RFA-CA-07-505: The American College of Radiology Imaging Network (ACRIN) (Limited Competition U01)

Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH) (http://www.nih.gov )

Components of Participating Organizations
National Cancer Institute (NCI) (http://www.cancer.gov)

Title: The American College of Radiology Imaging Network (ACRIN) (Limited Competition U01)

Announcement Type
This is a modification and reissue of a limited competition RFA-CA-03-502, which was released on December 19, 2002.

Request For Applications (RFA) Number: RFA-CA-07-505

Catalog of Federal Domestic Assistance Number(s)
93.226, 93.394, 93.395, 93.396

Key Dates
Release Date: February 9, 2007
Letters of Intent Receipt Date(s): March 10, 2007
Application Receipt Date(s): April 10, 2007
Peer Review Date(s): June/July 2007
Council Review Date(s): October 2007
Earliest Anticipated Start Date(s): January 2008
Expiration Date: April 11, 2007

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The Cancer Imaging Program, Division of Cancer Diagnosis and Treatment, the National Cancer Institute (NCI), invites applications for a limited competition Request for Applications (RFA) for the continued support of a unique, multi-center imaging network -- the American College of Radiology Imaging Network (ACRIN; hereafter referred to as the “Network”).
The overall objective of this limited competition RFA is to improve the use of imaging in cancer research and cancer care management through further support for the activities of the Network. The Network should continue to focus on investigator-initiated research involving key aspects of imaging technology assessment in oncology. Specific goals for the Network include:

Provision of a flexible organizational structure. The multi-disciplinary, scientific core participating institutions will continue efforts to support a meaningful and continuous interaction with the oncology and imaging science communities. This interaction will allow the Network to maintain and improve on participation in a fully integrated NCI Clinical Trials System and continually improve the quality of imaging science and its impact on cancer research.
Provision of core facilities to support research activities.
Conduct of clinical imaging science research in a full spectrum of relevant scientific areas of interest to both the oncology and imaging science communities.
Conduct of biostatistical methodological research specific for imaging trials supported by the Network.
Sharing research resources through compliance with and participation in the Cancer Biomedical Informatics Grid (caBIG). The Network will plan for appropriate analytical algorithms and bioinformatics software tools, ontologies, and data ultimately leading to the development of imaging informatics standards in all clinical trials.

Collaboration with the broader oncology community and NCI research efforts. This effort includes enhanced integration of the oncology perspective into Network activities, as well as establishing a culture for imaging research in the broader radiology community.
The Cancer Imaging Program anticipates awarding two competing U01 Cooperative Agreement grants under this limited competition re-issuance for continuation of the Network.
The funds set aside for two anticipated ACRIN U01 awards are $7,300,000 in total costs for the first year (FY2008); the two awards will made for up to 5 years each.
Eligible organizations include the current recipients of the ACRIN awards, which are the American College of Radiology-Philadelphia Headquarters and the Brown University-Biostatistics and Data Management Center.
The eligible applicants are expected to submit two linked applications (Network Headquarters application and Biostatistics and Data Management Center application). Both applications will be reviewed together and will receive a single score.
Eligible principal investigators: Any individual from eligible institutions with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups, from disadvantaged backgrounds as well as individuals with disabilities are always encouraged to apply for NIH support.
More than one Principal Investigator (PI), or multiple Principal Investigators (PIs), may be designated on each U01 application.
See Section IV.1 for application materials.
Telecommunications for the hearing impaired is available at: TTY 301-451-0088.

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
  1. Research Objectives

Section II. Award Information
  1. Mechanism(s) of Support
  2. Funds Available

Section III. Eligibility Information
  1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
  2. Cost Sharing or Matching
  3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
  1. Address to Request Application Information
  2. Content and Form of Application Submission
  3. Submission Dates and Times
    A. Receipt and Review and Anticipated Start Dates
      1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
  4. Intergovernmental Review
  5. Funding Restrictions
  6. Other Submission Requirements

Section V. Application Review Information
  1. Criteria
  2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
  3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
  1. Award Notices
  2. Administrative and National Policy Requirements
    A. Cooperative Agreement Terms and Conditions of Award
      1. Principal Investigator Rights and Responsibilities
      2. NIH Responsibilities
      3. Collaborative Responsibilities
      4. Arbitration Process
  3. Reporting

Section VII. Agency Contact(s)
  1. Scientific/Research Contact(s)
  2. Peer Review Contact(s)
  3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to provide continuing support for the maintenance and further development of the unique, multi-center imaging network – the American College of Radiology Imaging Network (ACRIN; hereafter referred to as the “Network”). The Cancer Imaging Program (CIP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI), invites applications for this limited competition Request for Applications (RFA) from eligible applicants. The program will fund, up to a maximum of 5 years, two linked U01 cooperative agreement awards to conduct rigorous, generalizable clinical trials essential to the improved use of imaging in cancer research and cancer care management.

The Network will continue to perform a broad spectrum of multi-institutional clinical trials in diagnostic imaging and image-guided therapy related to cancer. Similar to the treatment cooperative groups supported by DCTD, this Network will generate new trials in areas of high scientific opportunity relevant to both the oncology and imaging science communities. 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. The Network’s apparatus for conducting trials will continually be in place, thus providing a mechanism with considerable flexibility for allocating resources quickly to the testing of promising new imaging devices or agents, as well as promising new applications, in both limited-institution pilot studies and large multi-center settings.

ACRIN funding is designed to: (1) support a flexible organizational structure that will support a meaningful and continuous dialog with the oncology and imaging science communities, to integrate imaging into the NCI Cancer Clinical Trials System; (2) provide unique core facilities; (3) conduct clinical imaging science research in relevant scientific areas of interest to both the oncology and imaging science communities; (4) contribute to the integration of treatment protocols with modern molecular diagnostic and imaging and image-guided therapeutic techniques; (5) conduct biostatistical methodological research specific for imaging trials; and (6) develop and share research resources and comply with and participate in the Cancer Biomedical Informatics Grid (caBIG).

Two awards are anticipated for: (i) the Network Headquarters and (ii) Biostatistics and Data Management Center. The eligible applicants are expected to submit two linked applications for the respective components. Both applications will be reviewed together and will receive a single score.

Background

Fostering the development of imaging assessment of tumor biology in parallel with our advancing molecular understanding of the malignant state is an important priority for cancer medicine. Imaging cuts across the strategic objectives of the NCI focused on preempting cancer at every opportunity. The opportunity to further improve imaging technologies through imaging research, as part of an NCI transdisciplinary systems approach, will be instrumental in the development of an understanding of the causes and mechanisms of cancer; the expansion of the number of effective cancer prevention strategies; the identification of predictive factors that will assist in developing more personalized and successful treatment regimens; and contribute to the understanding of the factors that influence both cancer outcomes and quality of life. To support these goals and further improve clinical trials, the NCI funded the American College of Radiology Imaging Network (ACRIN).

