Full Text CA-93-032

DEVELOPMENT AND EVALUATION OF MINIMAL ACCESS SURGERY IN CANCER
TREATMENT

NIH GUIDE, Volume 22, Number 33, September 17, 1993

RFA:  CA-93-032

P.T. 34

Keywords: 
  Surgery 
  Cancer/Carcinogenesis 
  Clinical Trial 


National Cancer Institute

Letter of Intent Receipt Date:  October 20, 1993
Application Receipt Date:  December 22, 1993

PURPOSE

The Cancer Therapy Evaluation Program (CTEP), Division of Cancer
Treatment (DCT), National Cancer Institute (NCI) invites applications
for cooperative agreements from institutions or consortia, including
the DCT Clinical Trials Cooperative Groups, capable of and interested
in performing phase II and phase III evaluations of minimal access
surgery.  Minimal access surgery, which is synonymous with minimally
invasive surgery, has become increasingly prominent in the diagnosis
and treatment of benign conditions.  Case reports and small series
have been published documenting the use of minimal access surgery in
the care of patients with cancer.  The NCI is interested in a timely
evaluation of minimal access techniques that have the potential for
significantly decreasing the morbidity, cost, and inconvenience of
cancer treatment.  Determination of the effectiveness of minimal
access surgery in the treatment of cancer is critical, before minimal
access techniques become the standard of care for cancer therapy in
the community.

Phase III studies should be designed to evaluate minimal access
surgery versus standard surgery.  Phase II studies should evaluate
the practicality and safety of minimal access surgery for specific
tumor sites.  It is essential for institutions or consortia to have
surgeons with experience in minimal access surgery and evidence of
patient accrual to complete a phase II or III study or studies in a
timely manner.  Solid tumors that are relevant to this Request for
Applications (RFA) include cancers of the brain, lung, stomach,
pancreas, colon, ovary, endometrium, and cervix.

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,
Development and Evaluation of Minimal Access Surgery In Cancer
Treatment, 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

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Applications from
minority individuals and women, as well as new and experienced
investigators, are encouraged.  An applicant institution may consist
of a single institution or a consortium of institutions functioning
as an integrated unit under the guidance and direction of a single
Principal Investigator for the purpose of accessing a sufficient
patient population.  Foreign institutions are ineligible to apply or
be a collaborating institution within an application from a domestic
organization.  All accrued patients must be treated in the United
States.  It is essential for institutions/consortia to have surgeons
with experience in minimal access surgery and evidence of patient
accrual to complete a phase II or III study or studies in a timely
manner.

MECHANISM OF SUPPORT

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

Awards and level of support depend on receipt of a sufficient number
of applications of high scientific merit.  Because the nature and
scope of the research proposed (phase II versus phase III studies) in
response to this RFA may vary, it is anticipated that the size of
awards will vary also.  The total project period for applications
submitted in response to the present RFA may not exceed three years.
The anticipated award date is July 1, 1994.  Although this program is
provided for in the financial plans of the NCI, awards pursuant to
this RFA are 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 the NCI does not continue the program, awardees
may submit grant applications through the usual
investigator-initiated grants program.

FUNDS AVAILABLE

Approximately $750,000 in total costs per year for three years will
be committed to fund applications submitted in response to this RFA.
It is anticipated that the funds will be able to support two phase
III awards, four phase II awards, or some combination thereof.

RESEARCH OBJECTIVE

Background

Minimal access surgery has been proposed to decrease the trauma of
surgical access without limiting exposure of the operative field.
Approaches used include laparoscopic, thoracoscopic, endoluminal, and
perivisceral.  Advantages to minimal access surgery include
accelerated recovery and convalescence, with a corresponding decrease
in length of hospital stay and hospital expenses, as well as a
quicker return to normal activity.  Wound complications, including
infections, are also decreased.  Potential benefits include a
decreased incidence of post-operative pneumonia, deep vein
thrombosis, and adhesion formation.

In oncology, minimal access surgery may be useful to obtain adequate
tissue for accurate diagnosis of malignancy, to ascertain the degree
of spread, to stage the disease, and to assess operability.
Definitive cancer surgery may be performed using minimal access
techniques.  Recent reports have documented the use of minimal access
surgery in cancers of the brain, lung, stomach, liver, pancreas,
gallbladder, kidney, colon, ovary, endometrium, and cervix.

