Full Text CA-97-001
 
PHASE I TRIALS OF ANTI-CANCER AGENTS
 
NIH GUIDE, Volume 25, Number 40, November 22, 1996
 
RFA:  CA-97-001
 
P.T. 34

Keywords: 
  Autoimmunity 
  Clinical Trial 
  Chemotherapeutic Agents 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  January 17, 1997
Application Receipt Date:  March 12, 1997
 
PURPOSE
 
The purpose of this Request for Applications (RFA) is to provide
continued funding for a Phase I Clinical Trials Program to support
scientifically directed Phase I trials of promising anti-cancer
agents available through the National Cancer Institute (NCI) from the
NCI's drug screening program or referred to NCI from other sources,
(e.g., the pharmaceutical and biotechnology industry and academia);
and to conduct pharmacokinetic and laboratory studies in support of
the clinical trials such that their conduct leads to a greater
understanding of the relationship between drug administration and
biological changes in patients.  The Cancer Therapy Evaluation
Program (CTEP) of the Division of Cancer Treatment, Diagnosis and
Centers (DCTDC), NCI invites cooperative agreement (U01) applications
from institutions wishing to study these anti-cancer agents in Phase
I Clinical Trials.  Single Institution Phase I studies are preferred,
although laboratory studies may be conducted by collaborators at
other institutions. Strong justification and evidence of well
established collaborations must be supplied for multi-institutional
applications.  Studies begun under a predecessor cooperative
agreement may be completed under this cooperative agreement pending
agreement from the NCI Program Director.
 
The increasing number of promising new agents with diverse and novel
mechanisms of action makes it desirable to continue NCI support in
this area.  Institutions responding to this Request for Applications
(RFA) should be able to perform Phase I trials and establish the
pharmacological characteristics, in parallel with biochemical and
other appropriate biological studies, of the effects of these agents
on cancer cells and normal tissues.  It is expected that
pharmacokinetics and, where possible, other laboratory correlative
studies will be conducted in real-time, throughout the course of the
clinical trial to facilitate optimal utilization of the data in the
design and coordination of clinical trials with the agent.
Applications from any one institution may focus on studies of one or
more classes of agents or therapeutic approaches, reflecting the
interest, expertise, and experience of the applicant investigators or
a more general approach to the pharmacokinetic/pharmacodynamic
evaluation of new agents may be developed.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Phase I Trials of Anti-Cancer Agents, 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 for-profit and non-profit
organizations such as universities, colleges and hospitals, units of
State and local governments, and eligible agencies of the Federal
government.  Racial/ethnic minority individuals, women, and persons
with disabilities are encouraged to apply as Principal Investigators.
 
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 SPECIAL REQUIREMENTS, Terms and Conditions
of Award, NCI Staff Responsibilities. 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 awardee
activities or to limit the freedom of investigators.
 
Under the cooperative agreement, a relationship exits between the
recipient of the award and the NCI, in which the recipient is
responsive to the requirements and conditions set forth in the RFA.
Specifically, the Principal Investigator defines the details for the
project within the quidelines 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 - see INQUIRIES)
in all aspects of scientific and technical management of the project
in accordance with the Terms and Conditions of Award.
 
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.
 
FUNDS AVAILABLE
 
Approximately $5,500,000 in total costs per year for five years will
be committed to specifically fund applications submitted in response
to this RFA.  This funding level is dependent on the receipt of a
sufficient number of applications of high scientific merit.  It is
anticipated that approximately fifteen awards will be made.  The
earliest feasible start date for the initial awards will be February
1, 1998.  Although this program is provided for in the financial
plans of the NCI, the award of cooperative agreements pursuant to
this RFA is contingent upon the availability of funds for this
purpose.
 
This RFA is a one-time solicitation.  At this time the NCI has not
determined whether or how this solicitation will be continued beyond
the present RFA.  If it is determined that there is a sufficient
continuing program need, the NCI will either invite recipients of
awards under this RFA to submit competitive continuation cooperative
agreement applications for review or re-issue the RFA for
re-competition.  If the NCI does not continue the program, awardees
may submit grant applications through the usual
investigator-initiated grants program.
 
RESEARCH OBJECTIVES
 
A.  Background
 
The NCI currently holds over 200 active INDs for anticancer agents.
NCI actively supports the primary development of a diverse array of
anticancer therapeutic agents which originate from the NCI's
preclinical Developmental Therapeutics Program as well as from
academia; in these cases NCI often holds the only IND investigational
new drug application).  In addition, for agents derived from the
pharmaceutical/biotechnology arena where NCI feels that
co-development is in the best interest of improving the treatment of
cancer patients, NCI may file INDs and participate in collaborative
clinical development.  In the latter case, NCI often promotes the
exploration of important scientific questions which may not be the
primary focus of market-driven industry development, either because
of limited resources in the case of small companies, the need to
perform combination studies with other investigational agents for
which NCI holds an IND, or because of small commercial markets due to
the relatively low frequency of certain human cancers.  NCI support
facilitates the development of these important agents and
indications.
 
