Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Cancer Institute (NCI)
Funding Opportunity Title	NCI National Clinical Trials Network - Canadian Collaborating Clinical Trials Network (Limited Competition U10)
Activity Code	U10 Cooperative Clinical Research Cooperative Agreements
Announcement Type	New
Related Notices	October 20, 2017 - This RFA has been reissued as RFA-CA-17-058.
Funding Opportunity Announcement (FOA) Number	RFA-CA-12-504
Companion Funding Opportunity	RFA-CA-12-010; RFA-CA-12-011; RFA-CA-12-012; RFA-CA-12-013; RFA-CA-12-014
Number of Applications	Only one application from an eligible institution is allowed as defined in Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.394, 93.395
Funding Opportunity Purpose	This funding opportunity announcement (FOA) solicits applications from institutions/organizations to establish a Canadian Collaborating Clinical Trials Network for the NCI National Clinical Trials Network (NCTN). The goal of the NCTN is to develop and conduct state-of-the-art cancer treatment and advanced imaging clinical trials, especially large, definitive multi-institutional trials evaluating new cancer therapies and related clinical approaches for both adult and pediatric patients. The NCTN consists of six components each with its own FOA, which are: Network Group Operations Centers; Network Group Statistics and Data Management Centers; Network Group Integrated Translational Science Centers; Lead Academic Participating Site Centers; Network Radiotherapy and Imaging Core Services Centers; and a Canadian Collaborating Clinical Trials Network (covered by this FOA). The NCTN Canadian Collaborating Clinical Trials Network will be a full partner with the U.S. Network in the conduct of large-scale, multi-site clinical trials and help provide regulatory expertise/oversight for the conduct of NCTN trials in Canada. The competition for an award under this FOA is limited to eligible Canadian institutions.

Posted Date	July 23, 2012
Letter of Intent Due Date	December 15, 2012
Application Due Date(s)	January 15, 2013
AIDS Application Due Date(s)	Not Applicable.
Scientific Merit Review	June, 2013
Advisory Council Review	October, 2013
Earliest Start Date(s)	March 1, 2014
Expiration Date	January 16, 2013
Due Dates for E.O. 12372	Not Applicable.

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) is one of six FOAs that reflect the comprehensive effort by the National Cancer Institute (NCI) to transform the previous NCI-sponsored Clinical Trials Cooperative Group Program from supporting several individually operating Cooperative Groups into a new consolidated and integrated NCI National Clinical Trials Network (NCTN) Program. The overall goal for the entire NCTN Program is to conduct definitive, randomized, late phase clinical treatment trials and advanced imaging trials across a broad range of diseases and diverse patient populations as part of the NCI’s overall clinical research program for adults and children with cancer. The NCTN will also conduct, as necessary, smaller developmental studies preliminary to the definitive trials. The NCTN Program will be based on an integrated network of clinical trials groups that will collaborate with each other as well as with other NCTN components and other NCI-sponsored programs and investigators.

The NCTN Program will support the following components that will be individually awarded through the respective FOAs indicated below:

1) Network Group Operations Centers under RFA-CA-12-010 (U10) (up to 5 awards);

2) Network Group Statistics & Data Management Centers under RFA-CA-12-011 (U10) (up to 5 awards);

3) Network Group Integrated Translational Science Centers under RFA-CA-12-012 (U10) (5-7 awards);

4) Network Lead Academic Participating Sites under RFA-CA-12-013 (U10) (30-40 awards);

5) Network Radiotherapy & Imaging Core Services Centers under RFA-CA-12-014 (U24) (up to 1 award); and

6) Canadian Collaborating Clinical Trials Network RFA-CA-12-504 (Limited Competition U10) (this FOA, up to 1 award).

The new consolidated structure of the NCTN is designed to comprise five U.S. Network Groups (up to 1 pediatric group and up to 4 adult groups) and up to 1 Canadian Network Organization. Each U.S. Network Group will be organized around a dedicated Operations Center working with an affiliated Statistics and Data Management Center and other NCTN components as appropriate.

Note: An overview of the roles of individual NCTN components is outlined below. However, it is imperative that prospective applicants read the individual FOAs for those components for which they intent to apply.