In response to a competitive RFA issued in 1997, awards to ACRIN were approved in September 1998 and funding began March 1, 1999. ACRIN is a consortium of two linked U01’s (U01CA80098 [Headquarters -- Bruce Hillman, M.D., Chairman of Radiology at the University of Virginia, Principal Investigator] and U01CA79778 [Biostatistics and Data Management Center -- Constantine Gatsonis, Ph.D., Brown University, Principal Investigator]). It was created to establish a multi-institutional network for the systematic study and facilitation of the development and rigorous assessment of technologies relevant to imaging of cancer. The original RFA called for the conduct of expeditious, reliable, and comprehensive evaluations of new imaging modalities compared to standard techniques. It was envisioned that this cooperative group would provide for clinical testing of promising imaging technologies and/or devices as they emerged in order to derive appropriate preliminary and definitive information that could guide further phases of testing for established modalities.

ACRIN has succeeded in establishing an intrinsically collaborative, multi-disciplinary Network composed of physicians, scientists, methodologists, industry representatives, and patient advocates that not only achieved the goals of the original RFA, but is poised to address the scientific challenges of the NCI and oncology community in the future, thus improving both the quality and utility of imaging and image-guided therapeutics in oncologic clinical trials. ACRIN’s accomplishments are linked to their responsive, unique infrastructure, clear and relevant scientific plan, and focused quality assurance process. Their current state of organizational maturity is evidenced by their ability to provide multi-disciplinary, multi-institutional, clinical research that provides pertinence, validity, reliability, and generalizability to an extent not possible with single-institutional or observational studies while simultaneously addressing special challenges of imaging clinical trials in oncology (i.e., fast-developing technologies, quality control, operator dependence, expense, and recruitment hurdles). The Network has: established a broad collaborative base of ongoing relationships; streamlined the concept/protocol submission and evaluation processes to more fully involve scientific committees and expand sources of relevant trial ideas; enhanced the alignment of their activities with the oncology community by reorganizing its committee structure; become a member of the caBIG Imaging Workspace; established imaging core laboratories; contributed to the Oncology Biomarker Qualification Initiative (OBQI) to facilitate the development of biomarkers and evaluate their efficacy for predicting and monitoring response to therapy; created a Digital Imaging Network/Image archive; and, in collaboration with the Academy of Molecular Imaging (AMI) and the American College of Radiology (ACR), developed a clinical registry to assess the impact of positron emission technology (PET) on cancer patient management.

Objectives and Scope

The overall objective of this limited competition RFA is to improve the quality and utility of imaging in cancer research and cancer care through continuing support of a unique, multi-center imaging network -- The American College of Radiology Imaging Network (ACRIN). The Network will serve as an instrument for expert clinical evaluation of discoveries and technological innovations relevant to imaging science as applied in clinical oncology. The Network will continue to be focused on investigator-initiated research involving key aspects of imaging and image-guided therapeutic technology development and assessment in oncology. Anticipated benefits include, but are not limited to: (1) advancing imaging science as it applies to cancer; (2) improving appropriateness of cancer detection, diagnosis, and care; (3) incorporating imaging and image-guided therapeutic technologies into therapeutic cancer trials; (4) developing new techniques (imaging, quantification, analysis methods, etc.) that will improve cancer detection, diagnosis, and treatment; (5) facilitating imaging technology development and translational research in academia and industry; (6) elevating the role of imaging in the efforts to reduce cancer-related suffering and death; and (7) developing improved clinical trials methodology specifically relevant to imaging and image-guided therapies in cancer.

Specific goals for the Network include:

Provide a flexible organizational structure - Through the continued support and refinement of the established organizational structure. The scientific core member institutions of the group will continue to be a source of multi-disciplinary expert investigators from centers of academic excellence in clinical imaging sciences. These centers will be supplemented by the inclusion of additional institutions (academic or community-based) and representative subject experts in associated scientific and medical fields to best enable significant and adequate accrual within multi-center efforts. The Network will continue efforts to develop a meaningful and continuous dialog with the oncology community. This practice will allow the Network to maintain and improve on participation in a fully integrated NCI Clinical Trials System and continually improve the quality of imaging science and its impact on cancer research.
Provide core facilities to support research activities - The Network will provide central logistical, informatics, data management and archive, and financial management support and facilities to participating members and sites. These support and core facilities are required to ensure that imaging clinical trials will be conducted in a safe, efficient, and cost-effective manner. Further, such support will ensure that the trials are completed and the resulting data will be trustworthy.
Conduct clinical imaging science research, including: identifying and utilizing appropriate imaging tools in targeted surveillance, diagnosis, response to therapy and therapeutic trials; evaluating new imaging probes and methodologies in multi-institutional settings; enabling access to the images and associated data in an electronic format that is caBIG compliant; facilitating the evaluation of image-guided interventions; and developing standardized quantitative methods to produce evidence-based monitoring of response to therapy in clinical trials. Further, the Network will contribute to the development of publicly available electronic repositories of relevant and current imaging data in clinical trials that will serve as key databases for the development of future software tools and computer-aided methodologies.
Conduct biostatistical methodological research specific for imaging trials by: 1) providing support and methodological leadership to ACRIN investigators in the design, development and implementation of network studies; 2) coordinating the design, development and implementation of electronic data collection forms and procedures including pilot testing of data collection procedures and protocol implementation; 3) performing and supporting data collection and developing and maintaining a primary study database at the Data Management Center in Philadelphia for every ACRIN protocol; 4) continually monitoring, verifying, and ensuring the capture of good quality data, including checks of accuracy, completeness, and timeliness and guaranteeing the integrity of the ACRIN database; 5) continually monitoring and verifying compliance to all aspects of the protocol and to design and implement rigorous quality control for imaging and associated studies while providing methodological expertise for the design and implementation of a process for performing site audits; 6) designing and performing interim and final analyses of the data and subsequently generating relevant reports; 7) providing methodological leadership and support in summarizing and interpreting study findings and in preparing abstracts and manuscripts; 8) addressing methodological issues arising in the design and analysis of ACRIN studies and carrying out research on statistical methodology for the evaluation of imaging in cancer diagnosis and management; 9) monitoring quality of data and site performance; and 10) continuing to provide training and education of ACRIN research associates.
Share Research Resources by reporting data from ACRIN clinical trials to the NCI in a manner compliant with the standards specified by the NCI Clinical Trials Working Group (CTWG) and the Cancer Biomedical Informatics Grid (caBIG). These standards include the use of controlled vocabularies and common data elements as defined through caCORE (http://ncicb.nci.nih.gov/core) and must be submitted through reporting tools approved by the NCI. Specifications for the NCI trials data repository have been determined in conjunction with the NCI Program staff, the CTWG and caBIG communities. Up-to-date information and details about the reporting of the clinical trials data can be found at http://integratedtrials.nci.nih.gov and at http://caBIG.nci.nih.gov. The Network will plan for appropriate analytical algorithms and bioinformatics software tools, ontologies, and data management that will ultimately lead to the development and utilization of imaging informatics standards in clinical trials.

