Part I Overview Information

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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 301-451-5936.

Table of Contents

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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

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Section I. Funding Opportunity Description

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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

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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

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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

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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) 710-0267; Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

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: [email protected]

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: [email protected]

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

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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 criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Both Headquarters application and Biostatistics and Data Management Center (BDMC) Application will be evaluated together and will receive a single score.

The specific criteria for each type of application are listed below. Some elements (indicated below) will be evaluated JOINTLY for the Headquarters application and BDMC application

CRITERIA FOR HEADQUARTERS APPLICATION

Significance (to be evaluated jointly for the Headquarters application and BDMC application): Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Will the proposed efforts significantly advance the development of new cancer therapeutics?

ACRIN-specific elements Progress:

• Has the Network shown adequate progress during the previous funding periods in developing appropriate infrastructure/processes for flexibly capitalizing on new scientific opportunities in both the oncology and imaging sciences as they arise?
• Has the Network demonstrated adequate progress during previous funding periods in (1) the organization of their scientific committees,(2) implementation of the recommendations of the External Advisory Panel, and (3) defining and achieving the goals of their overall Scientific Plan?
• Does the Network portfolio of current research projects demonstrate active collaboration with other NCI-sponsored Cooperative Groups and other activities of interest to the NCI/NIH or FDA and Centers for Medicare & Medicaid Services (CMS)?
• Has the Network enhanced the integration between Headquarters and Biostatistical Data Management Center in terms of coordinated activities and communications?
• Has the Network implemented formalized quality-assurance and quality control programs?
• Has the Network demonstrated adequate productivity as evidenced by a peer-reviewed publication record?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

ACRIN-specific elements:

• Are there adequate plans for continued cooperation and coordination with the oncology and imaging communities, including the NCI, NIH, and other relevant Federal, academic and private agencies?
• Are the research plans, strategies, and protocols for each of the major areas of study meritorious? Do they take maximum advantage of contemporary scientific opportunities with consideration of the needs and interests of oncology and imaging science?
• Is there a feedback system among scientific leadership and biostatisticians, to assist potential ACRIN investigators in formulating relevant scientific questions and designing appropriate trials?
• Do the plans of the Network adequately address the issue of compliance with the NCI Cancer Clinical Trials System and relevant NIH/NCI-supported bioinformatics standards, including caBIG?
• Are the Network’s processes for decision-making, scientific prioritization, protocol generation, study activation and evaluation effective and efficient?
• For applications designating multiple PDs/PIs, is the leadership approach, including the designated roles, responsibilities, governance, and organizational structure consistent with the goals of the Network and the expertise of each of the PDs/PIs?
• How well designed are the Network's planned clinical trials? Will the design of these trails allow for scientifically sound and clinically relevant conclusions to be drawn?
• Is the participant membership of the Network adequate to support the successful execution of the Network's scientific plan in a timely manner and ensure adequate participant accrual.
• Are there defined plans and roles for patient advocates in the Network?
• Are there adequate metrics proposed for the monitoring and evaluation of progress of the Network toward meeting its strategic goals and objectives?
• Are there adequate metrics proposed for the evaluation of efficiency and effectiveness of participating sites?

Innovation (to be evaluated jointly for the Headquarters Application and BDMC application): Does the project challenge existing paradigms of clinical research; address critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator(s) and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

ACRIN-specific elements:

• Are the qualifications and experience of the PI(s) and other Network investigators appropriate to provide adequate scientific leadership for developing and implementing the Network’s goals and objectives?
• Is the available investigators and other dedicated personnel adequately experienced/skilled and sufficient for the Network’s objectives?
• Do the members of the scientific and administrative team bring complementary and integrated expertise to the Network?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

ACRIN-specific elements:

• Does the facility have adequate HIPAA compliant security
• Are the available facilities and resources, including hardware and information technology solutions, adequate for the Network goals and objectives? Can the facilities and resources meet expanded needs in the future?

CRITERIA FOR BDMC APPLICATION

The following criteria will be used for BDMC application.

This BDMC-specific portion of the evaluation involves two facets: 1) the performance and capabilities of the BDMC; and 2) the Network's integration of BDMC roles and responsibilities into the overall research program.

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

ACRIN-specific elements:

• Adequacy of Study Design. Is there evidence that the clinical trial protocols will have statistically proper design? Will the sample sizes be adequate to detect relevant and medically important differences? Are the estimates of patient/participant accrual rate realistic and in line with the needs of the proposed clinical trials? Are the study designs proposed appropriate for the questions to be tested? Are research endpoint selections adequately described and justified?
• Leadership Plan. Will there be adequate coordination between Headquarters and BDMC for both scientific and administrative collaboration in the development and conduct of the Networks research? If the application designates multiple PIs, does the Network leadership plan ensure that there will be sufficient coordination and communication among the PIs?
• Statistical Analyses and Data Management. Are analytical techniques, procedures, and policies adequate, appropriate, and consistent with accepted standards? Is there evidence that past publications of the Network leadership demonstrate thorough and state-of-the-art methodology, awareness of problems of multiple analyses, and sufficient independence and lack of bias of statistical collaborators? Are data management procedures adequate, appropriate, and consistent with accepted standards (including caBIG compliance)? Are procedures for the verification of data accuracy adequate? Is there clinical review of study data? Will there be adequate collaboration pertinent to statistical analysis and data management in the development and conduct of the individual Networks research projects?
• Quality Assurance/quality Control (if this aspect is responsibility of the BDMC). Do appropriate quality-assurance and quality control programs exist, including on-site audits that assure high-quality research and patient safety? Have costs for the on-site audit plan been accurately detailed? Is there sufficient funding allotted to carry out the multiple quality control tasks required?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

