's clinical trials.  In addition, quarterly data summaries
must be provided as described above for trials of agents for which
NCI holds the IND.

10.  Adverse Event Procedures

In order to be compliance with FDA regulations, all recipients of NCI
support for clinical trials, including groups and institutions
responsible for coordinating and monitoring such trials, must
promptly notify the NCI and any other sponsors of the trial of
adverse events (i.e., adverse drug reactions) according to directions
provided in the adverse event reporting section of the protocol.

The awardee shall notify all funded or unfunded
institutions/investigators participating in this project about the
above requirement and about the institutions'/investigators'
responsibility to report adverse events as specified in the protocol.

The awardee shall promptly notify the NCI Coordinator and, for
DCT-sponsored investigational agents, the appropriate Drug Monitor of
the Investigational Drug Branch, CTEP of serious or life-threatening
events, as instructed in the protocol.

11.  Performance Review

The group shall establish and follow policies and procedures for
assessing performance of its members and collaborators, 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.

12.  Procedures in the Event of Scientific Misconduct

If a duly authorized governmental or institutional body issues a
final determination that scientific misconduct has occurred or if the
awardee determines that other events have occurred which have
significantly affected the quality or integrity of the group data or
patient safety, the awardee is responsible for notifying the NCI
Coordinator, the collaborating investigators, the appropriate
Institutional Review Boards (IRBs), and other sponsors of the
affected work.

The awardee is also responsible, if the events described above have
occurred, for ensuring that submitted but unpublished abstracts and
manuscripts are corrected, if possible.  If publication deadlines
have passed or if abstracts and/or manuscripts containing the
affected data have already been published, the awardee is
responsible, within 90 days of learning of the event(s) significantly
affecting the quality of the group data or patient safety, for
submitting to NCI a re-analysis of the results deleting the false or
otherwise unreliable data, and disclosing within the text the
reason(s) for the reanalysis.  The awardee must submit the reanalysis
for publication.  The NCI may disseminate information about the
reanalysis as broadly as it deems necessary.

The awardee must use its best efforts to notify all scientists,
research laboratories, and other organizations to which the awardee
has sent research materials affected by false or otherwise unreliable
data.

True copies of data files and other supporting documentation from
studies affected by scientific misconduct or other findings affecting
the quality or integrity of data or patient safety shall be made
available to the NCI in a timely manner upon the request of the
Grants Management Officer, NCI.  The NCI reserves the right to
reanalyze, to publish, or to distribute its analyses of these data
when it is in the interest of public health.  Prior to release,
publication or distribution of such analyses, the NCI will provide
such analyses to the awardee.

13.  Data Files Available to NCI Upon Request

Upon the request of the Grants Management Officer, NCI, true copies
of data files and supporting documentation for all NCI- supported
protocols that have a major impact on patterns of care, as determined
by the NCI, shall be made available to the NCI in a timely manner.

14.  Notification of Patients by the Awardee During Patient's
Lifetime

In order for there to be an appropriate response in the event the NCI
determines, either while a protocol is active or (if relevant) during
the lifetime of the subjects following protocol closure, that a
medically important toxicity or side effect is associated with
protocol-directed treatment or that the medical care of one or more
subjects may have been compromised by scientific misconduct or other
finding affecting the integrity of the data or patient safety at the
awardee institution or at a third-party institution, funded or
unfunded, the awardee shall assure that the institution(s)
responsible for these subject(s') accrual, whether funded or
unfunded, will have procedures in place to: (i) contact each subject
individually at his or her last known address on file with the
institution and which give each subject contact appropriate
information and the right to communicate with an appropriate
institutional representative and, in the event of misconduct, to meet
with a physician not connected with the clinical trial or study in
which the subject has participated; and (ii) encourage subjects to
notify the institution of any changes of address.  The procedure must
provide for informing the subjects fully of:  the consequences of the
toxicity or misconduct for their care and well-being, if any, and the
availability of follow-up; and their opportunity to examine any
portion of their medical records relevant to the potential effect of
the toxicity or side effect upon them or that may be affected by
scientific misconduct or other findings affecting the quality or
integrity of the data or patient safety.

