Full Text CA-97-020
 
COOPERATIVE TRIALS IN DIAGNOSTIC IMAGING
 
NIH GUIDE, Volume 26, Number 28, August 22, 1997
 
RFA:  CA-97-020
 
P.T.


Keywords: 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  November 18, 1997
Application Receipt Date:  February 18, 1998
 
PURPOSE
 
The Division of Cancer Treatment, Diagnosis and Centers (DCTDC),
National Cancer Institute (NCI), invites applications for cooperative
agreements to establish a single national Network of investigators
that will perform multi-institutional clinical trials in diagnostic
imaging related to cancer. The Network will have the capability to
conduct a broad spectrum of clinical trials in imaging. Similar to
the treatment cooperative groups supported by DCTDC, this Network
will generate new trials in areas of high scientific opportunity.
Unlike most other major National Institutes of Health (NIH)
cooperative trials efforts, the structure and funding of this Network
will not be linked to specific clinical trials. Because the Network's
apparatus for conducting trials will be continually in place, this
mechanism has considerable flexibility for allocating resources
quickly to the testing of promising new imaging devices or agents,
both in limited-institution pilot studies and in large multi-center
settings. The initial focus of the Network will be cancer; once the
Network is functioning productively, consideration will be given to
broadening the agenda to include additional areas of medicine with
the support of other institutes of the NIH.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas. This Request
for Applications (RFA) is related to the priority area of cancer.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report: Stock #017-001-00474-0 or Summary Report: Stock
#017-001-00473-1), through the Superintendent of Documents,
Government Printing Office, Washington, DC  20402- 9325 (telephone:
202-512-1800).
 
ORGANIZATION
 
The Network will consist of a Headquarters office that coordinates
operations, a Biostatistics and Data Management Center (BDMC), and a
number of participating institutions in which the studies are
performed.  Participating institutions will be selected by the
Network's scientific leadership for their ability to contribute to
the particular trials in the Network's research repertoire.
Institutions will not be fixed "members" of the Network but will be
selected for participation in particular studies.  The Network will,
therefore, have the flexibility to recruit institutions that best
suit its scientific agenda, as this evolves over time. The scientific
leadership of the Network will be organized in scientific committees
covering high- priority topic areas in contemporary imaging.
Membership in these committees will be drawn in flexible fashion from
the entire community of expertise in imaging science in North
America. Thus, both the committee structure of the Network and the
membership in individual committees will change with time as
scientific opportunity warrants.
 
The Network shall be governed by a written constitution and bylaws,
which should describe criteria for inclusion and exclusion of
participants, procedures for selecting Network leadership and for
adapting the composition of Network leadership to changes in
scientific opportunity, and other details of governance.  The Network
shall be led by a Chair, who is ultimately responsible to the Network
and to the NCI for the content and conduct of the Network's research
program.  Beyond these general requirements, the structure and
management of the Network are the responsibility of the Network's
leadership.
 
The funding structure will consist of two cooperative agreements
supporting a Headquarters and a Biostatistics and Data Management
Center (BDMC). Participating sites, selected and credentialed by the
Network leadership, will be reimbursed for accrual on a per capita
basis by subcontracts from the Headquarters. In addition to accrual,
Headquarters funds will support operations and coordinating
functions, as well as the activities of the Network's scientific
committees. A Developmental Fund may be requested to support new
areas of particular opportunity. The BDMC award will support data
management and analysis and related research on clinical trials
methodology. The Network's quality assurance program may be supported
from either the Headquarters or the BDMC award, at the discretion of
the Network.
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by North American for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, professional societies, units of
state and local governments, and eligible agencies of the federal
government.  Foreign organizations outside North America are not
eligible.  Applications that include minority individuals and women
as principal investigators are encouraged.  Eligible organizations
may apply for either a Headquarters award, a BDMC award, or both.
 
Separate applications must be submitted for each type of award. Each
Headquarters applicant must identify in both a cover letter and in
the body of the application a single BDMC with which it is proposing
to collaborate.  Similarly, each applicant for a BDMC must identify
both in a cover letter and in the body of the application the
Headquarters with which it is proposing to collaborate. Potential
applicants for the Headquarters and BDMC must, therefore, identify
themselves to each other and establish affiliations both with each
other and with the scientific leadership and participating
institutional sites for the performance of the initial clinical
trials that constitute the beginning research agenda of the Network.
 
MECHANISM OF SUPPORT
 
The administrative and funding instrument to be used for this RFA
will be the cooperative agreement (U01), an assistance mechanism in
which substantial NCI scientific and/or programmatic involvement with
the awardee is anticipated during performance of the activity.  Under
the cooperative agreement, NCI's purpose is to support and stimulate
the recipient's activity by working jointly with the recipient in a
partner role.  The NCI does not assume prime responsibility for or a
dominant role in the activity, and the research conducted by the
awardee is at all times investigator- initiated.  Details of the
responsibilities, relationships and governance of the studies to be
funded under this cooperative agreement are discussed later in this
RFA under the section "Terms and Conditions of Award."
The total project period for applications submitted in response to
this RFA may not exceed five years.  The anticipated award date is
December, 1998.  Although this program is provided for in the
financial plans of the NCI, awards pursuant to this RFA are
contingent upon availability of funds for this purpose.
 
This RFA is a one-time solicitation.  If there is sufficient
continuing program need, NCI will invite the recipients of awards
under this RFA to submit competitive continuation cooperative
agreement applications for review.
 
FUNDS AVAILABLE
 
Approximately $3 million total cost will be available in FY-1999 for
the first year of support for awards made under this RFA; $4 million
(total) for FY 00; and $5 million (total) for FY 01, 02, and 03. Each
year following the first will have appropriate cost escalation in
conformity with NIH grants policy. A single Network of national scope
will be supported by the pair of awards made under this RFA. The
level of support will be dependent upon the level of merit of the
applications received and the availability of funds.  Funding beyond
the initial budget period will be contingent on the continued
availability of funds for this purpose, the continued progress of the
awardees, and the Network as a whole.
 
RESEARCH OBJECTIVES
Background
 
For a number of years, the NCI has sponsored clinical trials in
diagnostic imaging.  The centerpiece of multi-center trials support
has been the series of studies performed by the Radiologic Diagnostic
Oncology Group (RDOG).  Since 1987, this activity has conducted
individual imaging studies in prostate, lung, colon, pancreatic,
musculoskeletal, head and neck, ovarian, and pediatric tumors, as
well as a comparison of image-guided stereotactic breast biopsy to an
open surgical procedure.  Except for the last study, the prevailing
research agenda has involved comparisons between CT, MRI, and
ultrasound, as appropriate, at the various anatomical sites.  The
focus of these studies has been on accuracy of assessment of extent
of  disease in patients presenting with newly diagnosed cancer.  The
RDOG activity was recompeted on five occasions with five separate
RFAs; thus, a group was reconstituted anew for each research question
in the RDOG series.
 
The RDOG experience has been a very productive one for cancer imaging
and for the clinical radiology community.  It has been one of the
very few sources worldwide of information from randomized comparisons
of competing diagnostic modalities.  For this reason, the RDOG
studies have introduced rigorous methodology into the clinical
testing of new imaging technologies. The RDOG activity was intended
primarily to enable the comparison of already established imaging
modalities and was not focused on the early evaluation of imaging
techniques upon their introduction into the clinic.  Nor did it begin
to explore the full spectrum of promising diagnostic tools available
to the contemporary investigative imager.
 
The continued acceleration of the pace of technological and
scientific progress is now no doubt faster than it has ever been.
Existing imaging modalities undergo progressive technical
improvement.  The coupling of imaging with minimally invasive
diagnostic and therapeutic procedures will make interventions better
by limiting disfigurement, trauma, and expense. Further advances may
make the assessment of extent of disease in oncology much simpler;
for example, the availability of radionuclides attached to
tumor-seeking ligands may greatly simplify imaging diagnosis,
inasmuch as one injection of a suitable radiolabel might, in certain
clinical situations, obviate the need for multiple independent
imaging tests. The further development of techniques that mirror the
functional or biochemical characteristics of tumors, rather than
merely anatomic location and extent, is likely to illuminate major
correlates of prognosis non-invasively and provide guidance in
selecting appropriate therapy.  Thus, the future development of
imaging tools will proceed in parallel with an increasing
understanding of tumor biology and a more detailed molecular
understanding of the malignant state.
 
Paradoxically, this scientific progress comes at a relatively
difficult time for the introduction of innovative technologies into
medical practice.  Health care providers under increasing pressure to
contain costs are reluctant to make large capital investments without
the promise of significantly improved medical care and/or a reduction
in the cost of care.  More accurate images by themselves will not
necessarily motivate new equipment purchases without evidence that
the greater accuracy will translate into cost savings or better
clinical results.  These kinds of endpoints are most persuasively
assessed using rigorous clinical trials methodology.  The need for
rigor in the generation of clinical evidence is also conditioned by
the evolving domestic regulatory environment in the United States.
Historically, the procedures governing FDA approval of devices have
differed significantly from those relating to drugs, in that the role
of formal clinical trials has been much more circumscribed for
devices.  As innovations in imaging depart increasingly from existing
paradigms, and especially as imaging and intervention become much
more closely linked, the need for formal clinical evidence of safety
and effectiveness will assume overriding importance.
 
Objectives and Scope
 
The goal of this initiative is the creation of a Network that will
serve as an instrument for the expert clinical evaluation of
discoveries and technological innovations relevant to imaging. Its
activities will result in the following: 1) the expeditious,
reliable, and comprehensive clinical evaluation of new imaging
modalities; 2) the facilitation of technology development and
translational research relating to imaging in academia and in
industry; 3) the development of improved clinical trials methodology
specifically relevant to imaging and the early detection of cancer.
 
These goals are closely interrelated.  A Network of expert
investigators should provide unbiased, reliable evidence on the
relative merits of competing imaging methodologies for the staging of
cancer.  Where appropriate, this evaluation should include estimates
of the relative cost-effectiveness of diagnostic interventions and of
their impact on quality of life.  Private industry should find
collaboration with the Network a very appealing prospect for
generating reliable evidence on the medical worth of its products,
their safety and effectiveness, and their relative cost-effectiveness
compared to conventional diagnostic approaches.  This Network can
also be expected to establish productive partnerships with the
technology-assessment activities of third-party payers, whose
quandaries about which medical interventions should and should not be
reimbursed will be materially lessened by an increasingly firm base
of evidence.  In particular, having such information generated by a
research group unconnected with particular commercial concerns will
help payers with coverage decisions and providers with purchasing
decisions. The development of improved clinical trials methodology
for the evaluation of diagnostic devices will serve to expedite the
often lengthy process and enrich the information yield in a manner
that should benefit all constituencies - patients, sponsors, payers,
and regulators.
 
