From: kristoff@NET.BIO.NET (Dave Kristofferson)
Newsgroups: bionet.sci-resources
Subject: NIH Guide, vol. 21, no. 45, pt. 3, 18 December 1992
Date: 17 Dec 92 02:45:42 GMT
Distribution: bionet


$$XID RFA CA9307 CA-93-07 P1O1 *****************************************

PHASE I TRIALS OF NEW ANTI-CANCER AGENTS

NIH GUIDE, Volume 21, Number 45, December 18, 1992

RFA:  CA-93-07

P.T. 34; K.W. 0755015, 0715035, 0740020, 0710100

National Cancer Institute

Letter of Intent Receipt Date:  January 22, 1993
Application Receipt Date:  March 23, 1993

PURPOSE

The Division of Cancer Treatment (DCT), National Cancer Institute
(NCI) invites cooperative agreement (U01) applications from single
institutions wishing to perform Phase I trials of promising
anti-cancer agents in patients with cancer refractory to currently
available therapy and to conduct 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.  Patients should be treated only at
the applicant institution, although support for laboratory studies
may be conducted by collaborators at other institutions.

The increasing numbers of promising new agents with novel mechanisms
of action and the large number of institutions both capable of and
interested in conducting Phase I clinical trials of cancer therapies
makes it desirable to expand NCI grant support in this area.  The
need for increased resources for clinical development of a wide range
of novel anti-cancer agents has led to this request for cooperative
agreement applications to establish the pharmacological and initial
clinical characteristics of these agents.  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 the application from any one institution will focus on
studies of one or more classes of agents, reflecting the interest,
expertise, and experience of the applicant investigators.

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 New 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 "Healthy
People 2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202/783-3238).

ELIGIBILITY REQUIREMENTS

Domestic for-profit and non-profit organizations such as
universities, colleges and hospitals and governments and their
agencies are eligible to apply.  Applications from minority
individuals and women are encouraged.

MECHANISM OF SUPPORT

Support of this program will be through the cooperative agreement
(U01), an assistance mechanism in which substantial NCI programmatic
involvement with the recipient during performance of the planned
activity is anticipated.  The nature of NCI staff involvement is
described in the section SPECIAL REQUIREMENTS, Terms of Cooperation,
Nature of Participation by NCI Staff.  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 of Cooperation.

Except as otherwise stated in this RFA, awards will be administered
under PHS grants policy as stated in the Public Health Service Grants
Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised
October 1, 1990.

This RFA is a one-time solicitation.  However, if it is determined
that there is a sufficient continuing program need, the NCI will
invite recipients of awards under this RFA to submit competitive
continuation cooperative agreement applications for review according
to the procedures described in Review Considerations, Part A.

FUNDS AVAILABLE

Approximately $2,000,000 in total costs per year for four 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 six to eight awards will be made.  The total project
period for applications submitted in response to the present RFA may
not exceed four years.  The earliest feasible start date for the
initial awards will be December 1, 1994.  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.

RESEARCH OBJECTIVES

A.  Background

The purpose of this RFA is to provide support for single institution
Phase I clinical trials with investigational 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 not only the mediation of anti-cancer effects through
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
anti-tumor angiogenesis.  In addition, new strategies to overcome
resistance to conventional cancer therapeutic approaches are also of
interest.

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 may
sponsor (in the Food and Drug Administration sense) 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, DCT 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.  NCI sponsorship of
investigational agents increases the likelihood that agents will be
further developed so that they will ultimately be broadly available
for use in cancer treatment and will accelerate the time frame in
which this process would occur.

B.  Research Goals and Scope

The aims of this initiative are:  (1) to provide support for Phase I
trials of promising new anti-cancer agents in cancer patients; and
(2) to provide support for complete pharmacokinetic, pharmacodynamic,
and other important laboratory correlative studies in cancer patients
receiving these anti-cancer agents.  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).

Specific objectives and scientific approaches will be
investigator-originated and should reflect the creativity and
capability of the investigators.  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.  The Principal Investigator will select the specific
agents to be tested in accord with their area of scientific interest
and expertise and will develop a series of appropriate Phase I trials
with supporting protocol documents.  The NCI may provide
NCI-sponsored IND agents or provide assistance to the awardee
institution by sponsoring or co-sponsoring other selected agents.