Overview of Network Organization

General Considerations

Under the cooperative agreement U01 mechanism, the Network and NCI share responsibility for ensuring that the highest priority and relevant research is efficiently conducted within the limits of available research support and finite research resources. It is essential that research to be conducted involves the use of imaging and image-guided therapeutic approaches to address original questions of relevance to clinical oncology. Each research project should use sound methodology of established feasibility to provide answers to study questions in a reasonable time. Whereas all imaging and treatment modalities, as well as cancer sites are appropriate for investigations, there is no requirement for research activity of the Network in every modality, image-guided treatment, and/or disease site. Proper integration of the relevant applied clinical oncology perspective is essential. Standards of quality control must be as rigorous as those applied to therapeutic cancer trials.

The Network shall be governed by a written Constitution and By-laws, approved by NCI prior to award, which should describe: criteria for inclusion and exclusion of participants; procedures for selecting Network leadership and for adapting the composition of Network leadership; adjustments in response to changes in scientific opportunities; and other details of governance. A Chair, who is ultimately responsible to the Network and to the NCI for the content and conduct of the Network’s research program, shall lead the Network. However, more than one PI, or multiple PIs, may be designated on each U01 application (see Section III. Eligibility Information, sub-section 1.B. Eligible Individuals for more information). The application should describe the process by which the Network Chair was selected for this funding period and the policies and procedures that will govern the maintenance and transition of this key position in the future. Beyond these general requirements, the structure and management of the Network are the responsibility of the Network’s leadership.

The Network will maintain an organizational structure that provides for administrative and scientific oversight of all network activities. 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 and relevant NCI staff for their ability to contribute to the particular trials in the Network’s research repertoire. The Network should be organized in such a way that it has the flexibility to recruit institutions that best suit its evolving scientific plan. The Network can decide whether or not to have fixed or variable membership.

The Network of expert investigators established by ACRIN should continue to provide, in a timely manner, objective, reliable assessments of the relative merits of imaging and image-guided therapeutic methodologies applied to cancer. Where appropriate, any such evaluation should include estimates of the relative cost-effectiveness of diagnostic interventions and of their impacts on quality of life. Partnerships with industry to generate reliable evidence on the medical worth of its products, their safety and effectiveness, and their relative cost-effectiveness are encouraged. Similarly, collaborations with the technology-assessment and standardization activities of third-party payers and regulatory agencies (Centers for Medicare & Medicaid Services [CMS], Food and Drug Administration [FDA], etc.) and other NCI divisions are also encouraged. The development of improved clinical imaging trials methodology for the evaluation of diagnostic devices and agents 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.

The Network will broaden the type and degree of integration of the clinical oncology perspective into their activities. Activities considered to be responsive may include, but are not limited to, the following:

(1) Inclusion of clinical oncologists on the Network Steering Committee and External Advisory Panel;

(2) Active, early involvement of clinical oncologists in development of Network protocols;

(3) Naming of clinical oncologists as Principal Investigators (PIs) or co-PIs on Network trials;

(4) Active solicitation on a regular basis (perhaps annually) from each of the NCI-funded therapy cooperative groups of a short list of imaging questions of highest priority to each respective group;

(5) Active participation in NCI Clinical Trials Cooperative Groups inter-group activities;

(6) Increased number of presentations on the Network scientific goals and objectives, as well as policies for collaboration, data sharing, and publication at oncology-centric scientific meetings, academic institutions, industry forums, and other Federal agencies;

(7) Active participation in the NCI Disease Site Steering Committees, Clinical Trial Working Group, and Translational Research Working Group activities; and

(8) Development of a formal concept/protocol development process (similar to that developed by the Network Advocacy Committee) that requires formal, written clinical oncology review prior to being reviewed by the Protocol Review Committee (PRC) of CTEP.

The Network will provide for the education and training of imaging researchers in methods and procedures to develop and conduct rigorous, multi-institutional clinical trials of medical imaging technologies and therapeutics. The Network will play a significant role in the education of members of the radiology community in terms of their activities, policies, and procedures; the importance of clinical trials; and will actively participate in the establishment of a process to disseminate the standard operating procedures for executing and documenting image acquisition, management, and analysis.

Scientific plan, Research Plans and Need for Flexibility in Organization and Scientific Leadership

The scientific leadership (beginning at the level of Scientific Committees) of the Network will develop, articulate and follow a comprehensive, integrated, strategic research plan in consort with relevant oncology and imaging scientists and NCI staff. The purpose of this plan is to focus attention on long-term goals and to aid the Network in prioritizing competing research ideas within the Network Scientific Committees and the imaging and oncology communities. The Network’s scientific research agenda will consist of a robust portfolio of well-designed, limited-institution feasibility studies and large-scale, multi-institutional controlled trials. It is essential that the Network identifies and concentrates its energies on the most promising scientific opportunities. The Network will develop, articulate and follow a strategic plan that will outline research priorities with associated strategic budgetary formulations. The plan should include both short-term and long-term goals, as well as a balanced and interrelated program of small developmental and feasibility studies, larger pilot trials, and large-scale, multi-center efforts. Network leadership is responsible for finalizing and establishing its strategic research plan, and assuming responsibility for its execution and periodic evaluation. Both the External Advisory Committee and internal committees will be involved in the periodic evaluation of the Network strategic research plan.

Applications responsive to this RFA should include a process by which the Network proposes to develop, execute, and evaluate its strategic scientific research plan (including management of resources) and how both components (Headquarters and BDMC) will contribute. The process for the development, execution, and evaluation of the plan and specific plans for subject areas will be a major focus of the application review process.

The Network will, under the direction of the Chair or Co-Chairs, maintain an organizational structure that provides efficient development, implementation, and monitoring of the overall Network strategic scientific research plan, including strategic research resource management. The ACRIN External Advisory Panel members will review and provide periodic written comments on the strategic plan.