Scientific Agenda and the Need for Flexibility in Organization and
Scientific Leadership
 
The Network's scientific agenda will consist of a mix of limited-
institution feasibility studies and large-scale, multi-center
randomized trials.  It is essential that the Network identify and
concentrate its energies on the most promising scientific
opportunities, that studies be completed within reasonable periods of
time, and that the methodologies employed in studies be sound and,
where appropriate, innovative.
 
The Network's scientific committee structure should be organized
around broad subject areas within the imaging field.  As the Network
gains experience and its scientific activities shift and broaden, the
membership of committees and, indeed, the number and identity of the
committees themselves should change in response to scientific
opportunity.  Individual committees may well come and go as the
priorities of the Network evolve.  Highly qualified scientists and
physicians in imaging and related areas can be invited to assume
committee membership in a flexible manner as the need arises.
Neither the initial committee structure of the Network nor the
membership of the several scientific communities should be regarded
as fixed and unchanging in time.
 
To ensure that the Network's scientific leadership and committee
structure is adequately responsive to the most promising opportunties
in the field, exhibits the desired degree of flexibility in
composition and decision-making, and makes prioritization decisions
free of conflicts of interest, the organizational structure should
include an advisory panel of experts not directly involved in the
research activities of the Network. Appointment to this advisory
panel will be by mutual agreement between the Network Chair and the
Associate Director, Diagnostic Imaging Program (DIP).
 
Because imaging and treatment issues are often closely related and
will become more so as technology evolves over the next few years,
the Network will need meaningful participation from the radiotherapy,
surgical and medical communities.  In some of its activities, the
Network may need to relate programmatically to the treatment
cooperative groups supported by NCI.  It may, in fact, turn out that
certain kinds of trials, particularly those involving treatment, may
work best as intergroup studies with one or more of the
treatment-oriented cooperative groups.  The need for such liaisons
should be anticipated and provided for by the Network leadership.
 
The Network and its scientific committees should develop, articulate
and follow a research plan that summarizes the Network's thinking and
anticipated lines of investigation for each area on which it chooses
to focus. This plan should articulate both short-term and long-term
goals and will aid the Network in prioritizing competing research
ideas.  The plan will include a balanced and interrelated program of
small developmental and feasibility studies, larger pilot trials, and
large-scale, multi-center efforts; all types of trials should take
advantage of the Network's experience, expertise, and resources.  The
plans for each subject area will be a major focus of the peer-review
process.
 
Selection of Investigator-Participants and Study Sites - A Flexible
Approach
 
Investigators participating in Network research may come from either
academic, community, or industry settings. For participation in a
particular study, the Network leadership may solicit any site that
has the necessary technical qualifications and accrual potential to
contribute meaningfully to the study's execution and timely
completion.  Because the scientific agenda of the Network is expected
to include a broad range of trials, a correspondingly broad spectrum
of investigator specialty and expertise will be necessary. For
example, three hypothetical trials focusing on image-guided,
minimally invasive ablation of early prostate cancer, the staging of
an intrathoracic carcinoma by PET, and a comparison of virtual
colonoscopy to a fiber-optic procedure would likely require entirely
different investigative groups, and perhaps even largely
non-overlapping sets of institutions.  The Network will be
constructed in a flexible manner to permit the ad hoc affiliation of
qualified groups to participate in high-priority research across the
entire range of imaging studies relevant to cancer.  Accrual from
individual sites in the various trials will be reimbursed on a per-
case basis; the appropriate rates of reimbursement will be set by the
Network leadership.
 
The Network will establish policies and procedures for credentialing
participating sites and for conducting periodic review of the
performance of all sites through its quality control and quality
assurance procedures.  The review will examine patient accrual, data
accuracy and timeliness, protocol compliance, procedures for tracking
and follow-up of patients, and audit results.
 
Capabilities and Characteristics of the Network
 
In order to accomplish its research objectives, the Network should
have the following capabilities and characteristics: (1) dynamic and
visionary scientific leadership at the forefront of research in
imaging;  (2) ability to accrue large numbers of patients with cancer
to randomized clinical trials; (3) the capability to perform
limited-institution pilot trials of new imaging modalities, devices,
or agents, preparatory to multi-center randomized trials;  (4) a
statistical office led by individuals with experience in designing,
conducting, and analyzing clinical trials;  (5) the use of endpoints,
in addition to those that directly measure diagnostic accuracy, that
will enable an assessment of the broad impact of imaging innovations
on the patient and on medical practice (these include, for example,
cost-effectiveness and quality of life);  (6) an internal performance
review program that monitors the adequacy of accrual and the quality
of record-keeping;  (7) capability of dealing with regulatory
responsibilities such as Investigational Device Exemptions (IDE) and
Investigational New Drug (IND) applications to the Food and Drug
Administration (FDA), and drug shipments and handling;  (8)
quality-assurance and quality-control programs that  ensure both
patient safety and high quality of research data; (9) methods and
procedures for assuring inclusion in trials of adequate numbers of
women and minority patients;  (10) integration of members of the
patient advocate community into appropriate Network committees and
activities.
 
Functions and Responsibilities
 
The Network's two major organizational components have the following
responsibilities: Headquarters
 
The Headquarters is under the direct supervision of the Network's
Chair, who serves as Principal Investigator of the Headquarter's
award and implements the Network's scientific and organizational
policies. The Headquarters provides executive leadership, scientific
direction, and day-to-day administrative management of the Network.
The Headquarters houses the scientific leadership and committee
structure of the Network. Specific roles and responsibilities of the
Headquarters include the following:
 
a. develops the scientific agenda, specific research plans, and the
Network's overall research priorities. This includes establishment of
a process for soliciting the best ideas from the scientific
community, for prioritizing them, and for assembling a roster of
qualified participants.
 
b. provides logistical and financial support to the Network
scientific committees, monitors their productivity, and provides for
the election or appointment of their leadership;
 
c. oversees scientific and operational activities;
 
d. develops a constitution and bylaws specifying Network structure
and management, procedures for the selection of successor Chairs and
other leadership, terms of office, criteria for participation, and
other details of governance;
 
e. serves as the center of information dissemination to the Network
investigators and institutions, as well as to interested individuals
and organizations outside the Network;
 
f. provides overall management of Network resources, assuring
allocation to priority projects and maintenance of a high degree of
productivity from participants;
 
g. develops policies and procedures for the selection and
credentialing of participating sites and for all aspects of the
conduct of Network activities;
 
h. provides organizational and logistical support for Network
meetings;
 
i. conducts periodic review of the performance of participating sites
according to criteria established by the Network; this review should
focus on patient accrual and follow-up, data accuracy and timeliness,
protocol compliance, results of audits, and adherence to regulatory
requirements;
 
j. establishes a Data and Safety Monitoring Committee (DSMC) for
randomized clinical trials (and for any other trials that the Network
leadership may deem appropriate) that is independent of study
leadership, is clearly free of conflicts of interest, and has
formally documented policies and procedures approved by NCI; provides
organizational and logistical support to the DSMC;
 
k. develops procedures for study monitoring to assure compliance with
protocol design and protection of patients from research risks.  This
medical review should be coordinated with the quality assurance and
quality control programs of the Network;
 
l. encourages and provides financial support for the integration of
community participation (patients and patient advocates) into Network
activities by including them in Network meetings and on appropriate
committees;
 
m. fosters and monitors the inclusion of women and ethnic minorities
in Network clinical trials;
 
n. provides logistical and clerical support to the process of
protocol development; develops and implements standards for protocol
formatting;
 
o. ensures internal Network and NCI review and approval of protocol
concepts, final protocol documents, informed consents, and study
amendments; advises NCI of changes in protocol status;
 
p. produces and maintains current and accurate Network records;
 
q. oversees Network compliance with regulatory requirements
concerning the use of investigational devices and drugs, the
reporting of adverse events, and the protection of human research
subjects;
 
r. provides guidance to the participants regarding clinical trials
practices, including ethical issues involved in clinical research and
conflict-of-interest considerations;
 
s. tracks the progress of the Network's research and assures that the
results of trials are published in appropriate peer-reviewed journals
in a timely manner and in accordance with Network publication
policies;
 
t. verifies that all participating sites have a current approved
Cooperative Project Assurance (CPA) or Multiple Project Assurance
(MPA), as required on file with the Office for Protection from
Research Risks (OPRR), NIH.  Physicians in private practice must have
an approved Non-institutional Investigator Agreement (NIA) on file
with the Headquarters;
 
u. monitors and maintains appropriate records for protocols, informed
consents, assurances, and annual certifications of Institutional
Review Board (IRB) review and approval (HHS Optional Form 310) for
all participating sites;
 
v. manages and allocates financial resources from the Headquarters
budget and provides reimbursement for accrual to participating sites
based on a predetermined per-case rate.
 
Biostatistics and Data Management Center (BDMC)
 
The Network's statistical and data management staff are integral
collaborators in all stages of study development, conduct, analysis,
and reporting. The responsibilities usually assumed by this component
include:
 
a. ensures study feasibility and appropriateness of study design with
respect to stated study objectives;
 
b. ensures that there are clear and consistent definitions of study
objectives, eligibility criteria, primary analysis endpoints, and
guidelines for removal of patients from study where necessary;
 
c. develops appropriate designs to achieve specific study objectives;
develops innovative designs and analytical techniques to maximize the
information yield from trials of imaging devices;
 
d. implements plans for monitoring of study data, including planned
interim analyses of studies, where appropriate, and timely reporting
to the DSMC of all adverse events.  Interim study reports should be
prepared according to Network policies.  In general, reports of
accrual, eligibility, evaluability, and adverse events should be made
for each open study on at least a semi-annual basis;
 
e. implements appropriate registration, randomization procedures, and
accrual tracking procedures;
 
f. designs, develops, and implements forms (paper or electronic)
required to collect study data;
 
g. provides for all aspects of the collection and management of
Network study data, with due attention to quality and timeliness of
data submission;
 
h. contributes to all decisions regarding conduct of Network studies;
 
i. performs statistical analyses that use state-of-the-art
methodology and provides unbiased results;
 
j. co-authors articles and abstracts based on protocol results and
other Network data where appropriate; publishes on methodologic
issues in interventional studies relating to diagnostics.
 
Quality Control and Quality Assurance Program
 
To ensure the correctness and integrity of its research database, the
Network will establish quality-control and quality-assurance
programs, including the development and implementation of an on- site
audit program. According to the preference of the Network leadership,
quality control and quality assurance activities may be located
organizationally either in the Headquarters or the BDMC. The
responsible organization will then provide the necessary logistical
and financial support.The Network will take primary responsibility
for its own on-site monitoring program and will be responsible for
adherence to NCI's established procedures (these are described in a
document entitled  "NCI-CTMB Guidelines for On-Site Monitoring of
Clinical Trials for Cooperative Groups and CCOP Research Bases"
(hereafter "NCI-CTMB Guidelines") available from the Clinical Trials
Monitoring Branch, CTEP, NCI).
 