For certain benign conditions, minimal access surgery has become the
standard of care.  Laparoscopic cholecystectomy was first reported in
1989.  In 1992, it is estimated that more than 20 percent of all
cholecystectomies were performed using minimal access techniques.
Both patient preference and physician enthusiasm have engendered this
change, although there has not been a phase III evaluation of the two
techniques to ascertain differences in morbidity, mortality,
convalescence, and cost.  In gynecology, interval tubal ligations,
resections of ectopic (tubal) pregnancies, fulguration of
endometriosis, and ovarian cystectomies are done routinely via
laparoscope.  There is concern among the surgical community that
minimal access techniques may become the standard of care for
patients with cancer without direct evaluation against traditional,
open surgical techniques.

Objectives and Scope

Solid tumors potentially relevant to this RFA account for significant
cancer incidence, morbidity, mortality, and expense.  This RFA is
intended to promote phase II and III evaluation of minimal access
surgery in the management of patients with solid tumors.  This RFA is
not intended to duplicate or supplement support for any phase II or
phase III trials supported by any other mechanism.  Phase III studies
will evaluate minimal access surgery versus standard surgical
technique, including cancers of the brain, lung, stomach, pancreas,
colon, ovary, endometrium, and cervix.  Developmental phase II
studies will be aimed at broadening the applicability of minimal
access surgery for specific tumor sites by evaluating the
practicality and safety of this approach.

Each application is expected to focus on a specific type of solid
tumor.  An applicant institution may submit more than one
application.  In addition, an individual scientist, individual
institution, or consortium of institutions may be included on more
than one application (or tumor site).

All institutions accruing patients must be able to document adequate
surgical experience with minimal access surgery as well as adequate
patient accrual to complete a phase II or III trial in a timely
manner.  For phase III trials, outcomes of interest include morbidity
(acute and chronic), mortality, efficacy of treatment, length of
hospital stay, time to return to normal activities, quality of life,
and cost.  Applications should include an analysis of what outcomes
are expected to vary importantly between minimal access surgery and
conventional surgery.  It is recommended that costs be measured in
terms of health-related resource utilization, such as hospital days,
operating room time, office visits, and days until resumption of
normal activities.  Applications should include documentation of a
cost-related data source that is comprehensive and available to the
researcher.  Applications must include a statistical section
describing plans for analysis of data designed to test the
hypotheses, as well as a power/sample size analysis for cost and
clinical endpoints.  It is possible that collection of data on cost
from a subset of patients may be adequate.

For phase III trials, or phase II trials focusing on rare tumors,
investigators are encouraged to work with multi-center organizations
or form a consortium of institutions in order to access sufficient
number of patients to test the proposed hypotheses.

DEFINITIONS

AWARDEE - The organization to which a cooperative agreement is
awarded and that is responsible and accountable to the NCI for the
use of funds provided and for performance of the cooperative
agreement-supported project.

PRINCIPAL INVESTIGATOR (PI) - The single individual designated by the
awardee in the cooperative agreement who is responsible for the
scientific and technical direction of the project.

STATISTICAL CENTER - Applicant institutions proposing phase III
trials must have a Statistical Center for collection and analysis of
patient data.  Responsibilities will include participating in the
planning and coordination of study design methodologies, data
management, analysis, data monitoring, and reporting of data. The
Statistical Center need not be at the PI's institution.

NCI PROGRAM DIRECTOR - The CTEP Surgical Oncology Grants Program
Director, who will be coordinating DCT's interactions and providing
overall guidance within the NCI (see INQUIRIES below).  He/she is
available for consultation during preparation of applications as well
as the duration of research conducted through this cooperative
agreement.  He/she serves in a back-up role for the NCI Coordinator.

NCI COORDINATOR - The Head, Surgery Section, Clinical Investigations
Branch, CTEP, DCT, who interacts scientifically with the institutions
(see INQUIRIES below).

STEERING COMMITTEE - A committee composed of the PI, an investigator
from each institution collaborating with the Awardee Institution, and
the NCI Coordinator that will serve as the governing board of each
study (see Terms and Conditions of Award below).

COORDINATING COMMITTEE -  This committee will be established to
coordinate the activities among several Awardee Institutions
performing studies in a single tumor site.  This committee composed
of the members of the Steering Committee from each Awardee
Institution will serve as the governing board of the studies for that
tumor site (see Terms and Conditions of Award below).

SPECIAL REQUIREMENTS

Because the Terms and Conditions of Award discussed below 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.