Each Phase I awardee institution will be expected to complete on
average two to three Phase I trials per year, with each trial
encompassing 20-40 patients.  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.  Sufficient
numbers of patients at the applicant institution should be available
in order to allow completion of the trials in a timely manner.

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
performance 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 biweekly Phase I investigator data submissions, 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

A.  MINIMAL REQUIREMENTS FOR APPLICATIONS

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 ADRs 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 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
applicant should also request funding for the initial Phase I
strategy meeting.

B.  Terms of Cooperation

The following Terms of Cooperation are in addition to and not in lieu
of otherwise applicable OMB administrative guidelines, HHS grant
administration regulations at 45 CFR Part 74 and 92, and other HHS,
PHS and NIH grant administration policy statements.  The NCI
arbitration process for the cooperative agreement in no way affects
the rights of awardees to appeal selected post award administrative
decisions in accordance with PHS regulations at 42 CFR part 50,
subpart D and HHS regulations at 45 CFR part 16.

Nature of Participation by NCI Staff

The role of the Cancer Therapy Evaluation Program (CTEP) staff as
described throughout these terms of cooperation is to assist and
facilitate 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 DCT as a drug
sponsor as defined in CFR 21 Part 312.

1.  CTEP as a Scientific Resource for NCI-supported Phase I Clinical
Trials Investigations

The NCI Program Director (see INQUIRIES) 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 will assist the PI as appropriate
in developing information concerning the scientific basis for
specific trials and also will be responsible for advising the PI of
the nature and results of relevant trials being carried out
nationally or internationally.  The NCI Program Director 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 DCT.

The NCI Program Director will sponsor an initial Phase I strategy
meeting with the PIs to review the research plans proposed by each
individual research group to ensure that they are compatible with the
overall goals of the RFA, to ensure avoidance of duplication of
effort with other ongoing clinical trials and to ensure the most
effective use of available resources including investigational
agents.  An arbitration system, as detailed below, will be available
to resolve disagreements between the NCI and the awardee institution.

The NCI Program Director will sponsor semi-annual Phase I meetings 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.

2.  CTEP Assistance in Protocol Development

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 DCT investigational agents.  The PRC is chaired by
the Associate Director, CTEP, and is comprised of professional staff
of the DCT including drug monitors, disease coordinators, regulatory
staff, pharmacy staff and ad hoc reviewers external to NCI when
deemed appropriate by the PRC chairperson.

Communication at the various stages of protocol development is
encouraged as necessary to promote protocol development and
implementation.  All protocols should be preceded by a written
declaration of interest in conducting a particular study from the PI
using the format described in the Guidelines for Submitting LOIs -
Letter of Intent/Investigational Drug Trial (available upon request
from Dr. David Parkinson at the address listed under INQUIRIES).  The
LOI should be sent to the CTEP LOI Coordinator who receives, logs in
and schedules LOIs for review by the PRC (see Responsibilities of
Awardees).  The PRC will formally review the LOI.  Following LOI
review, the NCI Program Director 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,
including biologic response modifiers; d) the scientific rationale
and value of the proposed study, the design, the statistical
requirements; and e) the implementation of the study, if indicated.
The LOI mechanism is designed for preliminary review and is
recommended to expedite protocol development and implementation and
to facilitate agreement on study priority and design (see the DCT
Investigator's Handbook, pp 32-35, available on request from Dr.
David Parkinson at the address below, for further discussion of these
mechanisms).

3.  CTEP Review of Proposed Protocols

The awardee protocols will be reviewed by the PRC which meets weekly.
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.

An Investigational Drug Branch (IDB) Physician (Drug Monitor) is
assigned to each DCT IND agent to assist in the coordination of its
development.  Following the review of the protocol by the PRC, the
NCI Program Director will provide the PI with a consensus review
prepared by the IDB Drug Monitor.  The consensus review describes
required or recommended modifications and other suggestions, as
appropriate.  The NCI Program Director will not serve as the
consensus reviewer.  (See the DCT 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 by the NCI Program Director to the
PI as a consensus review within 30 days of protocol receipt by the
NCI.  The NCI Program Director 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.

Disagreements arising pursuant to protocol approval will be submitted
to an arbitration panel to determine the suitability of a protocol
that has been disapproved.  An arbitration panel composed of one
awardee institution 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, 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 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
above.

4.  Access to Data

The NCI will have access to all data generated under this cooperative
agreement and will periodically review the data.  Data must 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.  Source documentation will be reviewed
on-site three times per year by the NCI's Clinical Trials Monitoring
Service (CTMS).  The awardee institution will retain custody and
primary rights to the data consistent with current HHS, PHS, and NIH
policies.