Network Scientific Committee Structure, Prioritization of Research, and Efficiency of Study Development

Network executive leadership is responsible for providing a stable environment for the development and conduct of good imaging clinical trails and for managing the overall Network research resources. Leadership must prioritize the research plans and protocols of each Scientific Committee in the context of the Network’s overall scientific strategic plan.

The Network’s scientific committee structure (currently including five Disease Site Committees, Imaging Core Lab, and Informatics Committee) should continue to be organized around broad subject areas within the imaging field and closely aligned with the oncology research community. However, the strategic research plan in response to scientific opportunities in both the imaging and oncology communities should guide the number and identity of the committees themselves. Neither the committee structure nor the membership of the scientific committees should be regarded as fixed and unchanging in time.

In addition to the Scientific Committee structure, the Network will maintain two critical ancillary committees, which are as follows: (1) an active Advocacy Committee to ensure the integration of consumer advocates in concept / protocol development and the conduct of Network trials -- the Network is encouraged to support the advocacy committee in the promotion of the understanding and integration of imaging in cancer therapeutic trials; and (2) an active Special Populations Committee ensuring that all Network trials will promote the inclusion of special populations (i.e., minorities and other underrepresented/underserved populations variously distinguished by race, ethnicity, gender, age, socioeconomic status, geographic location, occupation, and education in Network clinical trials). The Network is encouraged to participate with NCI initiatives focused on overcoming cancer health disparities.

External Advisory Panel

To ensure that the Network’s scientific leadership and committee structure is adequately responsive to the most promising opportunities in both the fields of imaging science and oncology, 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 External Advisory Committee comprised of experts not directly involved in the research activities of the Network. Appointment to this Advisory Committee will be by mutual agreement between the Network Chair and the NCI represented by the Chief, DIB/CIP/DCTD/NCI. However, in order to maintain the largest possible reviewer pool for this RFA, applicants should not propose specific potential members of the Advisory Group and should not contact potential members prior to NIH review of application.

Membership in the External Advisory Committee will be drawn from the broad communities of oncology, imaging science expertise, industry (both pharmaceutical and device), and other relevant government agencies. Members will serve terms of 3 years and may be re-appointed. Membership in Network committees will be drawn from the broad community of expertise in oncology and imaging science as well. However, both the committee structure of the Network and the membership in individual scientific committees may change with time as the scientific opportunity warrants.

The External Advisory Panel will meet periodically (at least once per year) to monitor the progress of the Network towards meeting its strategic goals and objectives. A written critique assessing the progress to date will be provided annually to the Network chair and to the NCI.

Flexibility

In addition to maintaining a flexible scientific core organization, it is essential that the Network be flexible enough to permit creative investigation in light of unexpected opportunities. The potential to respond quickly to promising data and innovative ideas is an important facet of the collaborative agreement with NCI. Therefore, the Network should prepare to be able to modify research plans when relevant clinical oncology or imaging science data warrant such an adjustment.

Collaboration with Cancer Imaging Program Staff and Other NCI Staff

NCI CIP staff members assess certain clinical research trials from the perspective of all scientific opportunities competing for support and in the context of established national research priorities. Because of the major effort and commitment of resources required to develop and successfully mount definitive stage III or Phase III trials the Network should involve NCI CIP staff and, as appropriate, NCI disease-specific Scientific Steering Committees, NCI staff from CTEP, and other NCI staff, in the planning of such clinical trials at the earliest possible opportunity. The Network should collaborate with staff from other branches of the NCI on particular clinical research trials, as needed.

The Network is encouraged to collaborate with other NCI-funded programs and investigators (e.g., NCI Cancer Centers, Clinical Trials Cooperative Groups, Specialized Programs of Research Excellence [SPORES], early clinical trials networks, and R01 and P01 investigators). These collaborations may include, but are not limited to: advancing research ideas from feasibility studies to Phase III or stage III trials; providing correlative science services for large, multi-site studies; and participating in multi-site trials conducted throughout the NCI-supported clinical trials system. These types of collaborations should be considered as positive accomplishments at the time of peer review.

Conduct of Network Clinical Research

The Network should ensure that Good Clinical Practice (GCP) – an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects -- is followed by all sites and investigators within the Network. Information on GCP standards in Food and Drug Administration (FDA)-regulated clinical trials is provided at http://www.fda.gov/oc/gcp/default.htm.

The Network must have a detailed Quality Control and Quality Assurance plan. Systems must be in place to assure protocol adherence in the administration of protocol-prescribed intervention and therapy and in the uniform collection of data. Vigilance to detect honest errors, whether systematic, as well as data falsification, is especially important to imaging clinical trials since independent replication of most trials is not feasible.

Selection of Investigator-Participants and Study Sites

The Network will continue to provide a flexible organizational structure specifically designed to facilitate the inclusion of expert investigators and sites and the inclusion of appropriate participant populations as required for the rigorous assessment of both emerging and standard imaging technologies as they pertain to cancer detection and response to treatments and therapies.

The Network will maintain policies and procedures for credentialing participating sites and investigators 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, eligibility, inclusion of special populations, data accuracy and timeliness, protocol compliance, procedures for tracking and follow-up of participants, and audit results.

Capabilities and Characteristics of the Network

In order to accomplish research objectives set forth in the Network’s strategic scientific research plan, the Network should have the following capabilities and characteristics: visionary and experienced scientific leadership; ability to accrue large numbers of patients with cancer to randomized clinical trials; capability to perform limited-institution pilot studies of new imaging modalities, devices, or agents, preparatory to and in addition to multi-center randomized trials; a statistical office led by individuals with experience in designing, conducting, and analyzing clinical trials; statistical capability to use 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 (e.g., cost-effectiveness and quality of life); ability to conduct research on innovative designs and analytical approaches relevant to imaging and image-guided therapeutic studies; an internal site-performance review program that monitors the adequacy of accrual, protocol compliance and the quality of record-keeping; capability of handling regulatory responsibilities such as investigational device exemptions (IDE) and investigational new drug (IND) applications to the FDA, and drug shipments and handling; capability of providing quality assurance and quality control programs that ensure both patient safety and high quality of research data; ability to integrate members of the patient advocate community into appropriate network committees and activities; and ability to integrate members of the special populations community into appropriate network committees and activities.

Functions and Responsibilities

The Network’s programmatic responsibilities for the conduct of the research supported by these U01 agreements are described below. Certain responsibilities and guidance can be found in the NCI Clinical Trials Policy, the Investigator’s Handbook (which is entitled “A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis, NCI”). Cancer Imaging Program Guidelines for Cooperative Groups are currently under development to specifically provide guidance unique to the imaging U01 Cooperative Group -- ACRIN.