The increasing number of promising new agents with diverse and novel
mechanisms of action makes it desirable to continue NCI support for
the study of these agents.  The NCI will accelerate cancer treatment
development by supporting research applications whereby clinicians
and laboratory investigators can utilize their extensive experience
and expertise to study investigational agents in comprehensive Phase
I trials with appropriate laboratory and clinical correlations.  This
RFA provides an opportunity for clinical and laboratory investigators
within an institution to develop a program in drug development that
utilizes the strengths of pre-existing basic scientific expertise and
available clinical resources.  Scientific approaches will reflect the
scientific interest, creativity and capabilities of participants and
the agents available for study.  The investigators would bring to the
collaboration their specific biological and pharmacological
expertise, their ideas concerning clinical investigative strategies
unique to each agent, the necessary patient and investigative
resources for study of the agent, and their data management and
analytical abilities.
 
In an attempt to reduce the time period between new drug discovery
and the general introduction of an effective new therapy to patients,
the NCI offers assistance at many levels to investigators attempting
to develop active new cancer therapies. In addition to the funding
assistance offered to the investigator(s) by this RFA, NCI will
sponsor (in accord with Food and Drug Administration requirements) or
co-sponsor the agents under development.  An organization or
individual who assumes legal responsibilities for supervising or
overseeing clinical trials with investigational agents is termed a
sponsor. As sponsor of an investigational drug, DCTDC and
specifically, CTEP, is responsible for ensuring that clinical trials
proceed safely and rationally from the initial dose-finding studies
to a definitive evaluation of the role of the new drug in the
treatment of one or more specific cancer(s).  Fulfillment of this
goal obviously requires the active participation of CTEP staff
throughout the entire process.  An Investigational Drug Branch (IDB)
Physician is assigned to each DCTDC IND to assist in the coordination
of its development.  NCI sponsorship of investigational agents
increases the likelihood that agents will be fully developed so that
they will ultimately be broadly available for use in cancer treatment
and will provide resources to accelerate this process.
 
B.  Research Goals and Scope
 
The aims of this initiative are to:  (1) provide support for Phase I
trials of promising new anti-cancer agents in cancer patients; and
(2) provide support for complete pharmacokinetic, pharmacodynamic,
and other important laboratory correlative studies in cancer patients
receiving these anti-cancer agents.
 
Phase I clinical trials have as their objectives the characterization
of drug toxicity, maximally tolerated dose, pharmacokinetics, and
biological effects (pharmacodynamics) of drugs.  These anti-cancer
agents have traditionally been obtained either from the NCI drug
development program or through collaborative drug development
agreements with the pharmaceutical industry.  Recent advances in
understanding of the pathobiology of malignancy are leading to the
development of a wide range of novel anti-cancer therapeutic agents
that require Phase I testing.  These agents include, but are not
limited to, new classes of cytotoxic agents derived from natural
products, as well as rationally designed anti-cancer agents targeted
specifically to novel cancer cell targets, including surface
receptors, signal transduction molecules, transcriptional factors,
and particular DNA and RNA sequences.  Furthermore, mechanisms of
action of these new anti-cancer agents available for clinical study
include the mediation of anti-cancer effects not only through
classical cytotoxic mechanisms, but also through growth inhibition by
interruption of specific oncogene-associated biochemical functions,
inhibition of protein synthesis through targeted toxins, induction of
differentiation and/or programmed cell death (apoptosis), and through
inhibition of tumor angiogenesis and metastasis.  In addition, new
strategies to overcome resistance to conventional cancer therapeutic
approaches are also of interest.
 
The laboratory studies should be in support of the clinical trial,
such that their conduct leads to a greater understanding of the
relationship between drug administration and biological changes in
patients.  Laboratory studies would include pharmacokinetic studies
of cytotoxic, differentiation-inducing, targeted and/or other novel
anti-cancer agents, including monitoring of metabolites and
intracellular products when appropriate, or other relevant
pharmacology correlative studies; and the measurement of relevant
indicators of pharmacodynamic or biologic response (e.g., changes in
signal transduction pathways, induction or suppression of specific
gene function, other indications of differentiation induction, or
induction of apoptosis).
 
The investigators will define scientific objectives and experimental
approaches consistent with the goals of Phase I clinical trials.  The
investigators will select the specific NCI sponsored agents of
interest in accord with their areas of scientific interest and
expertise, and will develop a series of appropriate phase I trials
with supporting protocol documents. The Government will have access
to the data generated, will periodically review the data and may
perform special analyses of the data.  However, the awardees will
retain custody and primary rights to their data developed under these
awards.  Data will be submitted to the NCI's Clinical Trials
Monitoring Service at prescribed intervals.  Timely publication of
findings will be encouraged.
 