Assurance of Patient Safety and Study Quality
 
The multi-center nature of many Network activities presents a variety
of challenging methodologic problems regarding assurance of quality
and consistency in study conduct.  The need for formal mechanisms of
medical review and quality control is clear.  Other NCI-supported,
multi-center organizations have developed a number of approaches to
these matters.  The following are examples of the kinds of
considerations that will arise:
 
1.  Imaging quality control includes, but is not limited to, the
institution of suitable procedures to insure adequate control of
image quality; standardization of techniques for image acquisition
and processing across institutions, wherever appropriate;
standardization of terminology regarding abnormalities and findings
to be sought in images; quality-control measures to ensure accurate
interpretation of images.
 
2. Radiation therapy quality control may involve, for teletherapy,
either simultaneous (rapid turn-around) or retrospective review of
port films and compliance with protocol-specified doses for
individual patients.  Minimal standards for acceptability of
equipment may be required.  Each radiation therapy facility that
treats patients on Network studies will undergo periodic physics
review and equipment calibration by the Radiologic Physics Center
(RPC) in Houston, which has supplied each NCI cooperative group's
radiation therapy quality-control office with the physics data
necessary to conduct its case-level review.  Analogous
quality-control measures for image-guided brachytherapy should be
developed as needed.
 
3. The quality control of drug administration (e.g., radiolabeled
antibodies, investigational contrast agents, etc.) is usually carried
out through retrospective review of submitted flow sheets, with
determination of protocol compliance in dose administration and dose
modification.  The criteria vary considerably from study to study and
from group to group and depend heavily on the specific research
questions to be addressed.
 
4. Surgical quality control includes assessment by surgeons of the
adequacy of protocol- specified surgical procedures through review of
the operative notes, study specific surgical forms, and pathology
reports.  Standards of acceptability for specialized surgical
equipment or requirements for participation in workshops may be
necessary in some instances.  Where appropriate, surgical modality
committees may wish to draft handbooks of acceptable guidelines for
surgical procedures used in studies.
 
5. Pathology review is usually retrospective and may be either by a
committee within the Network or by an external reference panel.
Pathology review is not required by NCI for all cases but should be
employed when known variability in the accuracy of histologic
diagnosis is a potentially serious problem or when pathology data may
provide important prognostic information.
 
6. Appropriate quality control for other therapeutic or diagnostic
modalities (for example, standardization of centralized laboratory
procedures) is as essential to good data quality as those enumerated
above.
 
7.  Assuring the safety of individual patients participating in
studies, maximizing the quality of their medical care, and ensuring
that the interests of patient participants are not subsidiary to
those of scientific investigation is critical to Network activities.
All clinical treatment research carries with it the obligation to
insure optimal therapy for participating patients.  In this context,
accurate and timely knowledge of the progress of each study is a
critical Network responsibility and includes the following:
 
a. Accurate tracking of patient accrual to individual studies at the
participating sites and ensuring adherence to defined accrual goals.
 
b. Ongoing assessment of patient eligibility and evaluability and
correction of any specific problems that may occur.
 
c. Adequate measures to ensure timely submission of protocol-
required data for individual patients.
 
d. Adequate measure to ensure timely medical review and assessment of
the data from individual patients
 
e. Rapid reporting of morbidity in individual patients related to
diagnostic or therapeutic interventions, and measures to ensure
communication of this information to all parties with the need to
know, including the NCI and the Network's Data and Safety Monitoring
Committees.
 
f. Prompt assessment of the significance of such information in the
context of the entire study's experience.
 
g. Interim evaluation and consideration of measures of outcome, in a
manner to be specified in advance for each study in accordance with
established methodological procedures.
 
8. Quality Control and On-Site Auditing.  A related need is for
verification of the accuracy of data submitted from individual
investigators to the Network.  This need overlaps considerably with
the obligation of DCTDC as a sponsor of investigational devices and
agents. As a sponsor,  DCTDC must provide for visits to each trials
site for the purpose of:  (a) auditing medical records to verify data
accuracy, and  (b) assuring compliance with the regulatory
requirements of FDA, including appropriate storage and handling of
investigational agents.  The Network is, therefore, required to
establish a system of periodic on-site audits of participating sites,
with NCI oversight (see the "NCI-CTMB Guidelines").
 
Elements of the on-site audit program are as follows:
 
a. Regulatory Obligation.  As a sponsor of investigational agents and
devices, the DCTDC is required by FDA regulations to maintain an
on-site audit program.  Through formal agreements with the FDA, DCTDC
has delegated much of this responsibility to its investigative
groups, with NCI overseeing the process.  The specific purposes of
the audit programs are to document the accuracy of data submitted to
investigative groups and to verify investigator compliance with the
regulatory requirements for all clinical investigations.
 
b. Data Verification and Protocol Compliance.  By comparison of
submitted data with information contained in the patient's medical
records, this component of the on-site audit program seeks to assure
accuracy and completeness of research information integral to the
assessment of:
 
Patient eligibility
Compliance with protocol-defined procedures
End-point evaluation
Intervention-related toxicity
Protocol-required laboratory and diagnostic evaluations
Overall quality of record-keeping
Concomitant interventions or other information that might affect
study results but is not recorded on submitted study forms
 
c. Specific Regulatory Requirements.  This component of the on-site
audit program is intended to assess:
 
Documentation of IRB approvals, reapprovals and protocol amendments
Documentation of an IRB-approved properly signed and dated informed
consent document for each case audited; these documents include an
adequate description of the risks and benefits as contained in the
model informed consent submitted to NCI at the time of protocol
approval.
Security of investigational drug handling Adequacy of NCI drug
accountability records
 
d. Procedures.  The Network must establish and follow an on- site
audit program and audit procedures in accordance with the "NCI-CTMB
Guidelines". This requires that NCI be notified of all sites
participating in each Network clinical trial. This notification will
occur at the time of protocol submission to NCI either for protocol
review or for informational purposes (see under NCI Staff
Responsibilities, Section 3: Review of Proposed Protocols).  Sites
participating regularly in Network studies must be visited at least
once every 36 months.  All participants, however, are at yearly risk
of an audit.  Audits are conducted by peer investigators within the
Network.  A percentage of visits include NCI quality assurance staff
or their agents.  Protocols to be reviewed are selected by the
Network in accordance with procedures outlined in the "NCI- CTMB
Guidelines".  A sample of studies involving investigational agents or
devices is always included when the participating site has accrued
patients to such studies.  Individual cases are then randomly
selected by the BDMC for review.
 
A preliminary report must be faxed to CTMB within one working day of
the audit.  A final report of each audit is sent by the Network to
CTMB within ten weeks of the audit.  CTMB staff reviews the audit
findings as well as the Network's evaluation and response to the
results.
 
e. Network Evaluation and Response.  The discovery of actual fraud or
other serious misconduct during cooperative group audits has been
rare, but problems covering a wide spectrum of severity and type are
often found.  Most are appropriately dealt with by constructive
suggestions and are usually remedied through education of
investigators and data managers.  Notification of NCI is required in
the event of findings suggesting intentional misrepresentation of
data or disregard for regulatory safeguards, as well as other matters
of sufficient seriousness.  In such instances, CTMB staff should be
notified by telephone immediately, since other federal agencies may
require notification.  Procedures for immediate suspension of accrual
at the participating site may be required.
 
After reviewing the audit report and the Network's response, the CTMB
staff may recommend further action to the Network or the NCI may take
action independently.  In cases of suspected fraud or other serious
problems of compliance with regulatory requirements, the NCI may
request formal investigation by the Office of Research Integrity, the
Office for Protection from Research Risks, or the FDA.
 
9.  Data and Safety Monitoring Committees.  For randomized clinical
trials, the NCI has required cooperative trials organizations to
establish Data and Safety Monitoring Committees (DSMC) that are
independent of study leadership, are clearly free of conflicts of
interest, and have formally documented policies and procedures
approved by NCI.  The main objectives of the independent DSMC are to:
 
Ensure that the patients in the trial are protected and that their
interests are not made secondary to the interests of scientific
investigation.
 
Ensure that evaluation of interim results and decision- making about
continuation, modification, termination of accrual, and reporting of
results are made competently based on thorough evaluation.
 
Ensure that the credibility of trial reports and ethics of trials
conduct are above reproach with no actual or possible appearance of
professional or financial conflicts of interest.
 
Enable physicians entering patients to remain free of knowledge of
interim efficacy and toxicity data.  This permits physicians to
continue to approach their patients honestly and avoids the need to
modify informed consent based on statistically insignificant interim
results.
 
Enable study leadership to remain free of knowledge of (often
unreliable) interim efficacy and toxicity data, so that they may deal
honestly with their peers in encouraging them to enter patients in
the study and so that they do not put themselves or the study at risk
by inadvertently divulging interim results.
 
SPECIAL REQUIREMENTS
 
TERMS AND CONDITIONS OF AWARD
 
These special Terms of Award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations in CFR 45 Parts 74 and 92, and other HHS,
PHS, and NIH Grant Administration policy statements.
 
The administrative and funding instrument used for this program is a
cooperative agreement (UO1), 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 specific tasks and activities in carrying out the studies
will be shared among the awardees and the NCI Program Staff.
 
A.  Awardee Rights and Responsibilities
 
Certain of the awardee's generic programmatic responsibilities as an
investigator for the conduct of the research supported by this RFA
are described in two other NCI documents: (a) the Investigator's
Handbook (a Manual for Participants in Clinical Trials of
Investigational Agents Sponsored by the Division of Cancer Treatment,
Diagnosis and Centers, National Cancer Institute); and (b) the
"NCI-CTMB Guidelines."  Specific portions of these documents, as
enumerated in the following sections, are incorporated by reference
as terms of award.  These documents are available from the NCI upon
request.
 
Throughout these Terms and Conditions of Award "Participant" refers
to all awardees as well as all institutions and/or individual
investigators, both funded and unfunded, with whom they are
participating or collaborating.
 