It is understood that under regulations at 45 CFR Section 74.53, NCI
has a right of access to research records pertinent to the NCI
funding.  In exceptional circumstances, such as a public health
emergency, the institutions will be required to provide subject names
and treatments to the NCI in a format which allows direct
notification of the patient by the NCI.

15.  Attendance at Meetings

The Principal Investigator, Program Leaders, and the NCI Program
Director will meet at least once a year, at a site mutually agreed
upon by the Principal Investigator and the NCI Program Director.  The
purpose of this meeting will be to review progress, plan and design
research activities, and establish priorities.  Because NCI travel
funds are limited, the group's budget should assume that the annual
meeting will be held at NCI, and should include funds for travel of
group members to the meeting.  In consultation with the NCI Program
Director, the Principal Investigator may call more frequent meetings.
The Principal Investigator will be responsible for scheduling the
time and place of 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.

16.  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, shall have
access to all data generated under this Cooperative Agreement and may
periodically review the data.  The awardee shall retain custody of
and primary rights to the data, consistent with current HHS, PHS, and
NIH policies.

B.  NCI Staff Responsibilities

As described throughout these Terms and Conditions of Award, the role
of the NCI will be to assist and facilitate, not to direct, group
activities.

1.  NCI as a Scientific Resource for CATBRM Group Activities

The NCI will designate a Program Director to guide the overall CATBRM
program with the NCI.  The NCI Program Director will also coordinate
and facilitate NCI's role in each group.  The NCI Program Director,
and other NCI staff at the request of the NCI Program Director, will
serve as a resource available to the group for specific scientific
information with respect to treatment regimens, clinical trial
design, investigational agent management, and regulatory issues.  The
NCI Program Director will assist the group, as appropriate, in
developing information concerning the scientific basis for specific
trials.  The NCI Program Director will advise the group of potential
studies relevant to new approaches to cancer therapy in the area of
the group's interest and expertise, and will facilitate interactions
between the group and other investigators in the field (e.g., through
seminars and conferences).  Decisions requiring NCI approval will be
obtained through the NCI Program Director, who will also ensure that
required approvals from other NCI components are sought in a timely
fashion and obtained.

2.  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
likely that the group will develop subsequent protocols within the
objectives approved by peer review.  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; 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
these Terms and Conditions of Award.

3.  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.  NCI will review
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.

4.  Review of Quality Control and Study Monitoring

The NCI Program Director will coordinate any necessary NCI review and
approval of quality control and study monitoring mechanisms. NCI will
provide advice, as required, regarding these mechanisms.

5.  Review of Data Management and Analysis

The NCI Program Director will coordinate any necessary NCI review of
the group's mechanisms for data management and analysis.  When it
deems it appropriate, NCI will make recommendations to ensure that
data collection and management procedures 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.  The NCI will have access to all data
although they remain the property of the awardee institution.  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.

6.  Protocol Closure

The NCI Program Director may request that a CATBRM protocol be closed
to further patient accrual for the following reasons:  (a) the
protocol's accrual goal has been met; (b) there has been an
insufficient accrual rate; (c) there has been poor protocol
performance; (d) changes in drug availability make protocol
completion unlikely; or (e) for patient safety concerns.  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.

7.  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).  IND arrangements will
be established in discussions between the Principal Investigator and
the NCI Program Director, who will make recommendations, as required,
regarding IND filing.

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 to 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).

8.  Review of Compliance with Federally Mandated Regulatory
Requirements

The NCI Coordinator 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.  If so, the NCI Coordinator will
facilitate that review and approval.

9.  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
other data summaries.  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 and Conditions of Award, may result in a reduction in budget,
withholding of support, suspension, or termination of award.

10.  Assistance with cGMP Production of Investigational Agents

Upon recommendation of the NCI Program Director, the NCI may produce
investigational agents for a group, under current Good Manufacturing
Practice (cGMP) conditions, in its Monoclonal Antibody/Recombinant
Protein production facility (MARP).  Production of investigational
agents in the MARP will be contingent upon NCI review of the
project's feasibility and costs, and will require approval by the
Decision Network Committee (DNC) of the Division of Cancer Treatment,
NCI.

11.  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.

C.  Collaborative Responsibilities

Membership in the Group

Group membership includes the Principal Investigator, the Clinical
Investigations Leader, the Program Leaders and the NCI Program
Director.  The Principal Investigator will be responsible for
communication with NCI, through 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 (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.