The Networks’ two major organizational components will have the following responsibilities:

Headquarters. The Network’s Chair or Co-Chairs will directly coordinate all the scientific and administrative activities related to the operations of the Network in coordination with and support of the Biostatistics Data Management Center (BDMC). The Chair will serve as Principal Investigator (PI) on the Headquarters’ award and implement the Network’s scientific and administrative policies. The Headquarters will provide executive leadership, scientific direction, and day-to-day administrative management of the Network.

Specific roles and responsibilities of the Headquarters include the following:

a. Develops, manages, and supports the overall organizational structure of the Network, including constitution, by-laws, and Standard Operating Procedures (SOP);

b. Provides logistical and financial support to the Network scientific and administrative committees, monitors their productivity, and provides for the election or appointment of their leadership;

c. Manages overall resources (coordinating resource allocation, assuring allocation to priority projects in alignment with the strategic scientific research plan and maintenance of a high degree of productivity from participants in coordination with the BDMC);

d. Provides appropriate public relations and communications support to participating investigators and sites in coordination with the NCI’s Office of Communications and Education, Press Office, and Office of the Director, as needed -- this support will [include the development of communication and dissemination of research results plans for individual trials when appropriate and in the interest of public health;

e. Develops and ensures compliance to 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;

f. Supports the evaluation of promising ideas for research projects to be incorporated into strategic scientific plans and specific scientific committee research plans. This aspect includes the solicitation of research ideas from the scientific community, and prioritizing these ideas, and, subsequently, the most promising ideas are then incorporated into the Strategic Scientific Plan for further development/implementation. Support is also provided for the development of quality metrics to evaluate the various phases of clinical trial protocol development and execution generating from these research ideas, and for assembling and maintaining a roster of qualified participants.

g. Establishes a Data and Safety Monitoring Board (DSMB) for all clinical trials that is independent of study leadership, is free of conflicts of interest, and has formally documented policies and procedures approved by NCI;

h. Develops and ensures compliance with policies and procedures for the selection and credentialing of participating sites and for all aspects of the conduct of Network trials and activities;

i. Conducts periodic reviews 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. Provides logistical and organizational support to the DSMB;

k. Develops procedures for study monitoring to assure compliance with protocol design and regulatory requirements concerning the use of investigational devices and drugs, the reporting of adverse events, and the protection of human research subjects. This medical review should be coordinated with the quality assurance and quality control programs of the Network;

l. Provides and encourages logistical and resource 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, encourages and provides resource support for the inclusion of, special populations (i.e., minorities and other underrepresented/underserved populations variously distinguished by race, ethnicity, gender, age, socioeconomic status, geographic location, occupation, and education) in Network clinical trials;

n. Coordinates the development of the details of research studies, including definition of objectives and approaches, planning, implementation, and analysis as well as publication of results, interpretations, and conclusions of studies;

o. Establishes procedures for development and submission of Network studies/protocols to the CTEP Protocol and Information Office (PIO) and CIP in a timely fashion for review and approval by NCI;

p. Develops and implements standards for imaging protocol formatting;

q. Ensures internal Network and NCI review and approval of protocol concepts, final protocol documents, (including information required in PHS 398, Section E. Human subjects), informed consents, and study amendments; advises NCI of changes in protocols or protocol status per NCI guidelines )http://ctep.cancer.gov/handbook/index.html and http://ctep.cancer.gov/index.html);

r. Provides guidance to participant institutions regarding clinical trials practices, including ethical issues involved in clinical research and conflict-of-interest considerations;

s. Ensures compliance with all applicable Federal regulations concerning the conduct of human subjects research. Policies and guideline to be addressed include, but not limited to the following:

1. Office for Human Research Protection (OHRP) Assurances http://www.hhs.gov/ohrp/ and http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

2. Institutional Review Board (IRB) review of Network Protocols. Headquarters must assure that each Network protocol is reviewed and approved by each Network participating site’s IRB prior to patient entry, and assure that each protocol is reviewed annually by the IRB so long as the protocol is active.

3. Assuring appropriate informed consent: Headquarters must have procedures in place to ensure that each participating site is trained and understands the policies and procedures relevant to ensuring that participants are enrolled on studies with appropriate informed consent per NCI/NIH policy and federal regulations.

4.Refer to Section VIII. Other Information Required Federal Citations of this document.

Biostatistics and Data Management Center (BDMC)

The Network’s statistical and data management staffs are collaborators integral to all stages of study development, conduct, analysis, and reporting. The BDMC must:

a. Have a defined organizational structure and management plan with clearly defined roles and responsibilities for BDMC staff.

b. Have written Standard Operation Procedures (SOPs) specifying all aspects of data management, study monitoring, and data analysis for Network trials. The SOPs should include plans for training Network investigators and CRAs and site investigators about their responsibilities for data management and study monitoring.

c. Agree to abide by the Constitution and By-laws of the Network.

d. Help the Network develop the statistical research design and analysis plan for Network studies as well as for providing statistical analysis, interpretations and conclusions in regard to study data. In addition, the BDMC is responsible for developing common data elements specific to imaging clinical trials.

e. Provide data management including, but are not limited to: 1) providing central registration and randomization for all study subjects; 2) providing central storage, security, processing, and retrieval of study results (the data management system should incorporate security features consistent with DHHS guidelines and should have procedures for backing up the Network’s clinical and administrative data, including intermittent duplication of the database with storage at a remote facility); 3) protecting patient confidentiality at all steps in the submission and analysis of clinical trials data and ensuring the technical integrity and security of the data management systems; and 4) providing NCI in a timely manner, upon the request of the Grants Management Officer, 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;

f. Comply with all applicable federal regulations concerning the confidentiality of patient data (e.g., the Health Insurance Portability and Accountability Act [HIPAA]), human subjects protection, etc.) and maintains a data security policy; and

g. Work with Headquarters administration to ensure the timely submission of all competing and non-competing applications, as well as requests for use of unobligated funds and special project requests.