This FOA provides expanded information specific to Canadian Collaborating Clinical Trials Network and details needed to apply for a Canadian Collaborating Clinical Trials Network award.

For more than 50 years, the NCI has supported a standing clinical trials infrastructure the NCI National Clinical Trials Cooperative Group Program (also referred to as the "Group Program") funded through the Division of Cancer Treatment and Diagnosis (DCTD) to conduct large-scale, clinical treatment trials across the nation. The Group Program has successfully completed many important trials that have led to new treatments for cancer patients. Its activities have involved more than 3,100 institutions and 14,000 investigators enrolling between 20,000 to 25,000 patients in clinical treatment and advanced imaging trials each year over the past decade. The Group Program has promoted the evaluation of multi-modality treatments and combinations of novel agents. In addition, studies supported by Group Program have emphasized clinical trials in members of special populations (e.g., children, young adults, and underserved populations) and clinical trials focused on rare tumor types. This focus has allowed the Group Program to complement, rather than duplicate, research supported by the private sector.

Cancer medicine has evolved in recent years into a more molecularly-based discipline. Diagnosis is being improved through genetic sub-classification as well as functional imaging of tumors and new treatments are being developed aimed at specific cancer-related pathways. As part of its effort to take advantage of new discoveries in oncologic science, NCI asked the Institute of Medicine (IOM) in 2009 to review the NCI-sponsored Clinical Trials Cooperative Group Program. The IOM report (http://iom.edu/Reports/2010/A-National-Cancer-Clinical-Trials-System-for-the-21st-Century-Reinvigorating-the-NCI-Cooperative.aspx) noted that, despite its impressive record of accomplishment, the current trials system has become less efficient, has difficulty prioritizing studies, and has been underfunded for the number of trials that it conducts. The IOM report recommended that the existing adult Clinical Trials Cooperative Groups be consolidated into a smaller number of Groups, each with greater capabilities and appropriate incentives to promote better overall system integration. Consolidation should promote efficiency by encouraging a structural makeover of clinical trial group operations centers and statistics and data management centers. It should also facilitate prioritization in clinical research by focusing trials even more than before on questions unlikely to be addressed by the private sector.

Based on the IOM review recommendations as well as additional input received by the NCI from stakeholders across the oncology community, the NCI has developed a comprehensive plan to transform the previous NCI-sponsored Clinical Trials Cooperative Group Program that funded several separate organizations conducting cancer treatment trials into a new consolidated and integrated Program referred to as the NCI National Clinical Trials Network (NCTN).

The overall goal of the NCTN Program is to conduct definitive, randomized, late phase clinical treatment trials and advanced imaging trials across a broad range of diseases and diverse patient populations, as well as development efforts preliminary to those trials, as part of the NCI’s overall clinical research program for adults and children with cancer.

In order to achieve the overall goal of the Program, essential features of the NCTN will include:

• A coordinated, collaborative, and inclusive process, i.e., involving broad representation from the oncology community including academic and community clinical investigators, translational science investigators, biostatisticians, and patient advocates for generating concepts, primarily for late phase, definitive, clinical trials to evaluate innovative cancer treatments in specific cancers and/or with a focus on specific modalities (e.g., imaging, radiation, surgery);
• Prioritization of trial concepts for development and conduct by national NCI-managed disease and modality-specific steering committees composed of leading cancer experts and advocates from the extramural community, including Network Group representatives, as well as NCI, consistent with national priorities for clinical cancer research;
• Efficient and timely activation, conduct, and completion of clinical trials meeting all regulatory requirements, through the effective integration of scientific expertise and clinical trials management capabilities; and
• Incorporation of innovative science into clinical trials through collaboration among institutions and investigators with expertise in various medical specialties/disciplines relevant to treatment of adult and childhood cancers (e.g., pharmacology, clinical oncology, imaging) as well as those with expertise to integrate translational science into design and conduct of NCTN trials.