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.

D.  Arbitration

Any disagreement between award recipients and NCI on scientific or
programmatic matters (within the scope of the award) may be brought
to arbitration.  In such instances, an arbitration panel will be
formed, consisting 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.

Drug Information/INDs/Drug Supply

A.  Patent and license 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/license status of the agent(s) proposed for study.  Each
applying group is encouraged to employ the specific
patenting/licensing arrangement relevant to its application, but must
include this information (with any supporting documents) with the
application.

If a patent/license already exists or is pending for an agent, the
application should so state and identify the patent/license holder.
A letter, signed by the Principal Investigator and each Program
Leader, recognizing the patent/license holder and status, must be
submitted to the Scientific Review Administrator, Division of
Extramural Activities, NCI prior to peer review.

If patent/license coverage does not already exist for a proposed
study agent, or if new patents/licenses (e.g., use patents) are to be
filed, the application must include a description of procedures for
obtaining patent/license coverage for each such agent.  This is
essential to avoid patent/license 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/license
arrangements for each group member and member institution, must be
submitted to the Scientific Review Administrator, Division of
Extramural Activities, NCI prior to peer review.

B.  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.  Applicants are
encouraged to propose the IND arrangement most appropriate to the
goals of their applications.  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.  In some cases, it may be permissible under federal
regulations for group trials to be conducted without an IND.  In such
cases, primary responsibility for insuring that all applicable
federal regulations are met rests with the awardee.

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, or to justify proceeding without an
IND.  This information should include a description of currently
available preclinical data for the agent; a list of additional
preclinical studies which remain to be done in support of IND filing;
and 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 are likely to be
available in time to allow patient accrual to begin within 18 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  A group may conduct a trial without an IND only after
demonstrating that all applicable FDA requirements will be met,
consistent with the above guidelines.

C.  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 agents are to be obtained from pharmaceutical
companies, individuals, or other outside parties, letters of support
from those companies should be included with the application.
Applicants who propose obtaining agents from the NCI must discuss
their plans with the NCI prior to submitting an application.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH- supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.

Investigators proposing research involving human subjects should read
the "NIH Guidelines For Inclusion of Women and Minorities as Subjects
in Clinical Research," which have been published in the Federal
Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the
NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18,
1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 30, 1995, 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 the RFA in
response to which the application may be submitted.  Although a
letter of intent is not required, is not binding, and does not enter
into the review of a subsequent application, the information that it
contains allows NCI staff to estimate the potential review workload
and to avoid conflict of interest in the review.

Letters of intent are to be sent directly to:

Jon T. Holmlund, M.D.
Division of Cancer Treatment
National Cancer Institute
NCI-FCRDC, Building 1052, Room 253
Frederick, MD  21702-1201
Telephone:  (301) 846-1098
FAX:  (301) 846-5429

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be
used.  This form is available at most institutional offices of
sponsored research; from the Office of Grants Information, Division
of Research Grants, National Institutes of Health, 6701 Rockledge
Drive, Room 3032, Bethesda, MD 20892-7762, telephone 301/435-0714;
and from the program administrator listed under INQUIRIES.

This RFA requires the submission of a single application for the
proposed CATBRM group.  Because of the special requirements of this
RFA, additional written instructions regarding format will be
provided by the program administrator listed under INQUIRIES.
Potential applicants are urged to obtain the "Special Instructions to
Applicants" to avoid omitting essential information and to expedite
review.  If required information is not contained within the
application, the application will be returned without review.

The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
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.

On line 2 of the face page of the application form, the YES box must
be marked, the RFA number (RFA CA-95-017) must be included, and the
Title must be given as Cancer Therapy with Biological Response
Modifiers (CATBRMs).  Specific titles for the application should be
given on line 1.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed photocopies in one package to:

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight service)

At the time of submission, two additional copies of the application
must be sent to:

Toby M. Friedberg
Referral Officer
National Cancer Institute
Executive Plaza North
6130 Executive Boulevard, Room 636
Bethesda, MD  20892-7405
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-3428

Applications must be received by January 4, 1996.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.  If an
application is not responsive to the RFA, DRG staff will return the
application to the applicant.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NCI in accordance with the review
criteria stated below.  As part of the initial merit review, all
applicants will receive a written critique and may undergo a process
in which only those applications deemed to have the highest
scientific merit will be discussed, assigned a priority score, and
receive a second level review by the National Cancer Advisory Board.