Quality Control and Quality Assurance Program

Part I. Data Monitoring

To ensure the 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 expressed preference of the Network leadership, quality control and quality assurance activities may be located organizationally either in the Headquarters or the BDMC, however both components will participate in each activity. The responsible organization will provide the necessary logistical and financial support. To provide imaging quality assurance, diagnostic imaging data management, and clinical research support for participating sites conducting NCI-supported Network trials, the Network will provide for the following:

a. The development of systems at Headquarters to receive, review, and archive imaging studies, data, and treatment plans electronically while ensuring patient confidentiality;

b. Ensure technical compliance with protocols through data collection and rapid comprehensive case reviews of operating parameters, imaging instruments, data quality, and suitability for analysis or visual interpretation;

c. 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; measures to ensure accurate interpretation of images;

d. The education and training of all health care professionals involved in Network studies (Specifically, the education and training in clinical practices associated with the conduct of clinical trails, protocol specifics and compliance with regulatory guidelines. Also assures that key personnel have completed the NIH required education in the protection of human research participants and submitted documentation to NIH.);

e. Assistance, via personal contact and website instruction, to clinical research site participants in following data submission guidelines;

f. Standardization and improvement of diagnostic, screening and interventional imaging protocol guidelines and provision of leadership in developing clinical guidelines to incorporate new technologies and techniques into multi-institutional clinical trials;

g. The establishment of a database of imaging details of each protocol case for protocol analysis and clinical research;

h. Collaboration with the cooperative oncology groups, including the Cancer Trials Support Unit (CTSU) where appropriate.

i. Participating site performance evaluations: Procedures should be in place for placing participating sites on probation for inadequate performance and for removing participating sites from the Network if performance is not adequate during the probationary period or at any time during which the participating site does not meet established Network standards. Performance factors to be considered include the following: (1) accrual of adequate number of eligible participants into Network trials; (2) timely and accurate submission of required data; (3) conscientious observance of protocol requirement; (4) participation in study development, leadership, and publication; and (5) participation in Network leadership and or other Network activities.

j. Educational functions that address data collection, data management, and overall data quality. These include, but are not limited to: (1) training of new Clinical Research Associates (CRA) in the Network’s data submission policies and on-going training of all CRAs concerning changes in Network Procedures and instructions for data submission in new protocols; (2) instruction of site PIs on their responsibilities for study monitoring; (3) instruction of PIs and other investigators at participating sites of their responsibilities for complying with Network SOPs and federal regulations at their institution/site; and (4) training/guidance provided to all participants on how to comply with NCI/NIH policies and procedures (e.g., policies regarding human subjects protection, ethics, conflict of interest, and procedures such as AdEERs reporting), in addition to the policies and procedures of other governmental agencies (e.g., OHRP, FDA) that are also important to the conduct of clinical trials.

Part II. Auditing

An on-site audit program will be developed and maintained. In situations where NCI is the sponsor of an investigational agent used in a Network clinical trial, NCI will delegate much of the FDA-required auditing tasks to the Network. NCI (CIP) will oversee the auditing process. The Network leadership will oversee audits of each protocol at each participating institution. NCI defines the quality assurance function of an audit program as a process intended to verify study data that could affect the interpretation of primary study endpoints. This goal is accomplished through independent verification of study data with source documentation. The Network will provide for the following:

a. An on-site audit program for the purposes of: 1) assuring patient safety and study quality; 2) validating that data submitted to the Network can be supported by material in the institution’s source records (e.g., medical records, case report forms, reports, films, etc.); 3) verifying that quality control procedures mandated by the Network and by NCI are being followed; 4) confirming that policies designed for the protection of human subjects (e.g., IRB study approval, annual renewal, informed consent, etc.) are in effect; and 5) continuing education for Network clinical participants in good clinical research techniques and data management and quality control systems.

b. 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:

1. Accurate tracking of patient accrual to individual studies at the participating sites and ensuring adherence to defined accrual goals;

2. Ongoing assessment of patient eligibility and data integrity and correction of any specific problems that may occur;

3. Adequate measures to ensure timely submission of protocol-required data from individual patients;

4. Rapid reporting of morbidity and mortality 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 site Institutional Review Board, NCI and the Network’s DSMB (reporting must be in compliance with current NCI requirements for expedited Adverse Event Reporting, and specific time frames for occurrence and reporting requirements should be defined within the individual protocols);

5. Prompt assessment of the significance of adverse event information in the context of the entire study’s experience;

6. 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; and

7. Quality control/assurance and on-site auditing as mentioned above.

Part III. Adverse Event Monitoring and Patient Safety

A system for assuring timely reporting of all serious and /or unexpected adverse events to ensure potential patient safety issues can be identified and addressed quickly. Network protocols and procedures must adhere to current NCI requirements for expedited Adverse Event Reporting Guidelines, albeit modified to accommodate the requirements of clinical imaging studies (http://spitfire.emmes.com/study/epp/forms/AdEERSFAQS-12-22-2000.pdf). 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., contrast reactions, injury from devices, drug/imaging agent reactions, etc.) according to directions provided in the adverse event reporting section of the protocol and the Network’s Adverse Event Reporting Guidelines. The awardee will notify all institutions/investigators participating in this project, funded or unfunded, about the above requirement and about the institutions' and investigators' responsibility to report adverse events as specified in the protocol. The awardee will promptly notify the Program Director, DIB, CIP and the local IRB, of serious or life-threatening events, as instructed in the protocol and the Network’s Adverse Event Reporting Guidelines under Expedited Adverse Event Reporting.

Data and Safety Monitoring Committees

NCI requires cooperative trial organizations to establish Data and Safety Monitoring Committees (DSMB) that are independent of study leadership, are free of conflicts of interest, and have formally documented policies and procedures approved by NCI. The main objectives are to ensure that: 1) patients in trials are protected and that their welfare is not made secondary to the interests of scientific investigation; 2) the evaluation of interim results and make recommendations about continuation, modification, and termination of the trial; 3) the credibility of trial reports and ethics of trials conducted are above reproach with no actual or possible appearance of professional or financial conflicts of interest; 4) that physicians entering patients into the protocols remain free of knowledge of interim efficacy data; and 5) the study leadership is able 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.

The Network will establish a DSMB for all Network clinical trials. Establishment of separate DSMBs may be required for specific trials, e.g., large Phase III trials that involve substantial risk/benefit oversight, or trials that require specific expertise on the DSMB.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This FOA will use the NIH U01 cooperative agreement award mechanism.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH U01 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator (PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the PI, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures.

Eligible applicants are expected to submit two linked applications for two distinct Network components: (i) Headquarters application and (ii) Biostatistics and Data Management Center application. Both applications will be reviewed together and will receive a single score.

2. Funds Available

The NCI anticipates awarding two linked competing continuation U01 Cooperative Agreements in response to this limited competition RFA. The aggregate total costs requested (direct costs and Facilities and Administrative [F&A] costs) for both linked U01 applications may not exceed a maximum of $7,300,000 for the first year and $38,755,000 for the 5-year project period.

The anticipated start date for both of these linked 5-year awards is January 1, 2008.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

As this FOA is a limited competition opportunity that involves a continuation of the cooperative agreements supporting the American College of Radiology Imaging Network (ACRIN), only the current U01 ACRIN awardees are eligible to submit applications.