ACRIN-specific elements:

• Are the qualifications and experience of the PI(s) and other Network investigators appropriate to provide adequate scientific leadership for developing and implementing the Network’s goals and objectives?
• Are there sufficient and appropriately experienced personnel with the skills needed to develop and implement the Network’s objectives?
• Does the scientific and administrative team bring complementary and integrated expertise to the Network?
• Does the research experience and qualifications of the Principal Investigator(s) and other key personnel demonstrate understanding of design, administration, and analysis of multi-institutional clinical trials in imaging
• Are the roles of the staff adequately defined to accomplish the goals of the Network? Are there an adequate number of personnel to meet the assigned tasks?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

ACRIN-specific elements:

• Does the facility have adequate HIPAA compliant security
• Are the current facilities, including hardware and information technology solutions, adequate for current Network goals and objectives and capable of further development to meet future needs?

2. Review and Selection Process

2.A. Additional Review Criteria

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).
Are there strategies outlined to increase accrual of woman and minorities to clinical trails?

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget. Have costs for travel, office supplies, equipment and data management been adequately justified? Are detailed costs of participants provided? Are budgetary plans submitted for Network meetings and consultant fees? Are budgetary plans submitted that are aligned with and will allow for the execution of the strategic research plan?

2.C. Sharing Research Data

Data Sharing Plan: 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. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

The Network will formulate and submit a plan for the sharing of data with the application to the Program Director/DIB/CIP/DCTD/NCI. CIP/DCTD/NCI Program Staff will be responsible for the administrative review of the plan for sharing research data.

2.D. 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/part_ii_5.htm#availofrr and at http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

Not applicable

Section VI. Award Administration Information

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1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in Item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the PI as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local governments are eligible to apply), and other DHHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

Throughout these Terms and Conditions of Award, The American College of Radiology Imaging Network (ACRIN) funded by these U01 awards is also referred to as the Network. The Network refers to the organizational structure which is composed of the Network PIs, other key personnel, and participating organizations, all of whom agree to collaborate on research goals of the Network.

2.A.1. Awardees and Principal Investigators Rights and Responsibilities

Certain of the awardee and Principal Investigator s generic programmatic responsibilities as an investigator for the conduct of the research supported by this RFA are described in two NCI documents: (a) the Investigator's Handbook (a Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment, Diagnosis and Centers, National Cancer Institute); and (b) the "NCI-CTMB Guidelines." Specific portions of these documents, as enumerated in the following sections, are incorporated by references terms of award.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

Development of a Comprehensive Strategic Scientific Plan

It is the responsibility of the Network to:

• Develop a robust process for establishing, executing, and periodically updating, through external and internal evaluation, an overall strategic scientific plan. The Advisory Committee will review the strategic research plan. The Network leadership has the responsibility for the execution and periodic evaluation of the strategic research plan. The Advisory Committee will be involved in the process of periodic evaluation. Periodic progress reports, at a minimum annually, must be submitted to the Network Chair, the Program Director, DIB CIP, and the Chief, DIB/CIP/DCTD/NCI.
• The Network will, with NCI assistance, develop clinical protocols in accordance with the research interests, abilities, and goals of the Network. The Network leadership shall, designate other Network investigators to serve as Protocol Chairperson for each proposed study. Protocols for DCTD-sponsored investigational agents or devices will be developed in accordance with the instructions in the NCI Investigator's Handbook (http://ctep.cancer.gov/handbook/index.html).
• Coordination and Internal Oversight of Network Activities. In accordance with the Network constitution, bylaws, policies and procedures, the Network Headquarters (or BDMC as appropriate), under the oversight of the Network PIs and with NCI assistance, is responsible for coordinating and overseeing:
• Clinical trial protocol development and protocol submission;
• Clinical study conduct, quality control and study monitoring;
• Ordering drugs and/or imaging agents needed for clinical studies;
• Data management and statistical analysis;
• Clinical trial protocol amendments and/or status changes;
• Adherence to procedures of investigational drug management and federally mandated regulations; and
• Protocol and performance reporting.
• All the scientific and administrative decisions related to the Network-funded activities will be coordinated by the Network PIs with the assistance of the staffs of the Headquarters and BDMC. The Network PIs (or their designee) will be responsible for communication with the appropriate NCI staff.
• The Headquarters will establish policies and procedures for recruiting and credentialing participating sites. NCI will be notified of the sites participating in each protocol at the time of protocol submission to NCI either for review or for informational purposes (see under B. NCI Staff Responsibilities, Section 3: Review of Proposed Protocols).
• Protocol Review and Submission. The Network will establish an internal process by which concepts for clinical study protocols will be reviewed to assure alignment with the needs and interests of clinical oncology community, technical feasibility, and compatibility with the Network’s goals. The internal concept review/approval must precede protocol submission to the Protocol and Information Office, CTEP/NCI. This process should provide for a timely response to the investigators submitting the concepts, including a clear description of the criteria used in the decision process.
• Prior to protocol implementation, the Network Headquarters will submit protocols for review (and also information required in PHS 398, Section e. Human Subjects), to the CIP/CTEP/ACRIN Coordinator and the Protocol and Information Office/CTEP/NCI. Phase III protocols must be preceded by a concept-review letter describing the hypothesis to be investigated, the general design of the contemplated trial plus relevant information on accrual capabilities, including minority and gender accrual estimates, of the planned participating sites to document feasibility.