5.  CTEP Involvement in Protocol Closure

The NCI Program Director will monitor protocol progress.  When a
study involves a DCT IND agent, the Head, Quality Assurance and
Compliance Section, (QACS), Regulatory Affairs Branch (RAB), CTEP and
the IDB Drug Monitor and well as the NCI Program Director will
monitor protocol progress.  The NCI Program Director or the IDB Drug
Monitor may request that a protocol be closed to accrual for reasons
including:  (1) insufficient accrual rate; (2) accrual goal met; (3)
poor protocol performance; (4) patient safety and regulatory
concerns; (5) study results are already conclusive; (6) emergence of
new information that diminishes the scientific importance of the
study question; and (7) 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 identical to that
described above for protocol disapproval.

6.  CTEP involvement in Investigational New Drug Applications

a.  The NCI will have the option to cross file or independently file
an IND on investigational agents evaluated in the Phase I Clinical
Trials.  This would apply to agents not primarily developed in the
NCI drug development program.

b.  The NCI Program Director assisted by the Chief, 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.

c.  Investigators performing NCI funded Phase I Clinical Trials will
be advised by the NCI Program Director of potential studies that will
be relevant to new avenues of cancer therapy.  When this involves
investigational agents, the NCI Program Director assisted by 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).

7.  CTEP Review of Federally Mandated Regulatory Requirements

The Head, QACS, through the NCI Program Director, will advise the PI
regarding mechanisms to meet FDA regulatory requirements for studies
involving DCT-sponsored investigational agents and the Office for
Protection from Research Risks (OPRR) requirements for the protection
of human subjects by the awardee institution.  See Responsibilities
of Awardees.

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 biweekly Phase I investigator data submissions, and to produce
periodic routine reports of the results and special reports as
necessary.  Source documentation will be reviewed on-site three times
per year by the CTMS.

8.  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, and in reports
provided to the NCI Program Director by the CTMS.  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 Terms of Cooperation, may result in a
reduction of budget, withholding of support, suspension or
termination of the award.

Responsibilities of Awardees

It is the responsibility of the 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.  The PI shall, with CTEP
assistance, develop Phase I protocols for clinical cancer research in
accord with its research interests, abilities and goals and in accord
with research goals established at the Phase I strategy meetings and
submit them to CTEP (either to the 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.

1.  Protocol Development

The PI will designate a Protocol Chairperson for each proposed study.
The PI will be responsible for communication with the appropriate
CTEP staff.  The PI, with CTEP assistance, is responsible for
coordinating protocol development, protocol submission, study
conduct, quality control, 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.

2.  Protocol Submission

The PI will submit protocols to the CTEP Protocol and Information
Office in a timely fashion for review and approval by NCI.  All
protocols should be preceded by a written Letter of Intent (LOI) from
the PI to the CTEP LOI Coordinator declaring interest in conducting a
particular study.  The LOI will describe the hypothesis to be
investigated, the general design of the contemplated trial plus
relevant information on accrual capabilities to document feasibility.

3.  Study Conduct and Monitoring

The awardee institution is responsible for ensuring accurate and
timely knowledge of the progress of each study through:

a.  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/DCT Standard Case Report Form and the individual protocol.

b.  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.

c.  registration, tracking and reporting of patient accrual and
adherence to defined accrual goals;

d.  ongoing assessment of case eligibility and evaluability;

e.  timely medical review and assessment of patient data;

f.  rapid reporting of treatment-related morbidity (adverse drug
reactions) and measures to ensure communication of this information
to all parties;

g.  interim evaluation and consideration of measures of outcome, as
consistent with patient safety and good clinical trials practice; and

h.  timely communication of results of studies.

4.  Data Management and Analysis

The awardee institution will develop procedures to ensure that data
collection and management are:  (1) adequate for quality control and
analysis and (2) as simple as appropriate in order to encourage
maximum participation of physicians entering patients and to avoid
unnecessary expense.

5.  Investigational Drug Management

Investigators performing trials under this cooperative agreement must
be NCI registered investigators (Form 1572) and will be expected to
implement CTEP requirements described in the DCT Investigators'
Handbook for storage and accounting for investigational agents, to
abide by NCI/DHHS Drug Accountability Records (DAR) procedures, and
to comply with all FDA requirements for investigational agents.