1. Development of Network Research Agenda and Protocols
 
It is the responsibility of the Network to develop the details of the
research design, including definition of objectives and approaches,
the planning, implementation, and analysis of studies, and the
publication of results, interpretations, and conclusions of studies.
The Network shall, with NCI assistance, develop clinical protocols in
accordance with the research interests, abilities, and goals of the
Network. The Network leadership shall designate other Network
investigators to serve as Protocol Chairperson for each proposed
study.  Protocols for DCTDC-sponsored investigational agents or
devices will be developed in accordance with the instructions in the
Investigator's Handbook.  The Investigator's Handbook is a reference
handbook for all investigators who use DCTDC- sponsored
investigational agents in their clinical trials, irrespective of
funding mechanism.  The Investigator's Handbook describes, in
accordance with NCI-FDA agreements:
 
 Requirements for Protocol Development and Submission  Ordering
Investigational Drugs from NCI  Responsibility for Reporting of
Results to NCI  Adverse Event Procedures
 Accountability and Storage of Investigational Drugs
 Monitoring and Quality Assurance
 
2. Coordination and Internal Oversight of Network Activities
 
In accordance with the Network constitution, bylaws, policies and
procedures, the Network Headquarters (or BDMC as appropriate), under
the leadership of the Network leadership and with NCI assistance, is
responsible for coordinating protocol development, protocol
submission, study conduct, quality control and study monitoring, drug
ordering, data management, statistical analysis, protocol
amendments/status changes, adherence to requirements regarding
investigational drug management and federally mandated regulations,
and protocol and performance reporting.  All the scientific and
administrative decisions related to the Network- funded activities
will be coordinated by the Network leadership with the assistance of
the staffs of the Headquarters and BDMC. The Network leadership or
designee will be responsible for communication with the appropriate
NCI staff.
 
The Headquarters will establish policies and procedures for
recruiting and credentialing participating sites. NCI will be
notified of the sites participating in each protocol at the time of
protocol submission to NCI either for review or for informational
purposes (see under NCI Staff Responsibilities, Section 3: Review of
Proposed Protocols).
 
To ensure that the Network's scientific leadership and committee
structure is adequately responsive to the most promising opportunties
in the field, exhibits the desired degree of flexibility in
composition and decision-making, and makes prioritization decisions
free of conflicts of interest, the Network's organizational structure
should include an advisory panel of experts not directly involved in
the research activities of the Network. Appointment to this advisory
panel will be by mutual agreement between the Network Chair and the
Associate Director, DIP.
 
3. Protocol Submission
 
Prior to protocol implementation, the Network Headquarters will
submit protocols for review to the Protocol and Information Office,
CTEP, NCI.  Phase III protocols must be preceded by a concept- review
letter describing the hypothesis to be investigated, the general
design of the contemplated trial plus relevant information on accrual
capabilities of the planned participating sites to document
feasibility. For all non-Phase III trials that include a DCTDC
investigational agent or device, a Letter of Intent (LOI) must be
submitted to the Protocol and Information Office, CTEP. These two
mechanisms for preliminary review are intended to expedite protocol
development and implementation and to facilitate agreement on study
priority and design (see Investigator's Handbook, pp. 32-35). The
Network leadership, with the assistance of the Network Headquarters
staff, will communicate the results of the NCI review of protocols to
the participating investigators.
 
4.  Network Compliance with Federally Mandated Regulatory
Requirements
 
The Network must be in compliance with all FDA regulatory
requirements for studies involving investigational devices and agents
and NIH policies applying to the conduct of research involving human
subjects.  These regulations include but are not limited to CFR 21
Parts 50, 56 and 312 and CFR 45 Part 46. Participants are required to
follow established Network procedures for complying with the
federally mandated regulations.
 
  a. The Network must be able to demonstrate that each participant
has a current approved assurance number on file with OPRR.
 
  b. The Network must be able to demonstrate that each protocol,
amendment, and informed consent document is approved by the
responsible IRB prior to patient entry and at least annually
thereafter, as appropriate for the degree of risk of the protocol, as
stipulated by 45 CFR 46. Each investigator must have a current FDA
Form 1572 and curriculum vitae on file with the Pharmaceutical
Management Branch (PMB), CTEP.
 
  c. The Network must be able to demonstrate that each patient (or
legal representative) gives written informed consent prior to entry
on study.
 
  d. The Network must assure timely reporting of all serious and
unexpected toxicities to NCI.
 
  e. The Network must establish and maintain an on-site audit program
in compliance with the "NCI-CTMB Guidelines."
 
  f. The Network must have a method of providing, upon NCI request,
summary efficacy and toxicity data to be included in DCTDC's Annual
Report to the FDA for each investigational agent and device being
developed under NCI sponsorship.
 
  g. The Network must implement NCI requirements for storage and
accounting for investigational agents provided under DCTDC
sponsorship.
 
5. Investigational Drug Management
 
Investigators performing Network trials are expected, in cooperation
with the NCI, to comply with all FDA monitoring and reporting
requirements for investigational agents and devices. When new avenues
of cancer diagnosis or therapy involving investigational drugs are
pursued, the clinical information should be acceptable to the FDA for
inclusion in an eventual licensing dossier for drugs, biologicals, or
devices, as appropriate.
 
6. Quality Control and Study Monitoring
 
  a.  The Network shall establish and implement mechanisms for
quality control of  therapeutic and diagnostic modalities employed in
its trials.  Participants are required to follow Network procedures
for quality control.  Quality control at a minimum should consist
of:
 
 1) Imaging Devices: Where appropriate, review (concurrent
or retrospective) to assure accuracy of readings from the
study sites; compliance with protocol-specified diagnostic
parameters for individual patients; accuracy of device
calibration across participating institutions.
 
 2) Radiation therapy: Review (either concurrent or
retrospective) of port films and compliance with protocol-
specified doses for individual patients.  Determination of
adequacy of radiation delivery with assistance of the
Radiological Physics Center (RPC), whose functions usually
include equipment dosimetry, periodic institutional visits
and other aspects of physics review.
 
 3) Protocol-related Drug Administration: 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 and
study-specific surgical forms.
 
 5) 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 information relevant
to the trial.
 
b. The Network shall establish and implement mechanisms for
study monitoring and quality assurance.  Participants are required
to follow Network procedures for study monitoring.  The Network
is responsible for assuring accurate and timely knowledge of the
progress of each study through:
 
 1) tracking and reporting of patient accrual and adherence to
defined accrual goals;
 
 2) ongoing assessment of case eligibility and evaluability;
 
 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; and
 
 7) an on-site monitoring program. The awardee is
responsible for ensuring that all participating sites have
routine audits in accordance with the "NCI-CTMB
Guidelines" and that the results of audits are reported to the
NCI in accordance with the guidelines.  In the event that the
NCI determines that the awardee failed to comply with these
guidelines, the accrual of new patients to the Network's
protocols at the affected site shall be suspended immediately
upon notice of the NCI determination.  The suspension will
remain in effect until the awardee conducts the required
audit and the audit report or remedial action is accepted by
the NCI. The awardee will be responsible for notifying any
affected site of the suspension.  During the suspension
period, no funds from this award may be provided to the site
for new accruals, and no charges to the award for new
accruals will be permitted.
 
c.  Quality Assurance and Quality Control of Data. The
awardee must follow NCI-approved procedures developed by the
Network for quality assurance of data collected by the Network
and for the prevention and/or identification of false or otherwise
unreliable data.  The awardee must follow Network procedures for
the assurance of data quality and quality control in accordance with
Network guidelines and NCI policies. If there is any indication
through the quality assurance and/or quality control programs, or
through any other means, of a pattern of non-compliance with
protocol or regulatory requirements or a finding of possible
alteration of data, these findings must be reported in accordance
with the "NCI-CTMB Guidelines."
 
7.  Data Management
 
The Network shall establish and implement mechanisms for data
management that are: (a) adequate for quality control and analysis,
and (b) as simple as possible in order to encourage maximum
participation of physicians entering patients and to avoid
unnecessary expenses.  Participants are required to follow
Network procedures for data management.
 
8.  Data and Safety Monitoring Committees
 
The Network must establish and maintain a Data and Safety
Monitoring Committee (DSMC) for Phase III clinical trials.  The
policies and procedures of the DSMC must be approved by the
Associate Director, DIP.  The Network must comply with the
approved policies and procedures of the DSMC.
 
9.  Protocol Closure
 
The Network shall establish and implement mechanisms for
interim monitoring of results and monitoring protocol progress.  If
the Network wishes to close accrual to a study prior to meeting the
initially established accrual goal, the interim results and other
documentation should be made available to DIP staff for review
and concurrence prior to implementation of the decision by the
Network.  It is recommended that statistical guidelines for early
closure be presented as explicitly as possible in the protocol in
order to facilitate these decisions.  In the event that the DSMC has
recommended early closure, DSMC procedures regarding
notification of the Associate Director, DIP, must be followed.
 
10. Protocol Reporting Requirements
 
Reporting requirements will be in agreement with FDA regulation
and NCI procedures. NCI's procedures for data reporting from its
clinical trials organizations are currently in evolution and will be
provided to and discussed with the Network in detail at the
inception of Network activities. Interim reports of each activated
and ongoing study shall appear in the minutes of each Network
meeting and shall include specific data on patient accrual as well
as, when appropriate, detailed reports of treatment-associated
morbidity.  Quarterly accrual information must be provided by the
Headquarters or BDMC as appropriate to the Program Director,
DIP, for all active studies.  A system for providing such
information in a timely manner should be in place.  Participants
must provide accrual data to the Network in accordance with
Network procedures.
 
11. Adverse Event Procedures
 
In order to be in compliance with FDA regulations, all recipients of
NCI support for clinical trials must promptly notify the NCI and
any other sponsors of the trial of adverse events (i.e., adverse drug
reactions) according to directions provided in the adverse event
reporting section of the protocol. The awardee will notify all
institutions/investigators participating in this project, funded or
unfunded, about the above requirement and about the institutions'/
investigators' responsibility to report adverse events as specified
in
the protocol. The awardee will promptly notify the Program
Director, DIP, of serious or life-threatening events, as instructed
in
the protocol.
 
12. Performance Review
 
The Network shall establish and follow policies and procedures for
credentialing participating institutions and conducting periodic
review of the performance of each participating site. This review
should examine patient accrual, data accuracy and timeliness,
protocol compliance, long-term patient follow-up and audit results.
The mechanism will include a procedure for the Network
leadership to recommend an adjustment of funds within the
Network as appropriate for the level of participation in Network
activities, including (but not limited to) accrual.
 
13.  Procedures in the Event of Scientific Misconduct
 
If a duly authorized governmental or institutional body issues a
final determination that scientific misconduct has occurred or if the
awardee determines that other events have occurred which have
significantly affected the quality or integrity of the Network data
or
patient safety, the awardee is responsible for notifying the
Network's DSMC, the CTMB, the collaborating investigators, the
appropriate IRBs, and other sponsors of the affected work.
 
The awardee is also responsible, if the events described above have
occurred, for ensuring that submitted but unpublished abstracts and
manuscripts are corrected, if possible.  If publication deadlines
have passed or if abstracts and/or manuscripts containing the
affected data have already been published, the awardee is
responsible, within 90 days after learning of the event(s)
significantly affecting the quality of the Network data or patient
safety, for submitting to NCI a reanalysis of the results deleting
the
false or otherwise unreliable data, and disclosing within the text
the
reason(s) for the reanalysis.  The awardee must submit the
reanalysis for publication.  The NCI may disseminate information
about the reanalysis as broadly as it deems necessary.
 