The NIH Policy for research supported as an NIH Phase III Clinical Trials has been amended in Section II.B. of the NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research- Amended October, 2001 (go to http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm).

All Phase III Clinical Trials will require a description of plans to conduct analyses, as appropriate, by gender and racial/ethnic groups must be included in clinical trial protocols. Cumulative subject accrual and progress in conducting subset analyses must be reported to the CIP Program Director in the annual Progress Reports. Final analyses of gender and racial/ethnic differences must be reported in the required Final Progress Report or Competitive Renewal Applications (or Contract Renewals/Extensions) as stated in Section II.B. of the Guidelines.

For all non-Phase III trials that include a DCTD investigational drug/imaging agent or device, a Letter of Intent (LOI) must be submitted to the CIP/CTEP/ACRIN Coordinator and the Protocol and Information Office, CTEP. These two mechanisms for preliminary review are intended to expedite protocol development and implementation and to facilitate agreement on study priority and design (see Investigator's Handbook, pp. 32-35). The Network leadership, with the assistance of the Network Headquarters staff, will communicate the results of the NCI review of protocols to the participating investigators.

• Network Compliance with Federally Mandated Regulatory Requirements. The Network must be in compliance with all FDA regulatory requirements for studies involving investigational devices and agents and NIH policies applying to the conduct of research involving human subjects. These regulations include but are not limited to CFR 21 Parts 50, 56, and 312, and CFR 45 Part 46. Participants are required to follow established Network procedures for complying with the Federally mandated regulations.
• Investigational Drug/Imaging Agent Management. Investigators performing Network trials are must, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents and devices. When new avenues of cancer diagnosis or therapy involving investigational drugs are pursued, the clinical information should be acceptable to the FDA for inclusion in an eventual licensing dossier for drugs, biologicals, or devices, as appropriate.
• Quality Control and Study Monitoring.

The Network shall establish and implement mechanisms for quality control of therapeutic and diagnostic modalities employed in its trials. Participants are required to follow Network procedures for quality control. Quality control at a minimum should consist of:

• Imaging Devices: Where appropriate, review (concurrent or retrospective) to assure accuracy of device calibration across participating institutions.
• Image Interpretation: Where appropriate, review (concurrent or retrospective) to assure accuracy of readings from the study sites and compliance with protocol-specified diagnostic parameters for individual patients.
• Radiation therapy: Review (either concurrent or retrospective) of port films and compliance with protocol-specified doses for individual patients. Determination of adequacy of radiation delivery with assistance of the Radiological Physics Center (RPC), whose functions usually include equipment dosimetry, periodic institutional visits and other aspects of physics review.
• Protocol-related Drug/Imaging Agent Administration: Review of flow sheets with determination of protocol compliance in dose administration and dosage modification.
• Surgery: Assessment of adequacy of protocol-specified surgical procedures through review of operative notes and study-specific surgical forms.
• Pathology: Verification of pathologic diagnosis in cases where known variability in the accuracy of histologic diagnosis is a potentially serious problem and where pathology data may provide important information relevant to the trial.
• The Network will establish and implement mechanisms for study monitoring and quality assurance. Participants are required to follow Network procedures for study monitoring. The Network is responsible for assuring accurate and timely knowledge of the progress of each study through:
• Tracking and reporting of patient accrual and adherence to defined accrual goals;
• Tracking and reporting of women and minority accrual and adherence to defined accrual goals;
• Ongoing assessment of case eligibility and data integrity;
• Timely medical review and assessment of patient data and case report forms;
• Rapid reporting of treatment-related morbidity and measures to ensure communication of this information to all parties;
• Interim evaluation and consideration of measures of outcome as consistent with patient safety and good clinical trials practice;
• Timely communication of results of studies; and
• An on-site monitoring program.
• The awardee is responsible for ensuring that all participating sites have routine audits in accordance with the Network Guidelines (which shall be based on the CTMB guidelines) and that the results of audits are reported to the NCI in accordance with the guidelines
• Quality Assurance and Quality Control of Data. The awardee must follow NCI-approved procedures developed by the Network for quality assurance of data collected by the Network and for the prevention and/or identification of false or otherwise unreliable data. The awardee must follow Network procedures for the assurance of data quality and quality control in accordance with Network guidelines and NCI policies. If there is any indication through the quality assurance and/or quality control programs, or through any other means, of a pattern of non-compliance withprotocol or regulatory requirements or a finding of possible alteration of data, these findings must be reported in accordance with the Network and NCI Guidelines.
• Data Management. The Network shall establish and implement mechanisms for data management that are: (a) adequate for quality control and analysis; and (b) as simple as possible in order to encourage maximum participation of physicians enrolling patients and to avoid unnecessary expenses. Participating investigators and research associates are required to follow Network procedures for data management.
• Monitoring Plan and Data Safety and Monitoring Board. The Network must establish and maintain a Data and Safety Monitoring Board (DSMB) for all Network clinical trials. Individual DSMBs for large trials and trials that involve substantial risk/benefit oversight may be required. The policies and procedures of the DSMB must be approved by the Chief, DIB/CIP/DCTD/NCI. The Network must comply with the approved policies and procedures of the DSMB.