6.  Compliance with Federally Mandated Regulatory Requirements

The awardee institution 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:

a.  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.

b.  a system for ensuring timely reporting of all serious and
unexpected toxicities to the IDB, CTEP according to CTEP guidelines
(mailed annually to all registered investigators). This may require
reporting Adverse Drug Reactions (ADRs) by telephone to the IDB Drug
Monitor within 24 hours of the event and requires a written report to
follow within 10 working days.

c.  a system for ensuring that the required data is provided biweekly
to the CTMS.

7.  Attendance at Meetings

The PI or appropriate representative(s) of the awardee institution,
will attend the initial Phase I strategy meeting At the initial
strategy meeting, the investigators and the NCI Program Director,
assisted by other CTEP staff, will review the research plans proposed
by each individual research group to ensure that they are compatible
with the overall goals of the RFA, to ensure avoidance of duplication
of effort and to ensure the most effective use of available resources
including investigational agents.  The PI or appropriate
representative shall attend the semi-annual Phase I meetings 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.

8.  Reporting Requirements

Reporting requirements will be in agreement with FDA regulations and
NCI procedures.  Annual progress reports will be submitted to the NCI
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.

9.  Publication of Data

Timely publication of major findings is encouraged.  Publication or
oral presentation of work done under this agreement will require
appropriate acknowledgement of NCI support.  The NCI will have access
to all data generated under this cooperative agreement and may
periodically review the data.  The awardee will retain custody and
primary rights to the data consistent with current HHS, PHS, and NIH
policies.

STUDY POPULATIONS

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

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

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

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

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

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

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

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

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

LETTER OF INTENT

Prospective applicants are asked to submit, by January 22, 1993, 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:

David R. Parkinson, M.D.
Chief, Investigational Drug Branch
Cancer Therapy Evaluation Program
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-5223
FAX:  (301) 480-4663

Applicants who use express mail or a courier service are advised to
follow the carrier's requirements for showing a street address.  The
address for the Executive Plaza North is:

6130 Executive Boulevard
Rockville, MD  20852

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for cooperative agreements.  These forms are available at
most institutional offices of sponsored research; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, 5333 Westbard Avenue, Bethesda,
MD 20892, telephone (301) 496-7441; and from the NCI Program Director
named below.

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

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.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package to
the address below.  The photocopies must be clear and single sided.

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

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

Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
Bethesda, MD  20892

Applications must be received by March 23, 1993.  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 announcement that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application.  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 for completeness by the
DRG and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.
Applications that are judged to be non-responsive will be returned by
the NCI.  Applications judged to be non-responsive to this RFA may be
submitted as an investigator-initiated regular research grant (R01)
or program project grant (P01) at the next receipt date.  The
application would require modification in accordance with R01 or P01
guidelines.  The revised application would not be considered an
application for a cooperative agreement nor would it be considered a
response to an RFA.  Questions concerning the responsiveness of
proposed research to the RFA may be directed to program staff listed
under INQUIRIES.

Applications may be triaged by an NCI peer review group on the basis
of relative competitiveness.  The NIH will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are
complete and responsive will be evaluated in accordance with the
criteria stated below for scientific/technical review by an
appropriate peer review group convened by the Division of Extramural
Activities, NCI.  The second level of review will be provided by the
National Cancer Advisory Board.

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 for correlative laboratory studies and
evaluation of the data with respect to treatment administration or
treatment outcome

c.  adequacy of statistical approach for correlating research studies
with treatment outcomes in Phase I trials.

d.  adequacy of plans for effective collaboration among laboratory,
clinical, and statistical investigators.

e.  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 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
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 December 1, 1994.  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. David Parkinson
Chief, Investigational Drug Branch
Cancer Therapy Evaluation Program
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-5223
FAX:  (301) 480-4663

Direct inquiries regarding fiscal matters to:

Barbara A. Fisher
National Cancer Institute
Executive Plaza South, Room 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 29
FAX:  (301) 496-8601

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No 93.395, Cancer Treatment Research.  Awards are made
under the authorization of the Public Health Service Act, Title IV
Sections 301, 410, and 411, Part A (Public Law 78-410, 42 USC 241 as
amended, Public Law 99-158, 42 USC 285a) and administered under PHS
grants policies and Federal Regulations at 42 CFR Part 52 and 45 CFR
Part 74 and 92.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency
review.