Each Phase I awardee institution must have demonstrated experience in
conducting Phase I Clinical Trials.  Sufficient numbers of patients
at the applicant institution should be available in order to allow
completion of the trials in a timely manner.  In all categories of
diseases, the Principal Investigator must select those patients for
trial with the best performance status and with the minimum amount of
prior treatment consistent with ethical medical practice. The
Principal Investigator will ensure that these Phase I trials conform
to accepted standards of patient care.  For example, patients should:
 
a.  have a microscopically confirmed diagnosis of cancer;
 
b.  be staged by conventional methods and found to have disseminated
disease not amenable to curative intent therapy with surgery and/or
radiotherapy;
 
c.  have already received and failed appropriate initial systemic
treatment.  For diseases for which systemic treatment exists (e.g.,
the acute leukemias, diffuse non-Hodgkin's lymphomas, Hodgkin's
disease, testicular cancer, limited small cell lung cancer, ovarian
carcinoma), patients should have received the minimum extent of prior
treatment compatible with current ethical standards of care, and
should have a high performance status. For other diseases in which
only partially effective non-curative therapy is available (e.g.,
carcinomas of the head and neck, hormone-refractory prostatic
carcinoma, bladder and stomach cancer, sarcomas), entry of patients
with no prior therapy may be appropriate.
 
d.  receive appropriate initial and follow-up, hematologic,
biochemical, radiologic, and immunologic investigations; and
 
e.  have given a signed informed consent indicating that they are
aware of the investigational nature of the studies involved.
 
Each applicant institution is responsible for coordination of
protocol development and submission, study conduct, quality control,
data management and analysis, adherence to NCI requirements for
investigational agents, adherence to FDA/DHHS regulations, and
reporting of data from the Phase I trials.  For Phase I trials with
NCI-sponsored investigational agents, the NCI has contracted for a
Clinical Trials Monitoring Service (CTMS) to document regulatory
compliance, to maintain a computerized data base of the Phase I
investigator data submissions (currently biweekly), and to produce
periodic routine reports of the results and special reports as
necessary.  The awardee institution's source documentation will be
reviewed on-site three times per year by the CTMS.
 
SPECIAL REQUIREMENTS
 
Terms of Cooperation
 
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 purpose is to support and/or stimulate the recipient's
activity by involvement in and otherwise working jointly with the
award recipient in a partner role, but it is not to assume direction,
prime responsibility, or a dominant role in the activity.  Consistent
with this concept, the dominant role and prime responsibility for the
activity resides with the awardee for the project as a whole,
although specific tasks and activities in carrying out the studies
will be shared among the awardee and the NCI Project Scientist.  The
role of the Cancer Therapy Evaluation Program (CTEP) staff as
described throughout these terms and conditions of award is to
facilitate and assist but not to direct research activities. This
cooperative agreement is part of a larger program of investigational
agent development in the NCI.  Each of the CTEP staff listed below
has very specific and well defined responsibilities in terms of
investigational agent development and the role of  DCTDC  as a drug
sponsor as defined in CFR 21 Part 312.
 
1.  Awardee Rights and Responsibilities
 
It is the responsibility of the Principal Investigator (PI) to
develop the details of the research design, including definition of
objectives and approaches, planning, implementation, analysis, and
publication of results, interpretations and conclusions of studies.
A protocol is the detailed written plan of a clinical experiment.
The protocol must be mutually acceptable to the PI and to the CTEP
Protocol Review Committee (PRC), which must review and approve every
protocol involving DCTDC investigational agents.
 
a.  Protocol Development
 
The PI shall, with CTEP assistance, develop Phase I protocols which
define the scientific objectives and experimental approaches for:
 
1)  Anticancer agents identified by the NCI's drug screening program
or referred to NCI  from other sources, including the pharmaceutical
and biotechnology industry;
 
2)  Anticancer agents with novel mechanisms, including but not
limited to:  inhibitors of angiogenesis and metastasis,
differentiating agents, apoptosis-inducing agents, anti-sense
oligonucleotides and related gene-specific therapeutic agents, and
targeted cytotoxic agents.
 
3) Existing chemotherapeutic agents which, when administered with
colony stimulating factors or other agents to ameliorate
dose-limiting toxicities, can be given in doses substantially higher
than those previously tested or which on the basis of preclinical
studies might have increased anti-tumor effect in combination; and;
 
4)  novel combination pilots of importance to CTEP's drug development
program where dose, pharmacokinetic or drug interaction issues must
be carefully defined.
 
The protocols shall be conducted in accordance with the instructions
in the INVESTIGATOR'S HANDBOOK, A Manual for Participants in Clinical
Trials of Investigational Agents Sponsored by the Division of Cancer
Treatment, National Cancer Institute, Revised 10/93 (available from
the NCI Program Director).  The INVESTIGATOR'S HANDBOOK describes the
procedures for:
 
o  Requirements for Protocol Development and Submission
o  Ordering Investigational Drugs from NCI
o  Responsibility for Reporting of Results to CTEP
o  Adverse Event Reactions
o  Accountability and Storage of Investigational Drugs
o  Monitoring and Quality Assurance
 
The PI shall submit the Phase I protocols to CTEP (either to the
Letter of Intent (LOI) Coordinator or to the CTEP Protocol and
Information Office, the receiving office for all protocols sent to
CTEP), for review as appropriate, prior to their implementation.
 