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

Terms and Conditions of the Award

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

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

The cooperative agreements will require cooperation between the CTEP
staff (through the NCI Coordinator) and the Principal Investigator of
each of the Awardee Institutions.  The NCI Coordinator will assist in
coordinating the activities of the Awardee Institutions as defined
below and in facilitating exchange of information.

1.  Awardee Rights and Responsibilities

The Awardee is responsible for the proposed research project to
advance the goals of the RFA.  Awardee has primary authority and
responsibility to define objectives and approaches and to plan,
conduct, analyze, and publish results, interpretations, and
conclusions of their studies.  Awardee is responsible for accessing
sufficient numbers of cancer patients to meet accrual goals and for
providing expertise in minimal access surgery and experience in
clinical trials.

a.  Protocol Development

The PI, with NCI Coordinator's assistance, is responsible for
coordinating protocol development, protocol submission, study
conduct, quality control and study monitoring, data management and
analysis, protocol amendments/status changes, adherence to federally
mandated regulations, and protocol and performance reporting.  The PI
will be responsible for communicating with the appropriate CTEP staff
through the NCI Coordinator.

b.  Protocol submission

Prior to activation of the protocol(s), the PI will submit them to
the NCI Coordinator to solicit for comments and suggestions.  The PI
will communicate the NCI Coordinator's comments and suggestions to
the collaborating institutions.

c.  Quality Control

The Awardee will establish mechanisms for quality control of
therapeutic and diagnostic modalities employed in its trials. Quality
control at a minimum must consist of:

1.  Pathology:  Verification of pathologic diagnosis in cases where
known variability in the accuracy of histologic diagnosis is a
potentially serious problem and where pathology data may provide
important prognostic information.

2.  Radiation Therapy:  Review (either concurrent or retrospective)
of port films and compliance with protocol-specified doses for
individuals patients, where relevant.  Determination of adequacy of
radiation delivery with the assistance of the Radiological Physics
Center (RPC), whose functions usually include equipment dosimetry,
periodic institutional visits, and other aspects of physics review.

3.  Chemotherapy:  Review of flow sheets with determination of
protocol compliance in dose administration and dosage modification.

4.  Surgery:  assessment of adequacy of protocol-specified surgical
procedures through review of operative notes, study-specific surgical
forms, and, where appropriate, video tapes.

d.  Study Conduct and Monitoring

The Awardee will establish mechanisms for study monitoring including
an independent Data and Safety Board (see Collaborative
Responsibilities below).  The Awardee is responsible for ensuring
accurate and timely knowledge of the process of each study through:

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

2.  ongoing assessment of case eligibility and availability;

3.  timely medical review and assessment of patient data;

4.  rapid reporting of treatment-related morbidity and measures to
ensure communication of this information to all parties;

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

6.  timely communication of results of studies.

e.  Data Management and Analysis

The Awardee will develop procedures to ensure that data collection
and management are (a) appropriate for quality control and analysis;
(b) as simple as appropriate in order to encourage maximum
participation of physicians entering patients and to avoid
unnecessary expense; and (c) sufficiently uniform across the
consortia institutions.

For phase III trials, the Awardee must have a Statistical Center for
collection and analysis of patient data.  Responsibilities of the
Statistical Center will include participation in the planning and
coordination of study design methodologies, data management, and
analysis, data monitoring, and reporting of data.  A Statistical
Center is not required for phase II trials but some formal structure
is required for data management and analysis.

f.  Compliance with Federally Mandated Regulatory Requirements.

The Awardee is responsible for establishing procedures for all
participating institutions to comply with Office for Protection from
Research Risks (OPRR) requirements for the protection of human
subjects.  These procedures are methods for assuring that the Awardee
Institution and each institution participating in the research
conducted under this cooperative agreement has a current, approved
assurance 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; and that each patient (or legal representative) gives written
informed consent prior to entry on study.

g.  Progress review

For multi-institution trials, the PI will establish a mechanism for
assessing performance of its consortia participants, with particular
attention to accrual of adequate numbers of eligible patients onto
consortium trials, timely submission of required data and
conscientious observance of protocol requirements.  This mechanism
will include a procedure to recommend an adjustment of institutional
funds within the consortium as appropriate for the level of
participation in consortium activities, including but not limited to
accrual.