Research components involving clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998; go to http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials, go to http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety-monitoring plan as part of the research application. See the NIH Guide Notice on Further Guidance on a Data and Safety Monitoring for Phase I and II Trials for additional information at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available at http://www.cancer.gov/clinical_trials/.

• Protocol Closure. The Network shall establish and implement mechanisms for interim monitoring of results and monitoring protocol progress. If the Network wishes to close accrual to a study prior to meeting the initially established accrual goal, the interim results and other documentation should be made available to CIP staff for review and concurrence prior to implementation of the decision by the Network. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the protocol in order to facilitate these decisions. In the event that the DSMB has recommended early closure, DSMB procedures regarding notification of the Associate Director, CIP/DCTD/NCI, must be followed.
• Protocol Reporting Requirements. Reporting requirements will be in agreement with FDA regulation and NCI procedures. CIP DCTD’s and NCI's procedures for data reporting from its clinical imaging trials organizations are currently in evolution and will be provided to and discussed with the Network in detail when complete. Until that time the Network is required to submit trial data using the abbreviated Clinical Data Update System (CDUS). The Abbreviated CDUS Data Set is limited to protocol administrative information and patient demographic information. For each protocol, the lead Group or institution is responsible for compiling and submitting CDUS data for all participants in a multi-Institution or Inter-Group trial. The Abbreviated CDUS Data Set can be found in Section 1.3.1 of the CDUS Guideline, Version 3.0, May 3, 2002. The entire CDUS Guideline can be viewed/downloaded at http://ctep.cancer.gov/forms/CDUS30_InstructionsGuidelines_5-3-02.pdf

The Headquarters or BDMC must provide to the NCI/DIB/CIP Program Director quarterly appropriate update information for all protocols under development. This information should include the targeted timeline established for the development of each protocol, the current status of the protocol, and plans to assist the protocol development team in reaching their goal if appropriate.

Interim reports of each activated and ongoing study shall appear in the minutes of each Network meeting and shall include specific data on patient accrual as well as, when appropriate, detailed reports of imaging and treatment-associated morbidity. The Headquarters or BDMC must provide quarterly accrual information as appropriate to the Program Director, DIB, CIP, for all active studies. A system for providing such information in a timely manner should be in place. Participants must provide accrual data to the Network in accordance with Network procedures.

• Adverse Event Procedures. 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 (funded and unfunded) participating in the Network projects (funded and unfunded), about the above requirement and about the institutions'/investigators' responsibility to report adverse events as specified in the protocol. The awardee will promptly notify the Program Director (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.

• Procedures in the Event of Scientific Misconduct. The awardees must develop appropriate policies and procedures for handling scientific misconduct (for guidelines see http://ori.dhhs.gov/ and http://ori.dhhs.gov/documents/FR_Doc_05-9643.shtml).
• Data Files Available to NCI Upon Request. Upon the request of the Grants Management Officer, NCI, true copies of data files and supporting documentation for all NCI-supported protocols that have a major impact on patterns of care, as determined by the NCI, shall be made available to the NCI in a timely manner.
• Notification of Patients by the Awardee During Patient's Lifetime. In the event the NCI determines, either while a protocol is active or (if relevant) during the lifetime of the subjects following protocol closure, that a medically important toxicity or side effect is associated with protocol-directed treatment or that the medical care of one or more subjects may have been compromised by scientific misconduct or other finding affecting the integrity of the data or patient safety at the awardee institution or at a third-party institution (funded or unfunded, the awardee shall assure that the institution(s) responsible for these subject(s') accrual, whether funded or unfunded, will have procedures in place to: a) contact each subject individually at his or her last known address on file with the institution and which give each subject contacted appropriate information and the right to communicate with an appropriate institutional representative and, in the event of misconduct, to meet with a physician not connected with the clinical trial or study in which the subject has participated; and b) encourage subjects to notify the institution of any changes of address. The procedure must provide for informing the subjects fully of the consequences of the toxicity or misconduct for their care and well being, if any, and the availability of follow-up, and their opportunity to examine any portion of their medical records relevant to the potential effect of the toxicity or side effect upon them or that may be affected by scientific misconduct or other findings affecting the quality or integrity of the data or patient safety.

Under regulations in CFR 45 Part 74.53, NCI has right of access to research records pertinent to studies conducted with NCI funding. In exceptional circumstances, such as in a public health emergency, institutions may be required to provide subject names and treatments to the NCI in a format that allows direct notification of the patient by the NCI.