The PI shall designate a Protocol Chairperson for each proposed
study.  The PI will be responsible for communication with the
appropriate CTEP staff.  The PI is responsible for coordinating
protocol development, protocol submission, study conduct, quality
control and study monitoring, drug ordering, data management and
analysis, protocol amendments/status changes, adherence to
requirements regarding investigational drug management and federally
mandated regulations and protocol and performance reporting.
 
b. Protocol Submission
 
Communication at the various stages of protocol development is
encouraged as necessary to promote protocol development and
implementation.  It is recommended that protocols be preceded by a
written declaration of interest in conducting a particular study from
the PI using the suggested format described in the INVESTIGATOR'S
HANDBOOK, Appendix VII, GUIDELINES FOR SUBMITTING LOIs - Letter of
Intent/ INVESTIGATIONAL DRUG TRIAL.  The LOI shall describe the
hypothesis to be investigated with appropriate references or
supporting data, the general design of the contemplated trial plus
relevant information on accrual capabilities to document feasibility.
The LOI should be sent to the CTEP LOI Coordinator who receives, logs
in and schedules LOIs for review by the PRC.
 
The PI shall submit the Phase I protocols to the CTEP Protocol and
Information Office, the receiving office for all protocols sent to
CTEP, for review as appropriate prior to their implementation.
 
c.  Study Conduct and Monitoring
 
The awardee institution is responsible for ensuring accurate and
timely knowledge of the progress of each study through:
 
1)  establishing data management support capabilities that ensure
that data will be submitted via electronic transfer biweekly to NCI's
Clinical Trials Monitoring Service (CTMS). This data includes:
registration of each patient entered onto a Phase I protocol within
the previous two week period, and all data obtained on each
registered patient within the previous two weeks as specified by the
NCI/DCTDC Case Report Form and the individual protocol.
 
2)  establishing procedures for assigning dose level at the time a
new patient is entered, and assuring that the required observation
period has elapsed before beginning a higher dose level.
 
3)  registration, tracking and reporting of patient accrual and
adherence to defined accrual goals; appropriate attempts to accrue
patients who fulfill NIH Guidelines for accrual of women and
minorities to clinical trials with appropriate documentation and
reporting of accrual as specified by NIH Guidelines;
 
4)  ongoing assessment of case eligibility and evaluability;
 
5)  timely medical review and assessment of patient data;
 
6)  rapid reporting of treatment-related morbidity (adverse event
reactions) and measures to ensure communication of this information
to all parties;
 
7)  interim evaluation and consideration of measures of outcome, as
consistent with patient safety and good clinical trials practice; and
 
8)  timely communication of results of studies.
 
d.  Data Management and Analysis
 
The awardee will develop procedures to ensure that data collection
and management are:  a) adequate for quality control and analysis;
and  b) as simple as appropriate in order to encourage maximum
participation of physicians entering patients and to avoid
unnecessary expense.
 
f.  Investigational Drug Management
 
Investigators performing trials under cooperative agreements
involving a Division of Cancer Treatment, Diagnosis and Centers
(DCTDC) investigational agent must be NCI registered investigators
(Form FDA 1572) and will be expected to implement CTEP requirements
described in the INVESTIGATORS' HANDBOOK for storage and accounting
for investigational agents, to abide by NCI/HHS Drug Accountability
Records (DAR) procedures, and to comply with all FDA requirements for
investigational agents.
 
g.  Compliance with Federally Mandated Regulatory Requirements
 
The awardee is responsible for establishing procedures to comply with
FDA regulations for studies involving investigational agents and OPRR
requirements for the protection of human subjects. These procedures
are:
 
1)  methods for ensuring that the awardee institution has a current,
approved assurance on file with the OPRR; that each protocol is
reviewed and approved by the responsible Institutional Review Board
(IRB) prior to patient entry; that each protocol is reviewed at least
annually by the IRB so long as the protocol is active; that
amendments are approved by the IRB; that each investigator is
registered with the Drug Management and Authorization Section (DMAS),
CTEP with a current 1572 form on file; and that each patient (or
legal representative) gives written informed consent prior to entry
on study.
 
2)  a system for ensuring timely reporting of all serious and
unexpected toxicities to the Investigational Drug Branch, (IDB), CTEP
according to CTEP guidelines (mailed annually to all registered
investigators). This may require reporting Adverse Event Reactions
(AERs) by telephone to the responsible IDB Physician within 24 hours
of the event and requires a written report to follow within 10
working days.  (See 2. NCI Staff Responsibilities for definition of
responsible IDB Physician.)
 
3)  a system for ensuring that the required data is provided biweekly
to the CTMS.
 
h.  Reporting Requirements
 
Reporting requirements will be in agreement with FDA regulations and
NCI procedures.  Annual progress reports will be submitted to the NCI
in a non-competing continuation application and will include at a
minimum summary data on protocol performance by the awardee
institution, interim reports of each activated study including
specific data on patient accrual, as well as detailed reports of
treatment-associated morbidity and other relevant data.
 