The awardee must use its best efforts to notify all scientists,
research laboratories, and other organizations to which the awardee
has sent research materials affected by false or otherwise unreliable
data.
 
True copies of data files and other supporting documentation from
studies affected by scientific misconduct or other findings affecting
the quality or integrity of data or patient safety shall be made
available to the NCI in a timely manner upon the request of the
Grants Management Officer, NCI.  The NCI reserves the right to
reanalyze, to publish, or to distribute its analyses of these data
when it is in the interest of the public health.  Prior to release,
publication or distribution of such analyses, the NCI will provide
such analyses to the awardee.
 
14.  Data Files Available to NCI Upon Request
 
Upon the request of the Grants Management Officer, NCI, true
copies of data files and supporting documentation for all NCI-
supported protocols that have a major impact on patterns of care, as
determined by the NCI, shall be made available to the NCI in a
timely manner.
 
15.  Notification of Patients by the Awardee During Patient's
Lifetime
 
In order for there to be an appropriate response in the event the
NCI determines, either while a protocol is active or (if relevant)
during the lifetime of the subjects following protocol closure, that
a
medically important toxicity or side effect is associated with
protocol-directed treatment or that the medical care of one or more
subjects may have been compromised by scientific misconduct or
other finding affecting the integrity of the data or patient safety
at
the awardee institution or at a third-party institution, funded or
unfunded, the awardee shall assure that the institution(s)
responsible for these subject(s') accrual, whether funded or
unfunded, will have procedures in place to: a) contact each subject
individually at his or her last known address on file with the
institution and which give each subject contacted appropriate
information and the right to communicate with an appropriate
institutional representative and, in the event of misconduct, to meet
with a physician not connected with the clinical trial or study in
which the subject has participated, and b) encourage subjects to
notify the institution of any changes of address.  The procedure
must provide for informing the subjects fully of the consequences
of the toxicity or misconduct for their care and well-being, if any,
and the availability of follow-up; and their opportunity to examine
any portion of their medical records relevant to the potential effect
of the toxicity or side effect upon them or that may be affected by
scientific misconduct or other findings affecting the quality or
integrity of the data or patient safety.
 
Under regulations in CFR 45 Part 74.53, NCI has right of access to
research records pertinent to studies conducted with NCI funding.
In exceptional circumstances, such as a public health emergency,
institutions may be required to provide subject names and
treatments to the NCI in a format which allows direct notification
of the patient by the NCI.
 
16. Collaboration with Device or Drug Manufacturers
 
Joint projects and cost-sharing arrangements with industry are
encouraged. Companies are expected to be a major source of
technological innovation, and certain of its products are likely to
be
of great interest to the Network. These arrangements will be
worked out on a case-by-case basis by the Network leadership and
collaborating companies. The arrangement will in all cases
conform to PHS regulations and any applicable NCI policies on
interactions among industry, NCI-supported cooperative trials
networks, and NCI.  In all cases details of any financial or other
arrangements between the Network and industrial companies will
be available to NCI staff on request.
 
17. Progress Reporting
 
Annual progress reports will be submitted to the DIP, NCI in
accordance with guidelines provided by the NCI Program Director.
 
B.  NCI Staff Responsibilities
 
The role of NCI staff as described throughout these terms and
conditions of award is to assist and facilitate, but not to direct,
research activities.  This cooperative agreement is part of a larger
program of cooperative clinical trials in the NCI.
 
1. NCI Staff Interactions.
 
Because of the Network's diverse research agenda and the number
of tasks that have to be accomplished for the Network to realize its
goals, a number of NCI staff members from several organizational
units must interact with the Network. The NCI Program Director (a
staff member of the Diagnostic Imaging Program (DIP)), the
Associate Director for the DIP, and staff members of the three
branches of the DIP (the Functional Imaging Branch, the Image-
Guided Diagnosis and Therapy Branch, and the Imaging Diagnosis
Branch) will assist the Network as appropriate in developing
information concerning the scientific basis for specific trials and
also will be responsible for advising the Network of the nature and
results of relevant trials being carried out by other organizations
and potential studies relevant to new avenues of imaging diagnosis
and image-guided therapy. From the Cancer Therapy Evaluation
Program, DCTDC, the staff of the Pharmaceutical Management
Branch will assist the Network in the ordering and management of
investigational drugs; the Regulatory Affairs Branch will assist in
assuring that Network activities are in conformity with federal
regulations concerning the use of investigational devices and
medicinal agents; the Biometric Research Branch will consult with
the Network as needed in connection with biostatistics and issues
of clinical trials design; staff of the Investigational Drug Branch
(CTEP) and the Imaging Diagnosis Branch (DIP) will provide
updated information on the efficacy and toxicity of investigational
drugs or devices supplied to Network members under an
Investigational New Drug (IND) Application or an Investigational
Device Exemption (IDE) sponsored by DCTDC, NCI; staff of the
Clinical Investigations Branch will assist the Network, as needed,
in establishing liaisons with other clinical cooperative groups and
in protocol-related and medical matters relating to the diseases
under study. The Clinical Trials Monitoring Branch (CTMB) will
oversee implementation of the Network's quality assurance and
site visit monitoring program. The CTEP Protocol Review
Committee, supplemented by members of the DIP, is the NCI body
that will perform formal protocol reviews of submitted protocols of
the Network. From the Radiation Research Program, staff will
interact with the Network for studies involving image-guided
delivery of therapeutic radiation.  The DIP Program Director will
provide the awardees with a comprehensive list of the NCI staff
who will be involved, and the responsibilities of each NCI staff
member.
 
2. Protocol Development
 
A protocol is the detailed written plan of a clinical experiment.
The protocol must be
mutually acceptable to the Network and to the NCI.
Communication with relevant NCI staff, as outlined in #1 above, at
the various stages of protocol development is encouraged. NCI
staff from the several organizational units outlined above will
assist the Network in protocol design, as may be appropriate, by
providing information regarding: (a) the existence and nature of
concurrent clinical trials in the area of research, pointing out
possible duplication of effort; (b) comments on proposed trial
designs; and (c) relevant pharmacokinetic and pharmacodynamic
data on investigational agents proposed for study.
 
For proposed large multi-center trials, staff of the DIP and CTEP
will provide the Network a formal review of concepts for
protocols, commenting on study originality and scientific and
medical impact.  These two mechanisms for preliminary review are
intended to expedite protocol development and implementation and
to facilitate agreement on study priority and design (see the
"Investigator's Handbook," pp 32-35).
 
3. Review of Proposed Protocols
 
Network protocols will be reviewed by the CTEP Protocol Review
Committee (PRC), augmented by staff of the Diagnostic Imaging
Program, meeting at regular intervals for this purpose. Ad
hocreviewers, external to NCI, will be utilized when deemed
appropriate by the committee chairperson.  Formal protocol review
and NCI approval prior to activation are required for the following
types of studies: (a) all protocols utilizing NCI resources and
investigational agents regardless of IND or IDE sponsor; (b) all
protocols that permit entry of 100 or more patients; and (c) all
Phase III protocols.  Other protocols will be filed with NCI for
information purposes but will not require NCI approval.  Advisory
reviews of such protocols may be provided to the Network at
NCI's discretion.  For all protocols that require review, the
Associate Director for the DIP will provide the Network with the
Protocol Review Committee's consensus review that describes
recommended modifications and other suggestions, as appropriate.
 
The major considerations relevant to protocol review by the PRC
include: (a) the strength of the scientific rationale supporting the
study, (b) the medical importance of the question being posed, (c)
the avoidance of undesirable duplication with other ongoing
studies, (d) the appropriateness of study design including interim
monitoring plans if appropriate, (e) a satisfactory projected accrual
rate and follow-up period, (f) patient safety, (g) compliance with
federal regulatory requirements, (h) adequacy of data management,
(i) appropriateness of patient selection, evaluation, assessment of
toxicity, response to therapy and follow-up.
 
If a proposed protocol is disapproved, the specific reasons will be
communicated to the Network chairperson as a consensus review
within 30 days of protocol receipt by the Protocol and Information
Office (PIO), CTEP.  NCI will not provide investigational drugs or
permit expenditure of NCI funds for a protocol that it has not
approved.  The Program Director and other DIP staff will be
available to assist the Network in developing a mutually acceptable
protocol, consistent with the research interests, abilities and
strategic plans of the Network and of the NCI.
 
4. Review of Quality Control and Study Monitoring
 
Staff of the Clinical Trials Monitoring Branch (CTMB) will review
and provide advice regarding mechanisms established by the
Network for quality control of therapeutic and diagnostic
modalities employed in its trials.  CTMB staff will review and
approve the mechanisms established by the Network for study
monitoring including the Network's on-site auditing program. Staff
of CTMB, DIP, and/or the monitoring contractor may attend as
observers the on-site audits conducted by the Network; the
frequency of observer participation by NCI staff will be
determined by the CTMB.
 
5. Review of Data Management
 
Staff of the Biometric Research Branch (BRB) will review
mechanisms established by the Network for data management.
When deemed appropriate, staff will make recommendations to
ensure that data collection and management procedures are: (a)
adequate 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) generally compatible with the standard formats for electronic
data reporting to NCI.  The NCI will have access to all data
although they remain the property of the awardee institution.  Data
must also be available for external monitoring as required by
NCI's agreement with the FDA relative to the NCI's responsibility
as a sponsor of research with investigational drugs and devices.
 
6. Data and Safety Monitoring Committees
 
The NCI Program Director, assisted by BRB staff, will assess
Network compliance with NCI-established policies on Data and
Safety Monitoring Committees (DSMCs) for multi-center Phase III
trials.  One or more NCI staff members will serve as non-voting
members on the DSMC.
 
7. Protocol Closure
 
The Associate Director, Diagnostic Imaging Program (DIP), may
request that a Phase I or Phase II protocol study be closed to
accrual for reasons including: (a) insufficient accrual rate; (b)
poor
protocol performance; (c) patient safety; (d) study results are
already conclusive; and (e) emergence of new information that
diminishes the scientific importance of the study question. The
NCI will not provide investigational agents or permit expenditures
of NCI funds for a Phase I or Phase II study after requesting
closure, except for patients already on treatment and follow-up.
 