In the NCTN Program, a Network Group is defined as a clinical trials group with a dedicated Operations Center and an associated Statistics and Data Management Center responsible for the design and development of clinical trials as well as the conduct of trials via member institutions/sites that enroll patients. Member sites of Network Groups include institutions/sites that are funded either directly by the Network Group Operations Center for their participation in NCTN trials or through other funded key components of the NCTN (i.e., Lead Academic Participating Sites award) or through related NCI-sponsored programs that fund participation (i.e., Community Clinical Oncology Program, Minority-based Community Clinical Oncology Program). Network Groups are expected to collaborate with each other and with NCI to achieve the overall goal of the Program. Member institutions/sites of Network Groups will be able to enroll patients on all adult Phase 3 trials as well as select early phase trials, irrespective of the specific Network Group that is leading the trial. In addition, select trials for adolescent and young adults will be open to all member institutions/sites. Network Groups will also provide trial operations, data management, and statistical support for approved, multi-center Phase 2 and Phase 3 trials originating outside the Network.

Each Network Group will have an integrated organizational structure encompassing scientific leadership, statistics, clinical trial operations, data management, and administration. Network Groups will be funded through an Operations Center award (covering scientific leadership, trial operations, and general administration including oversight of member institutions/sites enrolling patients) and a separate Statistics and Data Management Center award (covering statistical design and data management). Organizations may also apply for a separate, integrated, translational science support center award with support from one or more Network Groups - i.e., Operations Center(s) and associated Statistics and Data Management Center(s) to facilitate integration of translational science into the design of clinical trials conducted by the supporting Network Group(s).

In addition to the awards described above, the NCTN Program will involve several awards to Lead Academic Participating Sites or institutions to support scientific leaders at those sites who are affiliated with one or more Network Groups to provide leadership in the design and conduct of trials as well as to support patient enrollments at their sites to NCTN trials. The Program will also support an award for an organization to provide core services related to incorporating appropriate quality assurance and credentialing of radiotherapy and imaging techniques/approaches in clinical trials to all the Network Groups and an award to sponsor a corresponding Canadian clinical trials organization to partner with the Network Groups in the U.S. in the design and conduct of NCTN trials.

Each of these key components of the NCTN Program is described briefly below.

• Network Group Operations Centers: The Operations Center will provide scientific leadership for developing and implementing multi-disciplinary, multi-institutional trials in a range of diseases and special populations with specific scientific strategy and goals. The scientific goals may include strategic innovation in advanced technology for specific research areas (e.g., advanced imaging methods/agents, radiotherapy) and the testing of innovative concepts and tools in prospective, multi-institutional clinical trials. Operations Centers will be responsible for trial operations including timely protocol development and management, compliance with FDA and OHRP regulatory and patient protection requirements, audits, training, quality assurance, and site support. The Operations Center is expected to be closely integrated with the Statistics and Data Management Center in all aspects of trial operations through jointly developed policies and procedures for clinical trial development and conduct. The Operations Center will also be responsible for Network Group administration, including financial management, monitoring of member institution/site performance, coordination of biospecimen collection from patients on clinical trials, and adherence to all applicable NIH/NCI policies and regulations. Network Groups Operations Centers will also provide trial operations for approved, multi-center Phase 2 and Phase 3 trials originating outside the Network Group.
• Network Group Statistics and Data Management Centers: These Centers will be responsible for providing the statistical expertise required to ensure effective scientific design and conduct of clinical trials as well as leadership in innovation in statistical methodology. The Centers will also be responsible for data management, data analysis, and statistical analysis for trials led by the Network Group (including approved, multi-center Phase 2 and Phase 3 trials originating outside the Network Group) as well as for translational and other ancillary studies associated with trials, working closely with trial operations staff from the associated Network Group Operations Center.
• Network Group Integrated Translational Science Centers: These awards will provide support for leadership and expertise to facilitate incorporating translational science into Network Group clinical trials.
• Network Lead Academic Participating Sites: These academic institutions/sites will provide scientific leadership in development and conduct of clinical trials in association with 1 or more adult Network Groups as well as substantial accrual to clinical trials conducted across the entire NCTN. The eligibility to apply for these awards is restricted to clinical academic centers. For the purposes of this award, clinical academic centers are distinguished from large medical centers whose primary mission is patient care, as in addition to patient care, clinical academic centers have comprehensive medical training programs and preclinical laboratories that perform basic science research.
• Network Radiotherapy/Imaging Core Services Centers: This institution/organization will provide scientific and technical expertise for incorporation of appropriate, integrated quality assurance and image data management for applicable clinical trials conducted by the NCTN that require specialized quality assurance or imaging data management and/or assessment. In addition, the centers will also provide similar services for other approved NCI-supported clinical trials programs (e.g., NCI/DCTD early phase clinical trials).
• Canadian Collaborating Clinical Trial Network: This Canadian organization will be a non-profit clinical trials organization capable of being a full partner with the U.S. Network in the conduct of large-scale, multi-site clinical trials. Incorporation of a Canadian Clinical Trials Network as a collaborating partner brings an additional advantage as U.S. Network Groups are anticipated to have Canadian member sites. A Canadian network will be able to help reduce duplicative regulatory staff at each U.S. Network Operations Center.