• Collaboration with Device Drug/Imaging Agent For-Profit Entities- Joint projects and cost-sharing arrangements with industry are encouraged. As companies are a major source of technological innovation, the Network may have interests in collaborating with industry on specific medical devices, drugs, or imaging agents. The collaborative arrangements will be worked out on a case-by-case basis by the Network PIs and respective companies. The arrangements shall in all cases conform to PHS regulations and any applicable NCI policies on interactions with for-profit entities, NCI-supported cooperative trials networks, and NCI. In all cases, details of any financial or other arrangements between the Network and for-profit entities shall be available to NCI staff on request.

2.A.2. NIH Responsibilities

In addition and beyond the usual programmatic stewardship, the NCI staff will provide technical assistance, advice, coordination, and/or other programmatic/scientific functions but without usurping the grant recipients dominant role and prime authority in conducting research activities. Since this cooperative agreement arrangement is a part of (albeit a distinct one) of a larger program of cooperative clinical trials in the NCI, multiple NCI staff members and layers of organization will be involved.

NCI Staff Interactions with the Network. NCI staff members from several organizational units will interact with the Network and its investigators.

• The NCI Program Director (a staff member of the Diagnostic Imaging Branch [DIB], Cancer Imaging Program [CIP]) will serve as Program Official providing normal program stewardship but will also have additional substantial programmatic involvement as a Project Coordinator/Collaborator.. Specifically, this individual will cooperate with the grantees and coordinate project-related activities such as:
  • Implementation of the Network's quality assurance (adverse event reporting) and site visit monitoring program;
  • Identification of other researchers/resources;
  • Assistance in processing FDA INDs for investigational drugs;
  • Advising the awardees on compliance with NIH policies such as human subjects protection, inclusion of women, minorities and children, etc;
  • Participation in various committees (including ACRIN Steering Committee, Leadership Committee, and project specific Executive Committees, External Advisory Panel, operational committees, etc) as a voting member as needed (the chairperson will be someone other than the Project Coordinator);
  • Other functions/activities associated with the coordination of long-term projects (organization/participation in annual meetings, membership on project oversight committees, internal review committees, etc.; technical monitoring to permit specified kinds or directions of the work; review of one stage of a project before work may begin on a subsequent stage during a current approved project period e.g., letters of intent, concepts submitted to the Concept and Protocol Review Committees of the Cancer Therapy and Evaluation Program (CTEP); execute the option to halt a project activity if technical performance requirements are not met or if program objectives have already been met.
  • The Project Collaborator will seek NCI waiver according to the NCI procedures for management of conflict of interest to enable her/him to attend peer review meetings of renewal or supplemental applications when necessary.
  • An arbitration term of award will be included in the notice of grant award (NGA) to provide special review procedures to arbitrate disagreements between NIH and awardees similar to that provided in the NGAs of the other NCI Cooperative Groups.
  • The existing NCI policies and procedures for managing conflicts of interest and maintaining confidentiality of non-public information will be adapted with regard to ACRIN Steering Committee, External Advisory Panel, Leadership Committee Teleconferences, etc. These policies and procedures will apply to all Committee participants, as well as participants in Task Forces. These policies and procedures will be similar to those already in place for other NCI Cooperative Groups (as defined in the NCI Clinical Trials Cooperative Group Program Guidelines (currently under development)) and will be discussed and presented to the grantee’s in writing during the pre-application meeting and in place by January, 2008.
• The Associate Director, CIP and the Branch Chief of DIB CIP and selected special assistants to the Associate Director, as well as selected staff members from the other three branches of the CIP (the Molecular Imaging Branch, the Imaging Technology Development Branch, and the Image-Guided Diagnosis and Therapy Branch) will not be involved in normal programmatic stewardship but will assist the Network, as Project Scientists/Project Coordinators when appropriate in functions/activities associated with the coordination of long-term projects. Branch Chief DIB, CIP and a Special Assistant to the Associate Director, CIP will specifically assist the Network in the interactions with the CTEP Protocol Review Committee acting as the CIP CTEP ACRIN Coordinators. The roles of these and other NCI staff members will include the following:
  • Sharing information pertinent to the scientific basis for specific clinical trials;
  • Advising the Network investigators of the nature and results of relevant clinical trials being carried out by other organizations and potential studies relevant to imaging-aided diagnosis and image-guided therapy;
  • Assisting in processing FDA INDs for investigational drugs;
  • Participating in committees as voting members as needed (the chairperson will not be the IC staff member);
  • Other functions including, but not limited to (a) the integration of ACRIN activities with other CIP and NCI initiatives; (b) participation in publications from the project; will not be involved in normal programmatic stewardship; (c) technical monitoring to permit specified kinds or directions of the work, including approval of changes in experimental approaches; (d)review or approval of one stage of a project before work may begin on a subsequent stage during a current approved project period e.g., letters of intent, concepts submitted to the Concept and Protocol Review Committees of the Cancer Therapy and Evaluation Program (CTEP):
  • CTEP ACRIN Coordinators will participate and/or coordinate (or assist grantees) in project activities, such as development of research protocols; data collection, data analyses, results interpretation; holding FDA IND for investigational imaging agents; or re-establishment of objectives during the course of a project.
  • CTEP ACRIN Coordinators will have an option to suggest a halt to a project activity if technical performance requirements are not met or if program objectives have already been met in consultation with the Associate Director of CIP and the Project Collaborator and within the charter of the appropriate Data and Safety Monitoring Board (s) of a given project;

The Project Scientists and Coordinators will conduct the listed above activities adhering to the NCI conflict of interest policy and procedures, as well as the arbitration procedures listed below.