If the progress review indicates poor performance by a participating
institution, the Awardee may replace the institution. Any changes in
the participation must be noted in the application for continuation
support (PHS 2590, rev. 9/91).  If in the course of the budget period
the Awardee chooses to change consortium institutions, the new
consortium institutions must have an approved Assurance of Compliance
for the Protection of Human Subjects on file with OPRR.  The Awardee
will be responsible for assuring that no patients are accrued to a
protocol at a participating institution until the protocol has been
reviewed and approved by the IRB.  If a change in consortium
institutions involves a change in key personnel or a change of scope
or research objectives, the Awardee must request the prior approval
of the NCI.  The procedure for requesting prior approval is described
in the "Methods for Grantees to Request Approvals", PHS Grants Policy
Statement, p.8-6 (rev. 9/1/91).

h.  Attendance at meetings

The PIs of the awardee institutions and the NCI Coordinator will meet
initially to discuss research plans and establish priorities.
Subsequent periodic meetings will be scheduled to review progress and
coordinate research activities.  Each Awardee should anticipate the
need to participate in one meeting per year to coordinate activities.

i.  Publication of Data

Timely publication of major findings by the awardees 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 data generated under this cooperative agreement and
may periodically review the data.  However, the awardee institutions
will retain custody and primary rights to the data developed under
these awards consistent with current HHS, PHS, and NIH policies.

2.  NCI Staff Responsibilities

a.  NCI Program Director, CTEP

The role of the NCI Program Director, CTEP, as described throughout
these terms of cooperation, is to assist and facilitate but not to
direct research activities.  He/she will serve in an administrative
capacity, will be involved in coordinating DCT's interactions, will
provide overall guidance within the NCI and will monitor progress.
He/she will serve in a back-up role for the NCI Coordinator.

b.  NCI Coordinator, CTEP

The NCI Coordinator will interact scientifically with the Awardees.
During the period of the award, the Awardees will have the primary
authority to determine research priorities and statistical needs.
The NCI Coordinator may provide appropriate assistance by
participating in the design of research activities, review of
protocols, establishment of priorities, and review of progress.  The
NCI Coordinator may seek advice from other appropriate CTEP staff
regarding the proposed protocol(s), including safety, quality
control, statistical design and tumor specific issues.  Although the
Awardee(s) are responsible for statistical analysis of data, NCI
staff may provide computer processing and statistical evaluations if
requested by the Awardee.  In addition, the NCI Coordinator also may
relay guidance on studies of cost analysis from the Applied Research
Branch, SP, DCPC, NCI, and the Agency for Health Care Policy and
Research, DHHS.

The NCI Coordinator will monitor protocol progress.  The NCI
Coordinator 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 permit the expenditure of 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, the arbitration
process described in "Arbitration" below will be established.

Progress will be reviewed at least annually by the NCI Coordinator as
well as the NCI Program Director on the basis of information provided
at the annual meetings with the PIs and the progress report(s)
submitted in the non-competing application(s).  In addition, periodic
accrual information may be requested from the PI by the NCI
Coordinator or the NCI Program Director for all active studies when
deemed appropriate.

The NCI reserves the right to reduce the budget, withhold support,
and to suspend, terminate or curtail a study or an award in the event
of insufficient patient accrual or progress, or noncompliance with
the terms of award, including these Terms and Conditions of Award.

3.  Collaborative Responsibilities

a.  Steering Committee

It is anticipated that decisions in all research activities conducted
under this cooperative agreement will be reached by consensus of the
collaborators participating in the project under the leadership of
the PI and that the NCI Coordinator will have the opportunity to
offer input to this process.

For multi-institutional trials, a Steering Committee composed of the
PI, one investigator from each collaborating institution, and the NCI
Coordinator will be the main governing board of the study and will
have primary responsibility for research design and protocol
development, participant recruitment and follow-up, data collection,
quality control, interim data and safety monitoring, final data
analysis, and preparation of publications.  All members of the
Steering Committee will have one vote.

For phase III trials, the Steering Committee will also include a
representative of the Statistical Center, who will have one vote.
The chair of the Steering Committee, who will be someone other than
the NCI Coordinator, will be selected by the its members.
Subcommittees will be established by the Steering Committee, as it
deems appropriate; the NCI Coordinator will serve on subcommittees as
he/she deems appropriate.