Interactions with Other NCI-supported Programs. In addition to the six key components of the NCTN that are described above and will be directly funded by the NCTN Program, other NCI grant and contract supported Programs and their awardees as well as NCI Advisory Committees will have important supporting roles in carrying out the research objectives of the NCTN Program. Thus, the NCTN awardees will be expected to interact as appropriate with such entities/programs as the NCI Clinical Trials Tumor Banks, the Community Clinical Oncology Program (CCOP) and Minority-Based Community Clinical Oncology Program (MB-CCOP), the NCI Cancer Trials Support Unit, the pediatric and adult NCI Central Institutional Review Boards, and NCI Advisory and Scientific Committees including the NCI Scientific Steering Committees.

The competition for an award under this FOA is limited to eligible Canadian institutions. The Canadian Collaborating Clinical Trials Network application must address the following 4 required functional components:

• Clinical Trial Development & Member Site Accrual Program This functional component should consist of a well-defined research strategy by the applicant for the development of clinical trials in specific disease areas and patient populations and a well-defined plan for robust accrual to NCTN trials by the applicant's member institutions/sites, both trials led by the applicant as well as trials led by other Network Group Operations Centers.
• Operational Management This functional component should describe the applicant's organizational structure, governance, standard operating procedures, and operational efficiency program in order to demonstrate the applicant's capability to develop, activate, and conduct clinical trials in a timely manner.
• Statistics Analysis and Data Management Program -This functional component should consist of a well-defined organization, approaches, policies, and procedures for statistical analysis of clinical trials in specific disease areas and patient populations and a well-defined plan for data management of NCTN trials, both trials led by the applicant (including approved, multi-center Phase 2 and Phase 3 trials that originate from outside the applicant's organization) as well as for translational and other ancillary studies associated with the trials.
• Program for Collaborations and Participation in Collective Management This functional component should consist of a well-defined plan for potential collaborations by the applicant with other Network Groups and NCI-sponsored investigators and programs as well as how the applicant plans to participate in the collective management of the NCTN.

PROGRAM EVALUATION: The NCTN program will be subject to external evaluation near the end of the funding period (to be coordinated by the NCI Program Staff). Such evaluation is part of NIH efforts to optimize the efficiency of the funded research. The evaluation process will involve monitoring and assessing the progress of the NCTN toward achieving its goals. This aspect includes evaluating the quality, value, and scientific impact of the clinical trials and other research activities conducted by the NCTN, timeliness of clinical trial development and completion, efficiency of operations, effort integration and collaborations across the Network, and interactions with other relevant NCI-sponsored organizations and programs. For the efficient evaluation of the NCTN Program, cooperation of all the NCTN awardees (for all types of the NCTN components) will be important and expected.

Funding Instrument	Cooperative Agreement
Application Types Allowed	New The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The National Cancer Institute intends to commit an estimated total of $3 million for up to 1 award in FY 2014. Future amounts will depend on annual appropriations.
Award Budget	Application budgets are not limited, but need to reflect actual needs of the proposed project.
Award Project Period	5 years

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• For-Profit Organizations (Other than Small Businesses)

Other

• Regional Organizations

Only eligible organizations headquartered in Canada are eligible to apply. U.S. and other non-domestic (non-U.S.) Entities (Foreign Institutions) from other countries are not eligible to apply."