Additional details on the roles of designated members of several units of the NCI Cancer Therapy Evaluation Program (CTEP, DCTD) and other NCI units as Project Scientists or Project Coordinators are provided below.

• The staff of the Protocol Review Committee will assume a primary role in the review and evaluation of the concepts and protocols submitted by the Network with the coordination and participation of the ACRIN CTEP Coordinators;
• The staff of the Pharmaceutical Management Branch will assist the Network in the ordering and management of investigational drugs;
• The staff of Regulatory Affairs Branch will assist the Network in assuring that Network activities are in conformity with Federal regulations concerning the use of investigational devices and medicinal agents;
• The staff of the Investigational Drug Branch, CTEP, and the Cancer Imaging Program (CIP) will provide updated information on the efficacy and toxicity of investigational drugs or medical devices supplied to Network members under an Investigational New Drug (IND) Application or an Investigational Device Exemption (IDE) sponsored by DCTD, NCI;
• The staff of the Clinical Investigations Branch will assist the Network, as needed, in establishing liaisons with other clinical cooperative groups and in clinical study protocol-related and medical matters pertinent to the diseases under study;
• The Biometrics Research Branch, Office of the Director, NCI, will consult with the Network, as needed, in with the area of biostatistics and issues of clinical trials design; and
• The CIP Program Director will provide the awardees with a comprehensive list of the NCI staff that will be involved, and the responsibilities of each NCI staff member. Staff members of other NCI Divisions will offer collaborative assistance to the Network as necessary.

Protocol Development. A protocol is the detailed written plan of a clinical experiment. The protocol must be mutually acceptable to the Network and to the NCI. Communication with relevant NCI staff, as outlined in above, at the various stages of protocol development is encouraged. NCI staff from the several organizational units outlined above will assist the Network in protocol design, as may be appropriate, by providing information regarding: (a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort; (b) comments on proposed trial designs; and (c) relevant pharmacokinetic and pharmacodynamic data on investigational agents proposed for study.

For proposed large multi-center trials, staff of the CIP and CTEP, DCTD, will provide the Network a formal review of concepts for protocols, commenting on study originality and scientific and medical impact. These two mechanisms for preliminary review are intended to expedite protocol development and implementation and to facilitate agreement on study priority and design (see the "Investigator's Handbook," pp 32-35).

Review of Proposed Protocols. Network protocols will be reviewed by the CTEP Protocol Review Committee (PRC), augmented by staff of the Cancer Imaging Program, meeting at regular intervals for this purpose. Ad-hoc external reviewers (not affiliated with the NCI), will be utilized when deemed appropriate by the committee chairperson and/or the CIP CTEP ACRIN Coordinator. Formal protocol review and NCI approval prior to activation are required for the following types of studies: (a) all protocols utilizing NCI resources and investigational agents regardless of IND or IDE sponsor; (b) all protocols that permit entry of 100 or more patients; and (c) all Phase III therapy and diagnostic protocols. Other protocols will be filed with NCI for information purposes but will not require NCI approval. Advisory reviews of such protocols may be provided to the Network at NCI's discretion. For all protocols that require review, the CIP CTEP ACRIN Coordinators will provide the Network with the Protocol Review Committee's consensus review that describes recommended modifications and other suggestions, as appropriate.

The major considerations relevant to protocol review by the PRC include: (a) the strength of the scientific rationale supporting the study; (b) the medical importance of the question being posed; (c) the avoidance of undesirable duplication with other ongoing studies; (d) the appropriateness of study design including interim monitoring plans if appropriate; (e) a satisfactory projected accrual rate and follow-up period; (f) patient safety and protections from risk; (g) compliance with federal regulatory requirements; (h) adequacy of data management; and (i) appropriateness of patient selection (including compliance with NIH inclusion policies for women, minorities and children), evaluation, assessment of toxicity, response to therapy and follow-up.

If a proposed clinical trials protocol is disapproved, the Protocol and Information Office (PIO), CTEP, will communicate the specific reasons to the Network chairperson as a consensus review within 30 days of protocol receipt. NCI will not provide investigational drugs or permit expenditure of NCI funds for a clinical study based on a protocol that it has not approved. The CIP CTEP ACRIN Coordinators will assist the Network in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the Network and of the NCI.

Review of Quality Control and Study Monitoring. NCI Staff of the CIP, DCTD, will review and provide advice regarding mechanisms established by the Network for quality control of therapeutic and diagnostic modalities employed in the clinical trials conducted by the Network. CIP staff will review and approve the mechanisms established by the Network for study monitoring including the Network's on-site auditing program. Staff of CIP, and/or its monitoring contractor, may attend as observers the on-site audits conducted by the Network. The frequency of observer participation by NCI staff will be determined by the CIP.