I.  Publication of Data
 
Timely publication of major findings is encouraged.  Publication or
oral presentation of work done under this agreement will require
appropriate acknowledgment of NCI support.  The NCI will have access
to all data generated under this cooperative agreement, will
periodically review the data and may perform special analyses of the
data.  The awardee will retain custody and primary rights to the data
consistent with current HHS, PHS, and NIH policies.
 
2.  NCI Staff Responsibilities
 
The role of the Cancer Therapy Evaluation Program (CTEP) staff as
described throughout these terms and conditions of award is to
facilitate and assist but not to direct research activities. This
cooperative agreement is part of a larger program of investigational
agent development in the NCI.  Each of the CTEP staff listed below
has very specific and well defined responsibilities in terms of
investigational agent development and the role of DCTDC as a drug
sponsor as defined in CFR 21 Part 312.
 
a.  Provision of NCI-sponsored Investigational Agents and
Responsibilities of IND Sponsor
 
CTEP will supply the investigational agents to be studied and will be
the Sponsor for these agents.  CTEP will submit Investigational New
Drug Applications to the FDA permitting DCTDC to act  as a drug
sponsor.  As a sponsor of an investigational drug, DCTDC, and
specifically CTEP, is responsible for seeing that clinical trials
proceed safely and rationally from the initial dose-finding studies
through the definitive evaluation of the new drug in the treatment of
one or more specific cancers.
 
b.  CTEP as a Scientific Resource for NCI-supported Phase I Clinical
Trials Investigations
 
An Investigational Drug Branch (IDB) Physician is assigned to each
DCTDC IND agent to assist in the coordination of its development.
The NCI Program Director and the responsible IDB physician will serve
as a resource available to the Principal Investigator (PI) for
specific scientific information with respect to treatment regimens
and clinical trial design.  The NCI Program Director and/or
responsible IDB Physician will advise the PI of potential studies
that will be relevant to new avenues of cancer therapy.  The NCI
Program Director and/or responsible IDB Physician will assist the PI
as appropriate in developing information concerning the scientific
basis for specific trials and also will advise the PI of the nature
and results of relevant trials being carried out under NCI
sponsorship.  The NCI Program Director and/or responsible IDB
Physician will also provide updated information on the efficacy and
toxicity of investigational new agents supplied to the PI under an
Investigational New Drug (IND) Application sponsored by the DCTDC.
 
c.  CTEP Assistance in Protocol Development
 
The CTEP Protocol Review Committee (PRC), must review and approve
every protocol involving DCTDC investigational agents.  The PRC,
which meets weekly, is chaired by the Associate Director, CTEP, and
is comprised of professional staff of the DCTDC including the IDB
Physicians, Clinical Investigations Branch disease coordinators,
regulatory staff, pharmacy staff and ad hoc reviewers external to NCI
when deemed appropriate by the PRC chairperson.
 
The PRC will formally review the LOI.  Following LOI review, the
responsible IDB physician will provide a Program response to the PI
and will address the following issues:  a) the existence and nature
of concurrent clinical trials in the area of research, pointing out
possible duplication of effort; b) information including relevant
pharmacokinetic and pharmacodynamic data concerning investigational
agents; c) availability of investigational agents; d) the scientific
rationale and value of the proposed study, the design, the
statistical requirements; e) the projected accrual rate; f)
correlative laboratory studies; and g) the implementation of the
study, if indicated.  The LOI mechanism is designed for preliminary
review and is recommended to expedite protocol development and
implementation, to avoid duplication and to facilitate agreement on
study priority and design (see the DCTDC Investigator's Handbook, pp
32-35, available on request from the NCI Program Director.
 
d.  CTEP Review of Proposed Protocols
 
The major considerations relevant to Protocol Review by CTEP include:
a) the strength of the scientific rationale supporting the study; b)
the medical importance of the question being posed; c) the avoidance
of unnecessary duplication with other ongoing studies; d) the
appropriateness of study design with respect to development of the
IND agent; e) a satisfactory projected accrual rate and follow-up
period; f) patient safety; g) compliance with federal regulatory
requirements; h) adequacy of data management; and I) appropriateness
of patient selection, evaluation, assessment of toxicity, response to
therapy and follow-up.
 
Following the review of the protocol by the PRC, the responsible IDB
physician will provide the PI with a consensus review prepared by the
IDB Physician.  The consensus review summarizes the PRC review and
describes required or recommended modifications and other
suggestions, as appropriate.  (See the INVESTIGATOR'S HANDBOOK, for
further information regarding protocol review at CTEP).
 
If a proposed protocol is disapproved, the specific reasons for lack
of approval will be communicated to the PI as a consensus review
within 30 days of protocol receipt by the NCI.  The NCI Program
Director and/or responsible IDB Physician will be available to assist
the PI in developing a mutually acceptable protocol, consistent with
the research interests, abilities and strategic plans of the PI and
of the NCI.  An arbitration system, as detailed below, will be
available to resolve disagreements between the NCI and the awardee.
 