For phase III trials, the Steering Committee will appoint an
independent Data and Safety Monitoring Board (DSMB).  The DSMB will
review the studies at least annually and report to the NCI
Coordinator.  The composition and operating procedures and policies
of this Board will be determined by the Steering Committee after the
issuance of the award.  The members of this Board will be selected
based on the members' technical and clinical experience, absence of
conflict of interest and knowledge of good clinical trial
methodology.  The size of the DSMB should be limited and should not
exceed seven voting non-government individuals.  The NCI Coordinator,
the NCI Program Director and the PI will participate as non-voting
members and will not chair the DSMB.  The Awardee agrees to abide by
the decisions of the DSMB.

b.  Coordinating Committee

If there is more than one Awardee for a tumor site, the Coordinating
Committee will serve as the governing board for all studies for that
tumor site.  In this situation, the NCI Coordinator will work with
the Coordinating Committee to develop a common collaborative protocol
for the Awardees, if necessary.  Awardees will be required to accept
and implement the common collaborative protocol and procedures
approved by the Coordinating Committee.  The Coordinating Committee
is composed of the members of the Steering Committee from each
Awardee.  All members of the Coordinating Committee will have one
vote.

For collaborative phase III trials, the Coordinating Committee will
also include one representative from each Statistical Center, who
will have one vote per representative.  The chair of the Coordinating
Committee, who will be someone other than the NCI Coordinator, will
be selected by the its members.  Subcommittees will be established by
the Coordinating Committee, as it deems appropriate; the NCI
Coordinator will serve on subcommittees as he/she deems appropriate.

For collaborative phase III trials, the Coordinating Committee will
appoint an independent Data and Safety Monitoring Board (DSMB).  The
DSMB will review the studies at least annually and report to the NCI
Coordinator.  The composition and operating procedures and policies
of this Board will be determined by the Coordinating Committee after
the issuance of the award.  The members of this Board will be
selected based on the members' technical and clinical experience,
absence of conflict of interest and knowledge of good clinical trial
methodology.  The size of the DSMB should be limited and should not
exceed seven voting non-government individuals.  The NCI Coordinator,
the NCI Program Director and the PI will participate as non-voting
members and will not chair the DSMB.  The Awardees agree to abide by
the decisions of the DSMB.

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters
between award recipients and the NCI may be brought to arbitration.
An arbitration panel will be composed of three members -- one
selected by the Steering Committee or Coordinating Committee (with
the NCI member non-voting) or by the individual Awardee in the event
of an individual disagreement, a second member selected by the NCI,
and the third member selected by the two prior selected members.
This special arbitration procedure in no way affects the awardee's
right to appeal an adverse action that is otherwise appealable in
accordance with the PHS regulations at 42 CFR part 50, subpart D and
HHS regulation at 45 CFR part 16.

STUDY POPULATIONS

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

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

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study. This information must be included in the form PHS 398 in
Sections 1-4 of the Research Plan, AND summarized in Section 5, Human
Subjects.  Applicants are urged to assess carefully the feasibility
of including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to included 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 must be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
disease, disorders, or conditions, including but nor 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 make to include human tissues from females and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

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

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
females and minorities in a study design is inadequate to answer the
scientific questions(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 applications.

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.

Note:  In addition to the requested information about the composition
of proposed study populations involving human subjects, peer review
groups need similar information about the clinical or regional
populations from which the samples are drawn in order to evaluate the
extent of participation by women and minorities.  To avoid delays in
review of such applications, the NCI advises that, as a minimum, the
application should provide gender/minority information on hospital
admissions, accruals to trials, and patient catchment areas.  Studies
involving non-hospital populations, such as community-based studies
should provide similar data abut populations in the area or region
from which the study subjects will be drawn.  In the absence of
current data, historical demographic information and/or previous
recruitment data for similar studies from the proposed study sites
should be provided.  Further, any specific plans for increasing
gender/minority representation in studies should also be included in
the application to facilitate review.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 20, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the names of key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of 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 directly to:

Dr. Roy S. Wu
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
to apply for cooperative agreements.  These forms are available at
most institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 435-0714; and from the NCI Program Director listed under
INQUIRIES.

All costs required for the proposed studies must be included in the
application and fully justified.  These costs include the additional
costs of clinical research, including patient accrual, quality
assurance, data management and data analysis, travel, an on-site
audit program, and an independent Data and Safety Monitoring Board.
If capitation costs are requested for 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 form, and others) and the
resultant cost.

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)

Travel funds for one meeting per year for the PI to coordinate
activities should be included in the budget.