Review of Data Management. Staff of the Biometrics Research Branch (BRB), Office of the Director, NCI, will review mechanisms established by the Network for data management. When deemed appropriate, BRB staff will make recommendations to ensure that data collection and management procedures are: (a) adequate for quality control and analysis; (b) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (c) generally compatible with the standard formats for electronic data reporting to NCI. The NCI will have access to all data, although they remain the property of the awardee institution. Data must also be available for external monitoring as required by NCI's agreement with the FDA relative to the NCI's responsibility as a sponsor of research with investigational drugs/imaging agents and devices.

Data and Safety Monitoring Committees. The NCI Staff, assisted by BRB staff, will assess Network compliance with NCI-established policies on Data and Safety Monitoring Committees (DSMBs) for multi-center Phase III trials. One or more NCI staff members will serve as non-voting members on the DSMB.

Clinical trials Protocol Closure. The Associate Director, CIP/DCTD/NCI, may request that Phase I or Phase II protocol study be closed to accrual for reasons including: (a) insufficient accrual rate; (b) poor protocol performance; (c) patient safety; (d) study results are already conclusive; and (e) emergence of new information that diminishes the scientific importance of the study question. The NCI will not provide investigational agents or permit expenditures of NCI funds for a Phase I or Phase II study after requesting closure, except for patients already on treatment and follow-up.

The Associate Director, CIP/DCTD/NCI, may request that the Network DSMB consider closing a Phase III protocol to accrual for reasons including: (a) insufficient accrual rate; (b) poor protocol performance; (c) patient safety; (d) study results are already conclusive; and (e) emergence of new information that diminishes the scientific importance of the study question. Any disagreement between NCI and the DSMB about protocol closure that cannot be resolved by discussion will be brought to Arbitration as outlined later under "Collaborative Responsibilities," except that the nominating parties will be the Associate Director, CIP/DCTD/NCI and the Chair of the DSMB. NCI will not provide investigational agents or permit expenditures of NCI funds for a Phase III study that has been closed, except for patients already on treatment or in follow-up.

NCI Involvement in Investigational Drug/Imaging Agent and Device Management. The NCI will have the option to cross-file or independently file an IND on investigational agents evaluated in trials supported under cooperative agreements. This applies to drugs not developed in the NCI drug development program. In the case of investigational devices, the NCI, Network investigators, and the device supplier will decide collaboratively which organization will hold the IDE.

The responsible NCI staff members, assisted by the staff of the Regulatory Affairs Branch (RAB) and the Pharmaceutical Management Branch (PMB), will advise investigators of specific requirements and changes in requirements concerning investigational drug/imaging agent or device management that the FDA may mandate.

Review of Compliance with Federal Regulations. DIB, CIP, and RAB staff will review and advise the Network regarding mechanisms established by the Network to meet regulatory requirements of the FDA for studies involving NCI-sponsored investigational agents and devices, and those of the Office for Protection from Research Risks (OPRR) for the protection of human subjects.

NCI Attendance at Network Meetings. NCI staff, as designated by the NCI Program Director and the Chief, DIB, CIP, will attend the regular Network meetings and will be invited as a non-voting observer to all Network leadership meetings.

Facilitating Collaboration with other Cooperative Groups. NCI staff will take an active role in promoting the timely completion of important studies, for example, by encouraging and facilitating inter-group collaboration when appropriate, or by assisting in the identification and mobilization of additional resources.

NCI staff will facilitate collaboration and promote standards of quality assurance for imaging sciences by identifying opportunities for the Network to provide imaging quality assurance services for other cooperative groups.

2.A.3. Collaborative Responsibilities

Development of Inter-group Activities. For certain types of scientific questions, particularly those involving the integration of imaging with therapeutic interventions, it may be desirable for the Network to seek collaboration with one or more of NCI's treatment cooperative groups. The investigators or NCI staff may initiate the establishment of these collaborations. From time to time the NCI holds disease- or modality-oriented strategy meetings for the purpose of jointly developing program priorities for future protocol development. Group investigators, NCI staff and other extramural investigators attend these meetings. The groups and NCI staff work together to facilitate the timely development of protocols resulting from the consensus developed at such strategy meetings. Investigators of the Network will be invited to attend these meetings as appropriate.

Investigational Drug/Imaging Agent and Device Development. When clinical trials of new imaging diagnostic or therapeutic approaches involving investigational drugs or devices are pursued, the clinical information resulting from these studies should be acceptable to the FDA for inclusion in a New Drug Application (NDA) or Product Manufacturing Application (PMA). In partnership with NCI staff and any collaborating drug or device company, the Network will develop protocols to obtain such information as needed.

Data and Safety Monitoring Committees (DSMB). Appropriate policies and procedures for the DSMB are a collaborative responsibility of the Network and involved NCI staff.

Patient Advocacy. The Network will establish and support the integration of the lay community participation into Network activities. This integration will be accomplished through encouragement and financial support for patient advocate involvement in Network activities, such as inclusion in Network meetings and appropriate committees. The Network will work with existing NCI groups designed to support patient advocate activities throughout the NCI clinical trials program. CIP staff will serve as liaison to the Network for NCI resources associated with patient advocacy relations.