The Associate Director, DIP, may request that the Network DSMC
consider closing a Phase III protocol to accrual for reasons
including: (a) insufficient accrual rate; (b) poor protocol
performance: (c) patient safety; (d) study results are already
conclusive; and (e) emergence of new information that diminishes
the scientific importance of the study question. Any disagreement
between NCI and the DSMC about protocol closure that  cannot be
resolved by discussion will be brought to Arbitration as outlined
later under "Collaborative Responsibilities," except that the
nominating parties will be the Associate Director, DIP, and the
Chair of the DSMC.  NCI will not provide investigational agents or
permit expenditures of NCI funds for a Phase III study that has
been closed, except for patients already on treatment or in follow-
up.
 
8. Involvement in Investigational Drug and Device Management
 
The NCI will have the option to cross file or independently file an
IND on investigational agents evaluated in trials supported under
cooperative agreements.  This applies to drugs not developed in the
NCI drug development program. In the case of investigational
devices, the NCI, Network investigators, and the device supplier
will decide collaboratively which organization will hold the IDE.
 
The NCI Program Director, assisted by the staff of the Regulatory
Affairs Branch (RAB) and the Pharmaceutical Management
Branch (PMB), will advise investigators of specific requirements
and changes in requirements concerning investigational drug or
device management that the Food and Drug Administration (FDA)
may mandate.
 
9. Review of Compliance with Federal Regulations
 
CTMB and RAB staff will review and advise regarding
mechanisms established by the Network to meet regulatory
requirements of the FDA for studies involving NCI-sponsored
investigational agents and devices, and those of the Office for
Protection from Research Risks (OPRR) for the protection of
human subjects.
 
10. NCI Attendance at Network Meetings
 
NCI staff, as designated by the NCI Program Director, will attend
the regular Network meetings and will be invited as a non-voting
observer to Network leadership meetings.
 
11. Facilitating Collaboration with other Cooperative Groups
 
NCI staff will take an active role in promoting the timely
completion of important studies, for example by encouraging and
facilitating intergroup collaboration when appropriate, or by
assisting in the identification and mobilization of additional
resources.
 
C.  Collaborative Responsibilities
 
1. Development of Intergroup Activities
 
For certain types of scientific questions, particularly those
involving the integration of imaging with therapeutic maneuvers, it
may be desirable for the Network to seek collaboration with one or
more of NCI's treatment cooperative groups.  Establishment of
these collaborations may be initiated by the investigators or NCI
staff.  From time to time the NCI holds disease- or modality-
oriented strategy meetings for the purpose of jointly developing
program priorities for future protocol development.  Group
investigators, NCI staff and other extramural investigators attend
these meetings.  The groups and NCI staff work together to
facilitate the timely development of protocols resulting from the
consensus developed at such strategy meetings.  Investigators of
the Imaging Network will be invited to attend these meetings as
appropriate.
 
2. Investigational Drug and Device Development
 
When trials of new imaging diagnostic or therapeutic approaches
involving investigational drugs or devices are pursued, the clinical
information resulting from them should be acceptable to the FDA
for inclusion in a New Drug Application (NDA) or Product
Manufacturing Application (PMA).  In partnership with NCI staff
and any collaborating drug or device company, the Network will
develop protocols to obtain such information as needed.
 
3. Data and Safety Monitoring Committees (DSMC)
 
Appropriate policies and procedures for the DSMC are a
collaborative responsibility of the Network and NCI staff.
 
4. Cooperative Group Chairs' Semi-Annual Meetings
 
The Chairs of each of NCI's treatment cooperative groups meet
semi-annually to discuss issues of relevance to the clinical trials
program.  The Chair of the Network will be invited to attend this
meeting, as many of the issues discussed are relevant to the
activities of the Network.
 
5. Cooperative Group Statisticians' Meeting
 
Similarly, the Network's Chief Statistician will be invited to attend
the annual group statisticians' meeting to discuss issues of
relevance to the clinical trials program.
 
D.  Arbitration
 
Any disagreement that may arise on scientific/programmatic
matters (within the scope of the award), between award recipients
and the NCI may be brought to arbitration.  An arbitration panel
composed of one Network nominee, one NCI nominee, and a
nominee with clinical trials expertise chosen by the other two will
be formed to review the NCI decision and recommend an
appropriate course of action to the Director, DCTDC.  The
arbitration procedures in no way affect the awardee's right to
appeal an adverse determination under the terms of 42 CFR Part
50, Subpart D, and 45 CFR Part 16.  The Network will not expend
NCI funds to conduct any study disapproved by NCI unless the
disapproval has been overturned by the arbitration process outlined
above.
 
INCLUSION OF WOMEN AND MINORITIES IN
RESEARCH INVOLVING HUMAN SUBJECTS
 
It is the policy of the NIH that women and members of minority
groups and their subpopulations must be included in all NIH-
supported biomedical and behavioral research projects involving
human subjects, unless a clear and compelling rationale and
justification are provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.
The new policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43) and supersedes and
strengthens the previous policies (Concerning the Inclusion of
Women in Study Populations and Concerning the Inclusion of
Minorities in Study Populations), which have been in effect since
1990.  The new policy contains some provisions that are
substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects
should read the "NIH Guidelines for Inclusion of Women and
Minorities as Subjects in Clinical Research," which was reprinted
in the Federal Register of March 28, 1994 (59 FR 14508-14513) to
correct typesetting errors in the earlier publication, and reprinted
in
the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.  Investigators also may obtain copies
of the policy from the program staff listed under INQUIRIES.
Program staff may also provide additional relevant information
concerning the policy.
 
LETTER OF INTENT
 
Prospective applicants for this RFA are requested to submit by
11/18/97 a letter of intent that includes a descriptive title of the
proposed research, the name, address, and telephone number of the
Principal Investigator, the identities of other key personnel and
participating institutions, and the number and title of the RFA in
response to which the application may be submitted.  Although a
letter of intent is not required, is not binding, and does not enter
into the review of a subsequent application, the information that it
contains allows NCI staff to estimate the potential review workload
and avoid conflict of interest in the review.
 
The letter of intent is to be sent to:
 
Anne Menkens, PhD
Diagnostic Imaging Program
National Cancer Institute
Executive Plaza North, Room 800
6130 Executive Boulevard
Bethesda, MD 20892
Rockville, MD 20852 (if using express mail)
Telephone 301-496-9531
FAX 301-480-5785
e-mail menkensa@dtpepn.nci.nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS-398 (revised 5/95) is to
be used in applying for these grants.  These forms are available at
most institutional offices of sponsored research; from the Grants
Information Office, Extramural Outreach and Information
Resources, NIH, 6701 Rockledge Drive, MSC-7910, Bethesda,
MD 20892-7910. Telephone 301-435-0714. E-mail address is
asknih@odrockm1.od.nih.gov.
 
The RFA label available in the PHS-398 (revised 5/95) application
form must be affixed to the bottom of the face page of the
application.  Failure to use this label could result in delayed
processing of the application such that it may not reach the review
committee in time for review.  In addition, the RFA title and
number must be typed on line 2a of the face page of the application
form and the YES box must be marked.
 
Submit a signed, typewritten original of the application, including
the Checklist and three signed photocopies, in one package to:
 
 Division of Research Grants
 National Institutes of Health
 6701 Rockledge Drive, MSC-7710
 Bethesda, MD  20892-7710
 Bethesda, MD  20817 (for express mail)
 
At the time of submission, two additional copies and all appendix
material must also be sent to:
 
 Ms. Toby Friedberg
 Division of Extramural Activities
 National Cancer Institute
 Executive Plaza North Building, Room 636
 6130 Executive Boulevard
 Bethesda, MD  20892
 Rockville, MD  20852 (for express mail)
 
It is important to send these additional copies to NCI at the time of
submission to DRG; otherwise the NCI cannot guarantee that the
application will be reviewed in competition with the other
applications received on or before the designated receipt dates.
 
Applications must be received by 2/18/98.  If an application is
received after that date, it will be returned to the applicant
without
review.  The Division of Research Grants (DRG) will not accept
any application in response to this RFA that is essentially the same
as one currently pending initial review, unless the applicant
withdraws the pending application.  The DRG will not accept any
application that is essentially the same as one already reviewed.
 
SPECIAL INSTRUCTIONS FOR PREPARATION OF THE
APPLICATION
 
Application Preparation
 
All applications must be submitted on the form PHS-398 (rev.
5/95).  Successful applications for each Network component will
be awarded as separate cooperative agreements to the sponsoring
institutions and will include the Terms and Conditions of Award
specified in this RFA.
 
Each individual application must contain a detailed budget for the
first 12-month period and a budget for the entire proposed project
period for direct costs.
 
All applications should describe the scientific and administrative
experience of key personnel and should include and follow the
PHS-398 form instructions for Biographical Sketches and Other
Support information.  On Page 2 of the PHS-398 form, in the
section entitled "Personnel Engaged on Project," it is imperative
that all applicants list all individuals and their institutions
participating in the scientific execution of the project in the
format
as specified including those with no requested salary support.  All
applicants must ensure that the list is complete using as many
continuation pages as necessary.
 
A key feature of this RFA is that it requires the Headquarters
application, submitted by the Network Chair, to list the BDMC
with which it is affiliated.  The BDMC application, submitted by
the Chief Statistician, must also identify the Headquarters with
which it is affiliated.
 
The specific application requirements are listed below for each
component:
 
Headquarters
 
The Network's proposed program of clinical trials should be
described in the application for support of its Headquarters.  The
application should characterize the Network's mission, its plans to
accomplish that mission, and present evidence of research
accomplishments by the Network's scientific leadership.  It should
specify the concrete research proposals of the Network, including
protocols for the initial studies the Network proposes to undertake.
It should outline the Network's strategy for each class or category
of investigation, including rationale and future plans; a clear sense
of direction should be evident.  In addition to its scientific
proposals, the Headquarters application should contain a
description of the Network's organizational structure, and the
operational procedures and policies to accomplish major Network
objectives and responsibilities.
 
RESEARCH PLAN FOR HEADQUARTERS
 
The following format is suggested for completing the "Research
Plan" section (see pages 19 through 23 of the PHS 398 application
brochure).  The "Research Plan" section is not subject to the page
limitations as stated in the form PHS 398.  However, the suggested
format and page recommendations are noted below.  The
application should be as concise as possible to ensure a thorough
review.
 
1.  Major Research Objectives (20 pages)
This section should concisely describe the Network's several major
research objectives.  This section should include plans for the
inclusion of women and minorities as research subjects in Network
studies.
 
2.  Organizational Structure (20 pages, including any
organizational charts)
This should include a clear description of the formal organizational
structure of the Network, including lines of authority and
responsibility, with particular attention to the relationship of the
organizational structure to the Network's major objectives.  The
organizational structure will include a number of scientific and
administrative committees, in addition to the two major functional
components (Headquarters and BDMC).  The committees will
have various research, quality control, and administrative
mandates.  Plans for interaction of the organizational elements
should be described clearly.  The proposed members of the
Network's leadership should be named, along with their
subspecialty affiliations.  Procedures for the selection of Network
leadership, for selecting and credentialing participating sites, and
for review of their performance should be described.
 