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• eRA Commons

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least4-6 weeks prior to the application due date.

With the restrictions defined below, any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 Application Guide.

Important Restriction

An individual who is designated as a PD/PI on the application for a Canadian Collaborating Clinical Trials Network MUST NOT be listed as a PD/PI on an application for any of the NCTN Components listed below:

• Network Group Operations Centers (RFA-CA-12-010);
• Network Group Statistical and Data Management Centers (RFA-CA-12-011);
• Network Lead Academic Participating Sites (RFA-CA-12-013);
• Network Radiotherapy and Imaging Core Services Centers (RFA-CA-12-014.

However, an individual who is designated as a PD/PI on the application for a Canadian Collaborating Clinical Trials Network can, if appropriate, be listed as key personnel in the application the Network Radiotherapy and Imaging Core Services Centers (RFA-CA-12-014), but not on the other applications listed above.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Each applicant organization may submit only one application in response to this FOA.

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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 IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, 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 PD(s)/PI(s)
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

The letter of intent should be sent to:

Meg Mooney, MD
Clinical Investigations Branch, Cancer Therapy Evaluation Program
National Cancer Institute
6130 Executive Boulevard, Room 7024, MSC 7340
Bethesda, MD 20892-7340 (for U.S. Postal Service regular or Express Mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: 301-496-2522
Email: ncictepanalyst@mail.nih.gov

Applications must be prepared using the PHS 398 research grant application forms and 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 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

At the time of submission, two additional paper copies of the application and all copies of the Appendix files must be sent to:

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 regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: 301-496-3428
Email: ncirefof@dea.nci.nih.gov ]

All page limitations described in the PHS398 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements: Section 3 - Research Strategy of the PHS 398 Research Plan must consist of the new sub-sections A-E with the following individual page limits as noted below.

A. Operations, Statistics, and Data Management Center Overview - 6 pages

B. Clinical Trial Development and Member Site Accrual Program- 12 pages

C. Operational Management 12 pages

D. Statistics Analysis and Data Management Program - 12 pages

E. Program for Collaborations and Collective Management - 12 pages

In addition to standard information, provide in this section documentation of important capabilities and available resources as indicated for specific functional components of the Canadian Collaborating Clinical Trials Network below. Relevant information may be provided in tabular form as listed below. Applicants are strongly encouraged to use, as appropriate, table templates provided in Part 4 - Appendices - Section II.A. of the Guidelines document for the NCTN Program (http://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policies) related to Operations Center activities.

Table 1. Key Leadership Staffing

Table 2. Primary Scientific Achievements for Trials by Disease Area, Trial Phase, & Trial #

Table 3. Other Important Achievements for Trials by Disease Area, Trial Phase, & Trial #

Table 4. List of Approved Applications for Use of Banked Biospecimens from Clinical Trials

Table 5. Summary Accrual for All Clinical Trials (All Diseases & All Phases)

Table 6. Summary Accrual For Major Disease Categories (All Phases)

Table 7. Summary Accrual For Trial Phase within Major Disease Categories

Table 8. Operational Timelines for Development of Clinical Trial Proposals

Table 9. Operational Timelines for Trial Conduct by Disease Category, Trial Phase/#

Table 10. Operational Timelines for Trial Completion by Disease Category, Trial Phase/#

Table 11. Summary of Onsite Auditing Activity for Clinical Trials

Applicants are strongly encouraged to use, as appropriate, table templates provided in Part 4 - Appendices - Section II.B. of the Guidelines document for the NCTN Program (http://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policies) related to Statistics and Data Management Center activities.

Table 1. Key Leadership Staffing

Table 2. Summary of General Data Timeliness

Table 3. Summary of Data Quality and Data Timeliness Serious AE Reporting

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:

This section must consist of the subsections A-E described below. For full details on the content and organization of the individual sub-sections please see the Guidelines document for the NCTN Program in Part 2 - Section II.G.2.