Applicants must state in their applications if they or any of their
collaborating investigators will/have submitted another application
or are participating as a collaborator in more than one application
in response to this RFA.  If the applicant or the collaborating
investigator is contributing the same population of patients to two
different studies in separate applications the applicant must choose
which study will get these patients if both studies are judged
meritorious by the reviewers.

Applicants must describe plans to accommodate stated program
requests, criteria, and staff involvement.

The RFA label available in the research grant application form PHS
398 (rev. 9/91) must be affixed to the bottom of the face page.
Failure to use this label could result in delayed processing of 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.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact, clear and single-sided
photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892-9912**

At the time of submission, send two additional copies of the
application to:

Ms. Toby Friedberg
Referral  Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892

Applications must be received by December 22, 1993.  If an
application is received after that date, it will be returned to the
applicant without review.  If the application submitted in response
to this RFA is substantially similar to a research grant application
already submitted to the NIH for review, but has not yet been
reviewed, the applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.  Therefore,
an application cannot be submitted in response to this RFA that is
essentially identical to one that has already been reviewed.  This
does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

All applications will be judged on the basis of the scientific merit
of the proposed project and the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA.  Although
scientific and technical merit of the proposed protocol is important,
it will not be the sole criterion for evaluation of a study.  Other
considerations, such as the importance and timeliness of the clinical
trial, access to patients, and multidisciplinary nature of the
studies, will be part of the evaluation criteria.

Review Method

Upon receipt, applications will be reviewed by the Division of
Research Grants (DRG) for completeness.  Incomplete applications will
be returned to the applicant without further consideration.
Evaluation for responsiveness to the program requirements and
criteria stated in the RFA is an NCI program staff function.
Applications that are judged non-responsive will be returned to the
applicant by the NCI.  An application judged to be non-responsive to
the RFA may be submitted as an investigator-initiated research grant
(R01) or program project grant (P01).  The applications would require
modification in accordance with either the 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 are to be directed to program staff listed under INQUIRIES.

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

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

Review Criteria

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

o  extent to which the application addresses the goals and objectives
of the RFA;

o  adequacy of applicant's plans for addressing the special
scientific and technical program requirements presented in the RFA;

o  demonstrated expertise both in minimal access surgery and conduct
of clinical trials;

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

o  demonstration of availability of and access to appropriate
patients for phase II/III trials;

o  adequacy of planned research to evaluate potential differences
between minimal access surgery and standard surgical techniques in
terms of effectiveness, morbidity (acute and chronic), mortality,
time of convalescence, cost, and quality of life;

o  adequacy of power/sample size analysis for clinical endpoints and
cost;

o  adequacy of the available facilities and data management
resources;

o  documentation of a cost-related data source that is comprehensive
and available to the researcher;

o  evidence of competence with regard to the mechanisms for quality
control, study monitoring, data management and reporting, and data
analysis.

o  plans for effective interaction and coordination among cooperating
institutions within an application and with the NCI;

o  adequacy of provisions for the protection of human subjects;

o  adequacy for plans for the inclusion of female and minorities.

The reviewers will critically examine the submitted budget and will
recommend an appropriate budget and period of support for each
meritorious application.

AWARD CRITERIA

Applications recommended by the National Cancer Advisory Board will
be considered for award based on (a) scientific and technical merit
of the application as reflected in the priority score, (b)
availability of resources and study population, and (c) availability
of funds.  Furthermore, the applicant organization must indicate a
commitment to accept provisions outlined under the SPECIAL
REQUIREMENTS section, Terms and Conditions of Award.  The anticipated
date of award is July 1, 1994.

Letter of Intent Receipt Date:                 October 20, 1993
Application Receipt Date:                      December 22, 1993
Review by the National Cancer Advisory Board:  May 30, 1994
Anticipated Award Date:                        July 1, 1994

INQUIRIES

Written and telephone inquiries concerning the objectives and scope
of this RFA and inquires about whether specific proposed research
would be response are encouraged.  Program staff welcome the
opportunity to clarity any issues or questions from potential
applicants.

Direct inquiries regarding scientific issues to:

Edward L. Trimble, M.D., M.P.H.
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Suite 741
Bethesda, MD  20892
Telephone:  (301) 496-2522
FAX:  (301) 402-0557

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

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

Direct inquiries regarding fiscal matters to:

Ms Carolyn Mason
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
6120 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 59
FAX:  (301) 496-8601

AUTHORITY AND REGULATIONS

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

.

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