3. Research Strategies and the Scientific Committees (10 pages
each)
The Network's scientific leadership must articulate plans that
summarize its specific objectives and lines of investigation in each
area chosen for study.
 
For each scientific committee, the application should:
 
a. Briefly describe the major scientific goals, strategies, and
broad research areas that the committee will be concerned
with.
 
b. Identify the specific research questions that the committee
plans to address.  Summaries of protocols representing the
initial studies of each committee should be provided within
the body of the application; samples of the full protocols are
to be included as an "Appendix"
 
4. Developmental Fund (15 pages)
Justification and plans for the use of Developmental Funds should
be carefully described, including the procedures the Network will
use for allocating these funds to areas of particular opportunity
during the period of support.
 
5. Quality Control and On-Site Auditing (5 pages)
If responsibility for quality control and on-site auditing will
reside
in the Headquarters, these functions should be described in detail
here, along with the associated budget request. If they are to reside
in the BDMC, they should be described in the BDMC application;
in that case, the Headquarters application should indicate how the
operational leadership of the Network, located in the Headquarters,
plans to deal with results of audits that indicate the need for
corrective action. There should be clear evidence of close
collaboration between the two organizational units.
 
6. Network Administration (5 pages)
This section should address the major roles and responsibilities of
the Network administrative staff together with other matters of
relevance to the management of the Network.  It should describe a
system to ensure capable, efficient, and responsible management
by the Network's leadership, as well as ways to identify and solve
problems.  Applications should clearly document that the proposed
Network Chair has the appropriate experience to qualify as the
Network's leader.
 
7. Data and Safety Monitoring Committees (DSMC) (5 pages)
The application should describe the Network policies and
procedures regarding DSMCs.  It should include proposed
membership rosters of the committee(s), and procedures for
avoiding conflicts of interest, such as financial disclosure.
 
8. Group Policies and Procedures (5 pages)
The application should describe Network policies regarding
conflict-of-interest issues, the training of the Network
investigators, nurses and data managers/clinical research associates
regarding ethics in the conduct of clinical research, and procedures
in the event of scientific misconduct.  The application should
document any ongoing ethics training of Network participants,
collection of conflict-of-interest statements from relevant
members, and other efforts to employ these policies.
 
BUDGET FOR HEADQUARTERS
 
The Headquarters budget should be presented in logical, discrete
units, with specific budgets for each unit as well as the composite
Headquarters request.  The standard PHS-398 form pages 4-5 are
to be completed for each unit, with additional pages for budget
justification to be used when necessary.
 
A separate budget page and item entitled "Developmental Fund"
may be included.  The purpose is to provide the Network
leadership with resources to support new initiatives and special
high-priority projects.  The first year's plans for this
Developmental Fund must be carefully justified, and the Network's
process for allocating the funds in subsequent years clearly
described.
 
The following budget guidelines apply specifically to the
Headquarters and BDMC budgets; the categories refer to the item
entitled "Detailed Budget for Initial Budget Period" on (Page 4) on
the PHS Form 398 grant application kit.
 
1. Personnel
Precise justification for the amount of effort requested for each
position is essential.
 
  a. Scientific - research costs include the time and effort involved
in developing the research agenda and repertoire of protocols for
the Network, and analysis and publication of the results of
Network research in peer-reviewed journals. Costs for the
operation of scientific committees, where much of this work goes
on, is permitted. These committees will be associated with specific
areas of investigation described in the Headquarters application
and will have responsibility for overseeing the development of
research plans and specific studies for these areas. The budget
justification in support of each scientific committee should be
linked to their scientific activities. Peer review of the science of
these committees will assist the Network leadership in prioritizing
its research agenda and allocating its resouces.
  b. Data Management - research costs include the time and effort
involved in the central collection, computerization and analysis of
primary patient data; determination of eligibility; registration and
randomization; forms development; etc.
  c. Laboratory Investigations - research costs include the time and
effort related to additional laboratory investigations specific to
the
research goals of the project, i.e., not associated with conventional
patient care.
  d. Administrative - research costs include the time and effort
involved in the overall management of the Network's resources,
compliance with regulatory activities, quality assurance and study
monitoring procedures.
 
2.  Consultant Costs
Reasonable consultant costs are allowed, if the consultant is
contributing directly to the conduct or development of Network
research.  Most of a Network's consultant costs should appear in
the Headquarters budget.  Clear and quantifiable justification is
required.  These costs include travel, per diem, and consultant fees,
if applicable and within institutional policy.
 
3.  Office Equipment
Justification should include percent of time used for Network
business as well as necessity for purchase.  The amount of funds
requested should be based on the percent of usage.  Include only
those equipment items that are required to conduct Network
protocols.
 
4.  Supplies
Research costs include those related to communication and
information dissemination among Network participants.
Quantitative justifications based on actual use should be provided.
 
5.  Travel
The importance of meetings to the accomplishments of the
Network's research objectives is obvious, as is the necessity to
maintain careful control of the size of this budget item.  The budget
for travel must be itemized and justified.  It should include:
trips by the Network's leadership and investigators on behalf of the
  Network to the NCI and other national organizations where the
  results of the Network research must be represented or where
  Network research strategies are to be discussed;
travel for committee members to committee meetings held
  separately from regular Network meetings;
travel for persons on the Headquarters staff who must attend the
  Network's regular meetings;
a reasonable number of carefully justified trips for potential
  Network participants to attend the semi-annual meetings, in
  order to encourage participation and assure input from
  important segments of the imaging research community and
  potential collaborators (see above regarding Developmental
  Fund).
 
6.  Alterations and Renovations
These costs are not allowable.
 
7.  Other Expenses
Research costs include those relating to communication and
information dissemination among Network members.  Include here
costs of equipment rental and maintenance (copiers, telephones,
computers), postage, copying and printing, etc., justified
quantitatively on the basis of previous experience, where relevant.
 
8.  Consortium/Contractual Costs
Research costs include support to Network members who are
responsible for committees or laboratory investigations, for the
research costs related to approved clinical trials activities, or for
patient accrual.  These third-party costs may be presented as
consortium arrangements (for substantive programmatic work), as
subcontracts, or as reimbursements based on formulas.
 
If third-party costs are requested for consortium/contractual
participants, a separate detailed budget page, with appropriate
justification, must be provided for each arrangement.  Indirect
costs to consortium/contractual participants are included in the
direct-cost level for the Headquarters.  Networks are encouraged to
structure their organization in a manner which minimizes the
burden of indirect costs on the overall Network budget.
 
Reimbursement for patient accrual is to be based on formulas that
should relate to reasonable average costs incurred by participant
institutions, as well as prior performance, including accrual
adequacy and assessment of data accuracy and timeliness.  A
description of how the formula was determined, including a line-
item budget breakdown of the research costs, must be included in
the application.  In addition, the application should include a plan
for disbursement of funds that includes consideration of
performance and quality factors including eligibility and
evaluability rates; data accuracy and completeness; and quality of
on-site audits, etc.  The funds received by participating sites for
patient accrual should be subject to modification based on results
of the Network's performance reviews.  These costs should be
included in the consortium/contractual costs category of the
Headquarters budget.
 
Consortium arrangements and all other contractual arrangements,
including all mechanisms for reimbursement for patient accrual,
must be formalized in writing in accordance with applicable Public
Health Service policy requirements (PHS Grants Policy Statement,
revised 9/94, Page 8-17).  A statement that the applicant
organization and the collaborating organization have established or
are prepared to establish a formalized agreement that will ensure
compliance with all pertinent federal regulations and policies must
be included in the application.  Also include all pertinent
biographical sketches and a list of all other support for all
relevant
consortium participants.
 
Biostatistics and Data Management Center
 
The BDMC is funded through a separate cooperative agreement.
Thus, a separate application is required which should address
operational roles and responsibilities discussed under "Research
Objectives,"  (B) Organization.  It should describe in detail the
Network's data management practices and procedures, its quality
control and study monitoring methodology, and its analytical
techniques and resources.
 
RESEARCH PLAN FOR BDMC
 
The following format is suggested for completing the "Research
Plan" section (see pages 19 through 23 of the PHS 398 application
brochure).  The "Research Plan" section is not subject to the page
limitations as stated in the form PHS 398, but is limited to 50
pages total.  The application should be as concise as possible to
ensure a thorough review.  Wherever appropriate, narrative should
supplement (rather than duplicate or replace) standard manuals,
which should be supplied.
 
1.  Roles and Responsibilities - List the major objectives of the
Network's BDMC.
 
2.  Organization and Facilities - Describe the organization and
facilities to accomplish the complex tasks of central data
management, quality control, study monitoring, and data analysis.
 
3.  Data Management Policies and Practices - Describe the flow of
data following submission from the individual investigators.
 
4.  Quality Control - Describe procedures for quality control and
accuracy verification.
 
5.  Study Monitoring Procedures - Describe the Network's
standard methods for ongoing study monitoring, including
interactions with study chairs.
 
6.  Study Design and Data Analysis - Describe the Network's
routine methodologic practices (e.g., methods of sample size
calculations, choice of testing and estimation procedures, interim
analysis policies, early stopping procedures, etc.)  Include plans
for
the inclusion of women and minorities as research subjects in
Network studies.
 
7.  Partnership in Network Research - Describe the role and
contributions of the Network's statisticians to Network research.
The involvement of statisticians in designing studies should be
documented.
 
8.  Independent Research - Describe research being conducted by
the statistical office of the Network using Network resources,
including the data base.
 
BUDGET FOR BDMC
 
See budget guidelines in this RFA referring to the Headquarters.
The statistical and data management center budget should be
presented in logical, discrete units with specific budgets for each
unit as well as the total Center's request.  The standard PHS-398
form pages 4-5 are to be completed for each unit, with additional
pages for budget justification to be used when necessary.
 
Quality Assurance and Quality Control Programs
 
This section should be located within the Application of the
organization (Headquarters or BDMC) that will bear responsibility
for the function. The section (to be included in the "Research
Plan", and limited to pages) should describe procedures for
data verification. In accordance with the "NCI-CTMB Guidelines,"
the Network is required to conduct routine on-site audits of
participants in NCI-supported clinical trials. Describe the method
by which the Network will structure and execute this program in
conformance with NCI's guidelines. Also, describe the interactions
that will occur with NCI.
 
As with other parts of the Applications, the Budget should be
presented in logical, discrete units with specific budgets for each
requested element. Personnel, travel expenses, and computer
systems to accomplish these tasks must be carefully and fully
documented.  Budgets should include travel for protocol chairs and
others who must perform quality control functions away from their
home institution and travel for the on-site audit program. A
separate budget for each function should be prepared.
 