Each Clinical and Laboratory Program will be evaluated on its
relevance to the group's objectives as well as its individual
scientific merit.

Requirements for Responsiveness to RFA

To ensure responsiveness to this RFA, applications must include:

1.  A primary emphasis on, and plan for, completing a translational
research project in the treatment of cancer with BRMs.  This must
include a clear timeline, which must in turn include at least one
clinical trial to begin patient accrual no later than 18 months after
award, and to complete all patient treatment and data analysis by the
end of the award period.  Preclinical work between the time of the
award and the initiation of the first clinical trial may be included
to support the clinical development of the agent(s) or approach(es)
proposed for study.

2.  A full protocol, or, at a minimum, an outline for the initial
clinical trial, in sufficient detail to permit assessment of the
scientific merit of the rationale, proposed clinical treatment and
laboratory monitoring approaches and proposed statistical analysis.
The description of the initial clinical trial should be commensurate
with the proposed timeline; e.g., applications proposing that a trial
be initiated within six months of award should include a full
protocol.  (Protocols or detailed outlines for clinical trials after
the first are not necessary for an application to be considered
responsive.)

3.  A description of the patent/license status of the agent(s) to be
studied, and of the group's plans to address patent/license issues.

4.  A description of the IND status of the agent(s) proposed for
study, including supporting information.

5.  A description of the group's plans to ensure the availability of
adequate drug supplies for the clinical trial, including supporting
material (e.g., letters of support from drug suppliers).

6.  A signed statement from the Principal Investigator and from each
Program Leader agreeing to accept the Terms and Conditions of Award.

7.  A description of the interrelationships among the members of the
group and the contribution of each to fulfillment of group
objectives.

8.  A description of the specific assistance the group believes it
will need from NCI to translate its preclinical findings into an
initial clinical trial - e.g., assistance with production or
procurement of investigational agents, assistance with IND- directed
studies, assistance with preparation/filing of an IND, etc.

Review Criteria

1.  Scientific, technical, or medical significance and originality of
the proposed research;

2.  Scientific, technical, or medical appropriateness of the overall
proposed timeline for the project;

3.  Appropriateness and adequacy of the experimental approach and
methodology proposed for each Clinical and Laboratory Program, and
for the project overall;

4.  Qualifications and research experience of the Principal
Investigator, Program Leaders and other staff, particularly, but not
exclusively, in the area of the proposed research;

5.  Availability of the resources necessary to perform the research;

6.  Appropriateness of the proposed budget and duration in relation
to the proposed research and the proposed project timeline;

7.  Quality of supporting data; evidence that studies to date warrant
further development of the proposed agents or approaches, and that
such development is feasible;

8.  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;

9.  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;

10.  Adequacy of plans for effective intra-group communication and
for ensuring group cohesiveness;

11.  Evidence of approval and commitment of institutions represented
by group members to group goals.

12.  Adequacy of plans to include both genders and minorities and
their subgroups as appropriate for the scientific goals of the
research.  Plans for the recruitment and retention of subjects will
also be evaluated.

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.

AWARD CRITERIA

The anticipated date of award is July 1, 1996.  In addition to
technical merit, the following will be considered in making awards:
(1) availability of funds; (2) availability of other resources
(including drug supplies for the proposed preclinical studies and
clinical trials); (3) program balance, including sufficient
compatibility of features to make a successful collaborative program
a reasonable likelihood; and (4) NCI program priorities.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Jon Holmlund, M.D.
Division of Cancer Treatment
National Cancer Institute
BRMP, NCI-FCRDC
Building 1052, Room 253
Frederick, MD  21701-1201
Telephone:  (301) 846-1098
FAX:  (301) 846-5429

Direct inquiries regarding fiscal matters to:

Eileen Natoli
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
6120 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 256
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 IV, 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.

The PHS strongly encourages all grant recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.
In addition, Public Law 103-227, The Pro-Children Act of 1994,
prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.

.

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