1.B. Eligible Individuals

Individuals from eligible institutions with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution to develop an application for support. Individuals from under-represented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

More than one PI, or multiple PIs, may be designated on the application. Additional information on the implementation plans and policies and procedures to formally allow more than one PI on individual research awards can be found at http://grants.nih.gov/grants/multi_pi. All PIs must be registered in the eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a single PI or multiple PI grant is the responsibility of the applicant organization in agreement with the other component and should be determined by the scientific goals of the overall Network. Applications for multiple PI grants will require additional information, as outlined in the instructions below, and the NIH review criteria for approach, investigator and environment will be modified as indicated below. For example, a weak or inappropriate PI can have a negative effect on the review. If the multiple PI grant option is elected, a contact PI must be named, as described in the instructions below. Multiple PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of all required reports.

Multiple PIs may be located at the same institution or at different institutions and may request budget apportionment between the PIs (see supplementary instructions below). For multiple organizations, a subcontract or consortium arrangement must be agreed on by the participating organizations, as described in special instructions below.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement athttp://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

Two separate applications must be submitted: One for Headquarters identifying in both a cover letter and in the body of the applications the collaboration with the BDMC and one for the BDMC identifying in both a cover letter and in the body of the application the collaboration with Headquarters. Both components must identify themselves to each other and confirm affiliations both with each other and with the scientific leadership and participating institutional sites for the performance of the ongoing and future clinical trials that constitute the beginning proposed research agenda of the Network.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact Grants Info -- Telephone: (301) 435-0714; Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-0088.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

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.

Nomination and Election of Network Chair: Prior to submission of application, a process for the nomination and election of a Network Chair should be developed and executed to establish the PI (or multiple PIs) for the Network, Headquarters component of this U01. A written explanation of the process used to establish the PI should be submitted at the time of application See Section IV. 6. Other Submission Requirements.

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 PI, must also identify the Headquarters with which it is affiliated.

Supplementary Multiple PI Instructions: If Multiple PIs option is used, the following instructions are to be followed.

Face page. Name of Principal Investigator (PI)

The PI is the individual(s) designated by the applicant organization to have the appropriate level of authority and responsibility to direct the project or program supported by the grant. The applicant organization may designate multiple individuals as PIs who share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PI is responsible and accountable to the grantee organization or, as appropriate, to a collaborating institution, for the proper conduct of the project or program, including submission of all required reports.

When multiple PIs are proposed, use Face Page (Continued) page to provide Items 3a-3h for all PIs. NIH requires one PI be designated as the “Contact PI” for all communications between the PIs and the agency. The Contact PI must meet the eligibility requirements for PI status in the same way as other PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The Contact PI may be changed during the project period. The Contact PI should be listed in block 3 of Form Page 1 (the Face Page), with additional PIs listed on the Face Page (Continued). All PIs must be registered in the eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

Format Page 2. Key Personnel

When multiple PIs are proposed, list the Contact PI first, then all additional PIs in alphabetical order. Then, list all Key Personnel, giving name and organization.

Multiple PI Leadership Plan:

For applications designating multiple PIs, a new section titled Leadership Plan should be included. The governance and organizational structure of the overall Network under this design should be described, including communication plans, publications, intellectual property issues, and procedures for resolving conflicts. The roles and shared administrative, technical, and scientific responsibilities for the Network should be delineated for the PIs, including responsibilities for human subjects and animal studies as appropriate. For competing continuation applications, the application should state how the research will be enhanced by employing a multiple PI approach. This section should also address the governance and organizational structure for Research Components that may have designated more than one PI.

SPECIFIC APPLICATION REQUIREMENTS FOR EACH COMPONENT

Each of the two Network component applications should follow distinct submission requirements as outlined below.

SUBMISSION REQUIREMENTS FOR HEADQUARTERS APPLICATION:

The Network's proposed program of clinical trials should be described in the application for support of its Headquarters. The Headquarters 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 clinical 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 Application: For Headquarters application submitted in response to this announcement, the standard PHS 398 instructions (http://grants.nih.gov/grants/funding/phs398/phs398.html)are modified as follows:

Standard Sections A-D of the Research Plan are substituted by the following new Sections 1-7 (specified below). A revised page limit of up to 115 pages total applies to these new sections (although the application should be as concise as possible to facilitate a thorough review). Other sections of the standard PHS 398 Research Plan (Sections E-L) remain unchanged and must be completed following the PHS 398 instructions (http://grants.nih.gov/grants/funding/phs398/phs398.html).

Section 1. Progress Report (up to 10 pages suggested). This section should provide a summary of the progress to date by the Network. This report, at a minimum should address the following: 1) Role and impact of the External Advisory Panel; 2) Concept/protocol development (idea generation and balance of portfolio) and review; 3) Development and execution of the overall Network Scientific Plan; 4) Quality Assurance Program; 4) Integration of the Headquarters and Biostatistical Data Management Center’s administrative, communication and scientific activities; 5) Scientific Committee structure (roles, membership selection, outcome tracking, idea generation, collaborations, publications); and 6) collaboration with and integration of the relevant oncology perspective in the overall Network and Scientific Committee level scientific plans.

Section 2. Major Research Objectives (up to 10 pages suggested). This section should describe the current process for scientific idea generation, protocol development, and the criteria used to ensure that each protocol project warrants scientific and monetary resources.

This section should concisely describe the Network's major research objectives. The Network’s scientific leadership must articulate a well-integrated scientific plan that will address the scientific priorities and opportunities for the translation of pre-clinical research of the relevant oncology and imaging sciences. Specific budgetary objectives and any plans for collaboration should be included, along with specific quality metrics developed for each research objective. This section should also contain plans for the inclusion of women and minorities as research subjects in Network studies.

Section 3. Organizational Structure (up to 10 pages suggested, including any organizational charts). This section 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. If more than one PI, or multiple PIs are designated, all these individuals should be listed on the Key Personnel page as PIs and the Leadership Plan for the Network application should address the governance and organizational structure with more than one PI. The organizational structure will include a number of scientific and administrative committees, an External Advisory Committee, and 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.

This section should also include a brief explanation of the process used to establish the PI of the Network at the time of application.

Section 4. Scientific Committees and their Research Strategies (up to 10 pages each (up to 70 Total) For each scientific committee (i.e., the five Disease Site Committees, Imaging Core Lab, Informatics Committee), the application should:

Briefly summarize each committee’s progress to date;
Briefly describe the major scientific goals, strategies, and broad research areas that the committee has been and will be concerned with; and
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");

Section 5. Quality Control, On-Site Auditing, and Adverse Event Reporting (up to 5 pages suggested). Quality Assurance and Quality Control Programs. This section should describe procedures for data verification. In accordance with the Network Auditing and Adverse Event Reporting 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. If responsibility for quality control, on-site auditing and adverse event reporting will be the responsibility of Headquarters, these functions should be described in detail here, along with the associated budget request. If these responsibilities 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.