NCI will not provide investigational agents or permit expenditure of
NCI funds for a protocol that it has not approved unless CTEP's
disapproval has been modified by the arbitration process outlined
below.
 
e.  Access to Data
 
The NCI will have access to all data generated under this cooperative
agreement and will periodically review the data and may perform
special data analyses.  Data must also be available for external
monitoring as required by NCI's Drug Master File Agreement with the
FDA relative to the responsibility of the NCI as an IND agent
sponsor.  The awardee will retain custody of and primary rights to
the data consistent with current HHS, PHS, and NIH policies.
 
f.  CTEP Involvement in Protocol Closure
 
The NCI Program Director and/or responsible IDB Physician and the
Head, Quality Assurance and Compliance Section (QACS), Clinical
Trials Monitoring Branch (CTMB) will monitor protocol progress. The
NCI Program Director or the responsible IDB Physician may request
that a protocol be closed to accrual for reasons including:  a)
insufficient accrual rate; b) accrual goal met; c) poor protocol
performance; d) patient safety and regulatory concerns; e) study
results are already conclusive; f) emergence of new information that
diminishes the scientific importance of the study question; and g)
failure to collect data in a timely manner.  NCI will not provide
investigational agents or permit expenditures of NCI funds for a
study after requesting closure (except for patients already
on-study).  If disagreements develop over NCI-recommended study
closure for reasons other than patient safety or regulatory concerns,
NCI will establish an arbitration process to resolve disagreements
between the NCI and the awardee.
 
g.  CTEP involvement in Investigational New Drug Applications
 
1)  The NCI Program Director and/or the Chief, Regulatory Affairs
Branch (RAB), CTEP, will advise investigators of specific
requirements and changes in requirements concerning IND sponsorship
that the FDA may mandate.  Investigators performing trials under
cooperative agreements will be expected, in cooperation with the NCI,
to comply with all FDA monitoring and reporting requirements for
investigational agents.
 
2).  The NCI Program Director and/or the Chief, RAB, CTEP, will
advise the investigators of the specific clinical information that
will be needed from the clinical trials for that information to be
acceptable to the FDA for inclusion in a new drug application (NDA).
 
h.  CTEP Review of Federally Mandated Regulatory Requirements
 
The Head, QACS, CTMB will review protocols to determine if the
awardee's mechanisms for meeting FDA regulatory requirements for
studies involving DCTDC-sponsored investigational agents and the
Office for Protection from Research Risks (OPRR) requirements for the
protection of human subjects are sufficient.  These comments are
incorporated into the protocol consensus review.  (See Awardees
Rights and Responsibilities).
 
For Phase I trials with NCI-sponsored investigational agents, the NCI
has contracted for a Clinical Trials Monitoring Service (CTMS) to
document regulatory compliance, to maintain a computerized data base
and to produce periodic routine reports of results and special
reports as necessary.  For these trials, source documentation will be
reviewed on-site three times per year by the CTMS.
 
I.  CTEP Review of Progress
 
Progress will be reviewed at least annually by the NCI Program
Director on the basis of the information provided at the semi-annual
Phase I meetings, in the continuation application, in the study
summary reports submitted via the CTEP Data Update reporting system
or by CTMS reports.  In addition, periodic accrual information may be
requested from the PI by the NCI Program Director for all active
studies when deemed appropriate.
 
Insufficient patient accrual or progress, or noncompliance with the
terms of award, including these Special Terms and Conditions of
Award, may result in a reduction of budget, withholding of support,
suspension or termination of the award.
 
3.  Collaborative Responsibilities
 
a.  Phase I strategy meetings
 
The NCI Program Director will sponsor semi-annual  Phase I strategy
meetings with the PIs to review relevant scientific information, to
review progress in the clinical trials, and to review the status of
newly available investigational agents in order to plan future
activities.  The PI will be responsible for making scientific reports
at these meetings as requested by Program Staff.
 
b.  The PI shall, with CTEP assistance as described in the above
terms for the NCI staff responsibilities, develop Phase I protocols.
The protocols must be mutually acceptable to the PI and to the CTEP
Protocol Review Committee (PRC).
 
4.  Arbitration
 
Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), excluding patient safety issues or
regulatory compliance, between award recipients and the NCI may be
brought to arbitration.  An arbitration panel composed of one awardee
nominee, one NCI nominee, and a third member with clinical trials
expertise chosen by the other two nominees will be formed to review
the CTEP decision and recommend an appropriate course of action to
the Director, DCTDC.  The arbitration procedures in no way affect the
awardee's right to appeal an adverse determination under the terms of
42 CFR Part 50, Subpart D, and 45 CFR Part 16.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Population, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines on the Inclusion of Women and Minorities as
Subjects in Clinical Research," which was reprinted in the Federal
Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting
errors in the earlier publication, and reprinted in the NIH GUIDE FOR
GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.
 
Investigators may obtain copies from these sources or from the
program staff or contact person listed under INQUIRIES.  Program
staff may also provide additional relevant information concerning the
policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by January 17, 1997, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator, the
names of other key personnel, and the number and title of the RFA in
response to which the application may be submitted.
 
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, it is requested
in order to provide an indication of the number and scope of
applications to be reviewed.
 