Cooperative Group Chairs' Semi-Annual Meetings. The Chairs of each of NCI's treatment cooperative groups meet semi-annually to discuss issues of relevance to the clinical trials program. The Chair of the Network will be invited to attend this meeting to discuss issues relevant to the activities of the Network.

Cooperative Group Statisticians' Meetings. Similarly, the Network's Chief Statistician will be invited to attend the annual group statisticians' meeting to discuss issues of relevance to the clinical trials program.

Cooperative Groups Quality-of-Life (QOL) Meetings. The Network’s Chief Statistician or his designee will be invited to attend the annual group QOL meeting to discuss issues of relevance to the clinical trials program.

Participation in the NCI-Supported Initiatives. The Network will be expected to participate, to the extent that is reasonable within the limits of their resources, in NCI-supported initiatives aimed at advancing clinical imaging in cancer therapeutic trials as recommended by both the Clinical Trials Working Group and Translational Research Working Group of the NCI.

Each full member will have one vote. NCI’s ex-officio members will have zero votes. Awardee and PI members of the Network Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Network Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D, and HHS regulations 45 CFR Part 16.

3. Reporting

It is expected that the Network will provide for continuous evaluation of its overall performance, specifically the adequacy of both the scientific and financial aspects of the Strategic Scientific Plan; quality assurance and quality control of both data and patient safety; inclusion of women and minorities in clinical imaging trails; and leadership of the Network.

Comprehensive Strategic Scientific Plan: Within 3 months of award the Network will develop, articulate and begin execution of a comprehensive strategic plan that will outline research priorities with associated strategic budgetary formulations. The plan should address both short-term and long-term goals and include a balanced and interrelated program of small developmental and feasibility studies, larger pilot trials, and large-scale, multi-center efforts. This document is not to be submitted with the application, but must be submitted to and approved by the Program Director, CIP, and the Associate Director, CIP/DCTD/NCI, within 8 months of award. However, the application should include a discussion of how this strategic plan will be developed.

External Advisory Committee: Within 1 months of the award, the grantee will have established a fully functioning External Advisory Committee with the requisite representation of the oncology, imaging science, and industry communities. A listing of the members of this committee, their charter and plan of operations will be provided to the Program Director/DIB/CIP/DCTD/NCI. Composition of said board will meet the requirements mentioned in the Section above entitled Scientific plan and Need for Flexibility in Organization and Scientific Leadership.

Annual Reports, Annual Progress Reports must be submitted to the Program Director, CIP/DCTD/NCI, in accordance with guidelines provided by the NCI Program Director and the NCI Office of Grants Administration.

In addition to Progress Report, the Network will separately submit to the Program Director, CIP/DCTD/NCI Annual Reports on The Strategic Scientific Plan. These reports should include at least the following elements:

• Progress to date in the active protocols, protocols under development, and those in review;
• Specific progress related to the identified clinical oncology needs;
• Specific progress related to advances in methodologies/technologies;
• Specific progress related to the translation of research opportunities from pre-clinical investigations of interest and relevance to the oncology and imaging science communities;
• How the strategic budget formulations relate to the execution of the planned agenda; and
• Activities of the Network focused on engaging the public in imaging clinical research through their advocacy base and activities of their special populations committee.

The NCI Program Director will review annual reports on Network compliance with the individual protocol plans to conduct analyses by gender and racial/ethnic groups via population tracking activities of the NCI. The NIH Policy for research supported as NIH Phase III Clinical Trials has been amended in Section II.B. of the NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research- Amended October, 2001 (http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm).

Cumulative subject accrual and progress in conducting subset analyses must be reported to the CIP Program Director in the annual Progress Reports. Final analyses of gender and racial/ethnic differences must be reported in the required Final Progress Report or Competitive Renewal Applications (or Contract Renewals/Extensions) as stated in Section II.B. of the Guidelines.

The Network will provide for a process of evaluation of the performance of the core leadership of the Network, including the Chair, as well as the performance of participating sites on an annual basis. This evaluation will result in an annual report to the Associate Director, CIP/DCTD/NCI.

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

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We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

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 (for express/courier delivery; non-USPS service)
Telephone: (301) 594-5225
Fax: (301) 402-3507
Email: [email protected]

2. Peer Review Contacts:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for express/courier delivery; non-USPS service)
Telephone: (301) 496-3428
Fax: ( 301) 402-0275
Email: [email protected]

3. Financial or Grants Management Contacts:

Ms. Amy Connolly
Grants Management Specialist
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard
EPS Room 243, MSC 7150
Bethesda, MD 20892-7150
Telephone: (301) 496-8786
Fax: (301) 496-8601
Email: [email protected]

Section VIII. Other Information

Required Federal Citations

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); and efficacy, effectiveness, and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (IRB) rules, as well as local, State, and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are: (1) first produced in a project that is supported in whole or in part with Federal funds; and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from: 1) currently funded NIH research projects; or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information," the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The Loan Repayment Program (LRP) is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for 2 years to the research. For further information, please see http://www.lrp.nih.gov.