Section 6. Network Administration (up to 5 pages suggested). 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. It should describe the process by which the External Advisory Committee will be selected, as well as its role and responsibilities. Applications should clearly document that the proposed Network Chair has the appropriate experience to qualify as the Network's leader. The application should describe the process by which the Network Chair was selected for this funding period and the policies and procedures that will govern the transition of this key position for future funding periods.

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.

Section 7. Data and Safety Monitoring Committees (DSMB) (up to 5 pages suggested). The application should describe the Network policies and procedures regarding DSMBs. It should include proposed membership rosters of the committee(s), and procedures for avoiding conflicts of interest, such as financial disclosure.

Budget for Headquarters Application

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.

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.

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 resources.
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.
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.
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; travel for advocacy group members to attend key meetings and participate in Network activities as appropriate.

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, etc.) as well as 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; charges related to approved clinical trials activities; and/or charges 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 that 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 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, pages 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.

SUBMISSION REQUIREMENTS FOR BIOSTATISTICS AND DATA MANAGEMENT CENTER (BDMC) APPLICATION

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," 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.

If more than one PI, or multiple-PIs are designated for the BDMC application the same guidelines and requirements apply as indicated throughout the instructions of the RFA for the Network in general and the Headquarters component.

Research Plan for BDMC Application: For BDMC application submitted in response to this announcement, the standard PHS 398 instructions (http://grants.nih.gov/grants/funding/phs398/phs398.html) are modified as follows:

Standard Sections A-D of the Research Plan are substituted by the following new sections 1-9 (specified below). A revised page limit of up to 50 pages total applies to these new sections. Other sections of the PHS 398 Research Plan (Sections E-L) remain unchanged and must be completed following the PHS 398 instructions (http://grants.nih.gov/grants/funding/phs398/phs398.html).

The application should be as concise as possible to facilitate peer review. Wherever appropriate, narrative should supplement (rather than duplicate or replace) standard manuals, which should be supplied as Appendix materials.

Section 1. Progress Report (up to 10 pages suggested). This section should provide a summary of the progress to date by the BDMC. This report, at a minimum should address the following: 1) Integration and communication with Headquarters; 2) dissemination of techniques and analysis tools; 3) timeliness, clinical relevance, generalizability, and conclusiveness of trial design as used and developed by the BDMC for Network trials.

Section 2. Roles and Responsibilities (up to 5 pages suggested): List the major objectives of the Network's BDMC.

Section 3. Organization and Facilities(up to 5 pages suggested) : Describe the organization and facilities to accomplish the complex tasks of central data management, quality control, study monitoring, and data analysis.

Section 4. Data Management Policies and Practices (up to 5 pages suggested) : Describe the flow of data following submission from the individual investigators.

Section 5. Quality Control (up to 5 pages suggested): Describe procedures for quality control and accuracy verification.

Section 6. Study Monitoring Procedures (up to 5 pages suggested): Describe the Network's standard methods for ongoing study monitoring, including interactions with study chairs.

Section 7. Study Design and Data Analysis (up to 5 pages suggested): Describe the Network's routine methodological 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.

Section 8. Partnership in Network Research (up to 5 pages suggested): Describe the role and contributions of the Network's statisticians to Network research. The involvement of statisticians in designing studies should be documented.

Section 9. Independent Research (up to 5 pages suggested): Describe research being conducted and planned research by the statistical office of the Network using Network resources, including the database.

Budget for BDMC Application

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.

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.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review, and Anticipated Start Dates
Letters of Intent Receipt Date(s): March, 10 2007
Application Receipt Date(s): April 10, 2007
Peer Review Date(s): June/July 2007
Council Review Date(s): October, 2007
Earliest Anticipated Start Date(s): January 2008

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed research;
Name, address, and telephone number of the PI;
Names of other key personnel;
Participating institutions; and
Number and title of this FOA.

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 NIH Institute or Center (IC) staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Barbara A. Galen, MSN, CRNP, CNMT
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN Room 6050, MSC 7412
Bethesda, MD 20892-7412 (for U.S. Postal Service express or regular mail)

Rockville, MD 20852-4910 (for express/courier delivery)
Telephone: (301) 594-5225
Fax: (301) 402-3507
Email: bgalen@mail.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (for U.S. Postal Service express or regular mail)
Bethesda, MD 20817 (for express/courier delivery; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all the appendix materials in pdf format (on a single CD) must be sent to:

Barbara A. Galen, MSN, CRNP, CNMT
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN Room 6050, MSC 7412
Bethesda, MD 20892-7412 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852-4910 (for express/courier delivery)

Telephone: (301) 594-5225
Fax: (301) 402-3507
Email: bgalen@mail.nih.gov

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NCI. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the PI in the eRA Commons at https://commons.era.nih.gov/commons/.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

The NCI is developing a policy that will require Clinical Terms of Award for clinical studies and trials when they are a component of any proposed research being funded by the NCI. The policy will require that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. The new policy will be posted in the NIH Guide. All funded applications will be expected to adhere to the new policy.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Data sharing promotes many goals of the National Institutes of Health's (NIH) research endeavor. Consistent with the goals espoused in the NCI June 2005 ‘Report of the Clinical Trials Working Group of the National Cancer Advisory Board, Restructuring the National Cancer clinical Trials Enterprise (http://integratedtrials.nci.nih.gov/ and http://integratedtrials.nci.nih.gov/ict/CTWG_report_June2005.pdf). NCI is focused on improving the standardization of tools and procedures for trial design, data capture, data sharing, and administrative functions to minimize duplication of effort. It is particularly important for unique data that cannot be readily replicated. Timely data sharing allows scientists to expedite the translation of research results into knowledge, products, and procedures to improve human health. NCI expects and supports the timely release and sharing of research data from NIH-supported studies for use by other researchers. The Network will formulate and submit a plan for the sharing of data with the application to the Program Director/DIB/CIP/DCTD/NCI. Please see the following draft NIH Statement on Data Sharing for guidance (http://grants1.nih.gov/grants/policy/data_sharing/index.htm).

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.
The following will be considered in making funding decisions:

Scientific merit of the proposed project as determined by peer review;
Availability of funds; and
Relevance of program priorities.

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score;
Receive a written critique; and
Receive a second level of review by National Cancer Advisory Board.

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criter