The letter of intent is to be sent to:
 
Michaele C. Christian, M.D.
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute
Executive Plaza North, Room 734
6130 Executive Boulevard MSC 7432
BETHESDA, MD  20892-7432
ROCKVILLE, MD 20852 (for express/courier service)
Telephone:  (301) 496-5223
FAX:  (301) 480-4663
 
APPLICATION PROCEDURES
 
A.  PREPARATION OF APPLICATION
 
Applications are to be submitted on the grant application form PHS
398 (rev. 9/96).  These forms are available at most institutional
offices of sponsored research; from the Grants Information Office,
Office of Extramural Outreach and Information Resources, National
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD
20892-7910, telephone (301) 435-0714, E-mail
ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed
under INQUIRIES.  Because the Terms of Cooperation discussed above
will be included in all awards issued as a result of this RFA, it is
critical that each applicant include specific plans for responding to
these terms. Plans must describe how the applicant will comply with
staff involvement as well as how all of the responsibilities of
awardees will be fulfilled.
 
An application from a currently funded program will be a competitive
continuation and must include a progress report, which at a minimum
consists of a summary of prior Phase I activities/accomplishments,
including a clear presentation of pharmacokinetic studies,
pharmacodynamic correlations and results, conclusions of correlative
laboratory studies and annual accrual over the funding period.  A
summary of accrual by gender and race and/or ethnicity to all Phase I
trials (reported by trial) conducted during the project period must
be provided.
 
ALL Applicants
 
1.  Investigators should include in the APPENDIX of the cooperative
agreement application draft copies of proposed protocols that might
be undertaken in the first year and should identify the particular
areas of laboratory expertise that would be utilized in the
performance of these trials.
 
2.  The applicant must demonstrate in the application the ability to
meet the following requirements:
 
a.  documented numbers of eligible patients with a history of
adequate accrual at the applicant institution to complete on average
two to three Phase I trials annually.
 
b.  laboratory support within the institution to perform
pharmacokinetic studies of cytotoxic, differentiation-inducing,
targeted, and/or other novel anti-cancer agents, including monitoring
of metabolites and intracellular products when appropriate, or other
relevant pharmacology correlative studies;
 
c.  laboratory support within the institution to measure relevant
indicators of pharmacodynamic or biologic response (e.g., changes in
signal transduction pathways, induction or suppression of specific
gene function, other indications of differentiation induction, or
induction of apoptosis);
 
d.  adequate central data collection and processing capabilities in
order to meet FDA requirements for the conduct of research using
investigational agents.  These specifically include:
 
e.  the capability to transmit patient data to the NCI's Clinical
Trials Monitoring Service (CTMS) on a biweekly basis.
 
f.  the capability of prompt reporting of AERs to CTEP for
investigational agents supplied by NCI in accordance with the CTEP
guidelines (mailed annually to all registered investigators).
 
g.  adequate pathology support for tumor classification and for
banking and distribution of tumor tissues for concurrent and future
studies.
 
h.  adequate mechanisms in place to ensure that all patients:
 
(1)  have histologically confirmed diagnosis of cancer;
 
(2)  have refractory disease not amenable to therapy with curative
intent using surgery, chemotherapy, and/or radiotherapy or any other
form of known effective therapy;
 
(3)  have acceptable performance status and acceptable renal, liver,
and hematologic function; and
 
(4)  have given signed informed consent in accordance with 45 CFR
Part 46, Protection of Human Subjects, indicating that they are aware
of the investigational nature of the studies involved.
 
I.  Evidence of a level of supportive care appropriate for the
treatment of patients with advanced malignancies;
 
j.  Intensive care and blood bank facilities on-site and functioning
24 hours per day.
 
k.  Adequate physician and nursing resources to comply with all
reporting requirements of NCI-sponsored Phase I trials.
 
l.  Appropriate drug accountability procedures as required for
utilization of NCI-supplied investigational agents.
 
3.  All costs required for these studies must be included in the
application and must be fully justified.  These costs include the
additional costs of clinical research associated with Phase I studies
including costs related to patient accrual, data collection, sample
handling, additional staff time, specific supply needs related to
required laboratory studies, quality assurance, data management and
data analysis, study monitoring, travel, and biweekly electronic data
submissions to the NCI's Clinical Trials Monitoring Service as
required by the reporting requirements for investigational agents.
 
4.  If capitation costs are requested as reimbursement for patient
accruals, the cost per patient must be broken down and justified,
e.g.:
 
a.  estimate of physician time spent on research (e.g., to obtain
informed consent, to fill out data forms, and others) and the
resultant cost.  Time spent delivering standard medical care is not
allowable.
 
b.  estimate of Clinical Research Associate/data manager or nurse
time to meet research requirements (e.g., compiling and mailing data,
specimens) and the resultant cost.
 
c.  cost of mailing or handling research-related patient specimens,
forms, materials (e.g., slides, X-ray)
 
d.  other consultant costs (e.g., pathology, radiology).
 
5.  Travel funds for two meetings per year for two representatives
from the awardee institution should be included in the budget.
 
The RFA label available in the PHS 398 (rev. 5/95) must be affixed to
the bottom of the face page.  Failure to use this label could result
in delayed processing of the application such that it may not reach
the review committee in time for review. In addition, the RFA number
and title must be typed on line 2a of the face page of the
application form and the YES box must be marked.
 
Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package:
 
DIVISION OF RESEARCH GRANTS
National INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD 20817 (for express mail)
 
At the time of submission, two additional copies of the application
must also be sent to:
 
Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892
Rockville, MD 20852 (for express mail)
 
Applications must be received by March 12, 1997.  If an application
is received after that date, it will be returned.
 
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
 
A.  Review Procedure
 
Upon receipt, applications will be reviewed by the Division of
Research Grants (DRG) for completeness and by the NCI for
responsiveness.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.
 
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NCI in accordance with the review
criteria stated below.  As part of the initial merit review, all
applications 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.
 
The review group will assess the scientific merit of the studies
using the following review criteria:
 
B.  Review Criteria
 
The factors considered in evaluating the scientific merit of each
application will be:
 
1.  scientific, technical, medical significance and originality of
proposed research as reflected in the protocols, research plans and
strategies that address the clinical and laboratory considerations
for Phase I studies using cytotoxic and biologic agents alone or in
combination; evidence that the proposed scientific studies would
contribute to a greater understanding of the nature of the
therapeutic agent, which may include, but are not limited to, an
understanding of its mechanism of action, mechanisms of resistance,
or differences among patients with respect to pharmacology or
metabolism.
 
2.  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research including:
 
a.  adequacy of plans for the development, implementation and
analysis of Phase I clinical trials
 
b.  adequacy of plans, equipment and resources to carry out
pharmacokinetic and pharmacodynamic analyses in a timely manner.
 
c.  adequacy of plans for correlative laboratory studies and
evaluation of the data with respect to treatment administration or
treatment outcome
 
d.  adequacy of statistical approach for correlating research studies
with treatment outcomes in Phase I trials.
 
e.  adequacy of plans for effective collaboration among laboratory,
clinical, and statistical investigators.
 
f.  adequacy of mechanisms for quality control, study monitoring,
data management and reporting, data analysis, investigational drug
management, and compliance with regulatory requirements
 
3.  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research including:
 
a.  experience and competence of the Principal Investigator and
clinical investigators in the development, implementation and
analysis of Phase I trials.
 
b.  experience in the daily management and treatment of patients with
various malignant tumors and assessment of eligibility/evaluability
of these patients in cancer clinical trials.
 
c.  experience of the investigators in obtaining blood and/or tissue
specimens for research purposes from patients entered onto clinical
trials and the evaluation of those data with respect to treatment
administered or treatment outcome.
 
d.  experience in performance of pharmacokinetic/pharmacodynamic
laboratory/correlative studies relevant to the development of a class
of anticancer therapeutic agents and evaluation of the data with
respect to treatment administration or treatment outcome
 
4.  availability of resources necessary to perform the research
including:
 
a.  adequacy of the available facilities for clinical and
pharmacokinetic/pharmacodynamic laboratory/correlative studies, data
management resources, and patient population.
 
b.  demonstration of availability of and access to appropriate
numbers of patients eligible to receive defined treatments on phase I
clinical trials and/or to human tissue with the associated
pathological data and clinical follow-up.
 
5.  adequacy of provisions for the protection of human subjects and
the humane treatment of animals (if laboratory studies involving
animals are proposed).
 
6.  Adequacy of the plans for inclusion of women and minorities.
 
7.  Commitment to accept provisions outlined under Terms of
Cooperation.
 
The reviewers will also judge the appropriateness of the proposed
budget and duration in relation to the proposed research.
 
AWARD CRITERIA
 
The anticipated date of award is February 1, 1998.  In addition to
the technical merit of the application, NCI will consider how well
the applicant institution meets the goals and objectives of the
program as described in the RFA, availability of resources, and
balance of study populations.
 
INQUIRIES
 
Written and telephone inquiries concerning the objectives and scope
of this RFA and inquiries about whether or not specific proposed
research would be responsive are strongly encouraged and may be
directed to the program staff listed below.  The program staff
welcome the opportunity to clarify any issues or questions from
potential applicants.
 
Direct inquiries regarding programmatic issues to:
 
Dr. Michaele C. Christian
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute
Executive Plaza North, Room 734
6130 Executive Boulevard, MSC 7432
BETHESDA, MD  20892-7432
Telephone:  (301) 496-5223
FAX:  (301) 480-4663
Email:  christim@DCT.NCI.NIH.GOV
 
Direct inquiries regarding fiscal matters to:
 
Crystal Wolfrey
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Boulevard MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 256
FAX:  (301) 496-8601
Email:  WOLFREYC@GAB.NCI.NIH.GOV
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No 93.395, Cancer Treatment Research.  Awards are made
under the authorization of the Public Health Service Act, Title IV
Sections 301, 410, and 411, Part A (Public Law 78-410, 42 USC 241 as
amended, Public Law 99-158, 42 USC 285a) and administered under PHS
grants policies and Federal Regulations at 42 CFR Part 52 and 45 CFR
Part 74 and 92.  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 and contract 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 routing 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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