REVIEW CONSIDERATIONS AND CRITERIA
 
Upon receipt, applications will be reviewed for completeness by
DRG and for responsiveness by the NCI.  Incomplete and non-
responsive applications will be returned to the applicant without
further consideration.
 
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer-
review group convened by the NCI in accordance with the review
criteria stated below.
 
The peer review process may include a site visit to Network
facilities.  The Scientific Review Administrator is responsible for
all aspects of the peer-review process, and, if a site visit is
warranted, will negotiate with the Network chairperson the date,
duration, and content of the site visit.
 
Because of their interrelatedness, applications from both
components of the Network are prepared and submitted
simultaneously. For each pair of applications, the content of the
Headquarters application is evaluated first.  If the initial review
committee recommends the Headquarters application for further
consideration, the committee then assigns a priority score
representing the overall peer-review evaluation of the Network and
recommends a period of award (generally three to five years).  The
committee then evaluates the application of the corresponding
BDMC.  The committee also develops budgetary recommendations
for each scored application.  If a particular Headquarters
application is not recommended for further consideration (NRFC),
the application of the corresponding BDMC is not reviewed and
that particular pair of applications cannot be funded.
 
The review criteria employed by the site visit team and the initial
peer-review committee for each operational component are
summarized below.
 
Headquarters
 
1. Merit of Specific Research Plans - How meritorious are the
research plans, strategies, and protocols for each of the major areas
of study? Do they take maximum advantage of contemporary
scientific opportunities? Do they contain an appropriate balance of
innovative pilot studies and larger multicenter comparative trials?
Are there adequate plans in place for flexibly capitalizing on new
scientific opportunities as they arise?
 
2. Overall Network Priorities - Does the Network have appropriate
and effective processes in place for setting scientific priorities?
Are
the overall priorities of the Network appropriate?  Are its resources
well directed?
 
3. Key Personnel - Do the research experience and qualifications of
the Principal Investigator demonstrate understanding of the
imaging sciences, of the design, administration, and analysis of
multi-institutional clinical trials, and of relevant laboratory
studies?
 
4. Research Methodology - How well designed are the Network's
planned clinical trials?  Will their design allow clinically
important
conclusions to be drawn?
 
5. Patient Accrual - Is the participant membership of the Network
adequate to support the carrying out of the Network's scientific
agenda in a timely manner?
 
6.Timeliness of Study Completion - Will the Network be able to
carry out its planned studies in a reasonable period of time?  Will
intergroup collaboration be utilized when necessary to satisfy the
requirements for timely completion?
 
7. Efficiency of Study Development - Will the process of study
development proceed in an efficient and timely manner?  Do
mechanisms exist to ensure the rapid development and
implementation of important studies?
 
8. Developmental Fund Plans - Are plans for the use of any
developmental funds appropriate and consistent with the
Network's overall goals and priorities?  Will the fund be well
managed with appropriate oversight?
 
9. Network Structure and Administration - Will the Network be
well administered by the Chair and the Headquarters staff?  Do its
organization and infrastructure allow it to meet its major objectives
and goals?
 
10. Publication Plans - Has the Network developed plans that will
encourage and permit timely publication of research in quality
peer-reviewed journals?
 
11. Network Cohesion - Are the Network's organizational and
administrative plans likely to lead to a well functioning, cohesive
research group? Will the Network function as a cohesive research
team?
 
12. Interdisciplinary Coordination and Collaboration - Will there
be adequate interdisciplinary participation in protocol development
and design?  Do protocol investigators reflect the modalities
utilized?  Are there adequate plans for collaboration and interaction
with other clinical trials organizations and with industrial sources
of scientific and technological expertise?
 
13. Participants - Are the criteria for initial and continuing
participation in Network studies adequate?  Do the Network's
periodic evaluations of its participants emphasize both high-quality
recordkeeping and adequate patient accrual?
 
14. Patient Advocate Participation - Are there defined plans and
roles for patient advocates in the Network?  Have they been
included in the budget to attend Network meetings?
 
15. Adequacy of Plans for Recruitment of Special Populations - Do
plans include both genders and minorities and relevant subgroups
as appropriate for the scientific goals of the research? Are federal
guidelines for the inclusion of women and minorities as research
subject being followed?  Are there strategies outlined to increase
accrual of women and minorities to clinical trials? Plans for the
recruitment and retention of subjects will also be evaluated.
 
16. Facilities - Are the offices, computer support systems, and
overall patient-facility commitments adequate to ensure a smoothly
functioning Headquarters?  Are there any problems with the
structural layout that might serve as an impediment to a focused
and well-coordinated Headquarters?
 
17. Staff - Are the roles of the Headquarters staff adequately
defined to accomplish the goals of the Network?  Is there an
adequately committed staff to cover the multiple tasks of the
Headquarters?
 
18. Budget - Have costs for travel, office supplies, equipment and
data management been adequately justified?  Are detailed costs of
participants provided?  Are budgetary plans submitted for Network
meetings and consultant fees?
 
19. Advisory Panel - Are there processes or structures in place to
ensure that the decision-making and priority-setting of the Network
is likely to be flexible and free of conflicts of interest?
 
20. Protection of Human Subjects - Are suitable procedures in
place to assure the protection of research subjects in accordance
with applicable federal regulations?
Biostatistics and Data Management Center
 
This portion of the evaluation involves two facets: 1) the
performance and capabilities of the BDMC; 2) the Network's
integration of BDMC roles and responsibilities into the overall
research program.
 
1. Collaboration in Research - Will there be adequate statistical and
data management  collaboration in the development and conduct of
the Network's research?
 
2. Adequacy of Study Design - Is there evidence that the protocols
will be properly designed statistically?  Will the sample sizes be
adequate to detect realistic and medically important differences?
Will the assumptions be adequately justified?  Is the expected
accrual rate carefully estimated?  Are the designs used appropriate
for the study questions?  Are endpoint selections and sequential
monitoring plans adequately described and justified?
 
3. Data Management - Are data management procedures adequate,
appropriate, and consistent with accepted standards?  Are
procedures for the verification of data accuracy adequate?  Is there
clinical review of study data?
 
4. Statistical Analyses - Are analytical techniques, procedures, and
policies adequate, appropriate, and consistent with accepted
standards?  Is there evidence that past publications of the Network
leadership demonstrate thorough and state-of-the-art methodology,
awareness of problems of multiple analyses, and sufficient
independence and lack of bias of statistical collaborators?
 
5. Key Personnel - Does the research experience and qualifications
of the Principal Investigator demonstrate understanding of design,
administration, and analysis of multi-institutional clinical trials
in
imaging?
 
6. Independent Research - Is there evidence of innovation in the
development of novel designs and analytical approaches relevant to
imaging studies?
 
7. Computing Resources - Are computing resources adequate and
appropriate to support Network activities?
 
8. Facilities - Are the offices, computer hardware, and overall
parent facility commitment adequate to assure smooth and efficient
function?  Are there deficiencies in the structural layout which
might serve as an impediment to coordination of Network research
efforts?
 
9. Staff - Are the roles of the staff adequately defined to
accomplish the goals of the Network?  Is there an adequate number
of personnel to meet the assigned tasks?
 
Quality Assurance and Quality Control Programs
 
These criteria should be applied to the QA/QC section of
whichever application (Headquarters or BDMC) it is included in.
 
1. Do appropriate quality-assurance and quality-control programs
exist, including on-site audits that assure high-quality research and
patient safety?
 
2. Have costs for the on-site audit plan been accurately detailed?
Is
there sufficient funding allotted to carry out the multiple quality-
control tasks required?
 
NETWORK CONSTITUTION AND BYLAWS
 
The proposed Network Constitution and Bylaws and the Network's
Policies and Procedures must be reviewed and approved by the
Associate Director, DIP.  This document is not to be submitted
with the application, but must be submitted and approved before an
award can be made by NCI.
 
AWARD CRITERIA AND DATE
 
Applications recommended by the National Cancer Advisory Board will
be
considered for award based upon (a) 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 Terms
and
Conditions of Award.  The anticipated date of award is December,
1998.
 
EVALUATION OF THIS INITIATIVE
 
The organizational structure and broad functional parameters
stipulated for the Network by this RFA are certainly not the only
ways to support a national clinical trials program in imaging.
Before deciding whether this initiative should be reissued,
therefore, the NCI wishes to have an assessment of the
effectiveness of this mechanism over the first few years of its
operation. Accordingly, approximately 3 1/2 years following the
first-year award date (in the event of five-year awards), the
leadership of the Network and the staff of NCI's Diagnostic
Imaging Program will present an assessment of the Network's
achievements to the NCI's Board of Scientific Advisors (BSA).
The BSA will pay particular attention to the following aspects of
Network functioning:
 
Has the research agenda of of the Network taken appropriate
  advantage of available scientific opportunity?
Are the Network's processes for decision-making, scientific
  prioritization, protocol generation, and study activation
  effective and efficient?
Has the Network accrued to activated studies with appropriate
  speed?
In comparison with the experience in past years, has there been a
  greater variety of clinical approaches tested and a more
  satisfactory translational research thrust in clinical imaging
  since the implementation of this initiative?
Is the nature of the Network's scientific agenda and activities
  sufficiently productive to suggest that imaging technology
  assessment is best served by continuing an activity of this kind,
  or can the necessary work be accomplished better or more
  efficiently by other means?
 
On the basis of its evaluation the BSA will advise the NCI on
whether the initiative should be continued and recompeted after the
first project period is completed. Note that this assessment is
entirely separate from the formal peer-review process by which any
applications in response to a reissued RFA will be evaluated.
 
INQUIRIES
 
Written and telephone inquiries concerning this RFA are
encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.  Direct inquiries regarding
scientific and/or administrative issues to:
 
Anne Menkens, PhD
Diagnostic Imaging Program
National Cancer Institute
Executive Plaza North, Room 800
6130 Executive Boulevard
Bethesda, MD 20892
Rockville, MD 20852 (if using express mail)
Telephone
FAX
e-mail menkensa@dtpepn.nci.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Crystal Wolfrey
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Boulevard
Bethesda, MD 20892
Rockville, MD 20852 (if using express mail)
Telephone: 301-496-7800 Ext. 282
FAX: 301-496-8601
Email: wolfreyc@gab.nci.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.395, Cancer Treatment Research.  Awards are
made under authorization of the Public Health Service Act, Title
IV, Part A (Public Law 78-410, as amended by Public Law 99-158,
42 USC 241 and 285) and administered under PHS grants policies
and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and to promote the non-use of all
tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the
American people.
 
In addition, Public Law 103-227, the Pro-Children Act of 1994,
prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library,
day care, health care, or early childhood development services are
provided to children. This is consistent with the PHS mission to
protect and advance the physical and mental health of the
American people.
 
.

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