Sub-Section A. Operations, Statistics, and Data Management Center Overview (up to 6 pages)

This section should provide a general overview of the Operations, Statistics, and Data Management Center of the Canadian Collaborating Clinical Trials Network organization and

describe the general features and operations of the organization. The applicant should provide a

diagram illustrating the organizational structure of the organization in this section and describe

how the Canadian Collaborating Clinical Trials Network would interact with the other key

components of the NCTN Program.

Sub-Section B. Clinical Trial Development & Member Site Accrual Program (up to 12 pages)

This functional component should consist of a well-defined research strategy by the applicant for the development of clinical trials with a specific research focus and patient populations that complement the research strategy of the U.S. NCTN Program. In particular, the applicant should address how its research agenda will complement the NCTN Program as a whole even though the applicant would be expected to participate in only a limited portion of the NCTN Program. The applicant should address the plan/process it will use to help decide what research collaborations to pursue with the NCTN Program. The applicant should highlight its most important achievements over the past 5-6 years as well as its most promising current and future research initiatives and trials as an indication of its potential to contribute to the NCTN Program. This section should also include information on the applicant’s senior research teams (for scientific research committees and administrative committees) and the applicant should also describe how it will mentor new/young investigators in clinical trial research.

NOTE: Information on the applicant’s scientific leadership in clinical trial development as well as achievements of its past (over the prior 5 to 6 years) and current clinical trial development program may be summarized in tables as described in the Resources Section above.

This functional component should also consist of a well-defined plan for accrual to NCTN trials by the applicant's member institutions/sites. This plan should encompass accrual to the occasional trial led by the applicant as well as trials that will be led by U.S. Network Groups Operations Centers. Emphasis should be placed on potential overall accrual across the entire NCTN. This section should present information on the potential of the applicant to accrue patients to oncology clinical treatment trials and advanced imaging trials in a publicly funded clinical trials system across a broad range of diseases, including rare cancers, via its member institutions/sites.

NOTE: The applicants are expected to highlight the track record of the applicant team and its member sites for accrual over the past 5-6 years, in addition to details presented in accrual summary tables to be included under "Resources", as indicated above.

Sub-Section C. Operational Management (up to 12 pages)

This functional component should describe the applicant's organizational structure, governance, standard operating procedures, and operational efficiency program in order to demonstrate the applicant applicant's capability to develop, activate, and conduct clinical trials in a timely manner. The scope and authority of the applicant's leadership team for operations, statistics, and data management, the Director of Operations position, and the Executive/Advisory Committee should be described, including succession planning for key leadership positions. This description should also include the relationship/rules for institutional membership in the Canadian Collaborating Clinical Trials Network as well as financial management policies.

For applications designating multiple PD(s)/PI(s), a leadership plan related to the multiple PD(s)/PI(s)

designation must be included in the appropriate section of the application (i.e., Multiple

Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) Leadership Plan section of the PHS 398). A rationale for choosing a multiple PD(s)/PI(s) approach should be described. The governance and organizational structure of the leadership team for the Canadian Collaborating Clinical Trials Network should be described including communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the organization should be delineated for the PD(s)/PI(s), including responsibilities for human subjects in clinical studies. If budget allocation is planned, the distribution of resources to specific components of the organization and/or the individual PD(s)/PI(s) should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote of the Notice of Award.

The applicant's plan for operational efficiency in study development, trial activation, and timely completion of studies it leads as well as timely activation within Canada for NCTN trials that the Canadian Collaborating Network decides to participate in. The applicant team should describe how they will provide regulatory support for Canadian sites to participate in NCTN trials led by U.S. Network Groups

Also explain how the Canadian team will use the NCI standard tools and services for the conduct of clinical trials (e.g., Clinical Data Management System, Oncology Patient Enrollment System, and Regulatory Support System for the NCTN). Address how the Canadian Collaborating Network will assure compliance with NCI, NIH, and HHS policies and all applicable U.S. federal regulations regarding the protection of human subjects in clinical research. Explain how the Canadian Collaborating Network will address study monitoring and reporting (e.g., explain how these aspects are covered by the applicant’s policies on Data Safety and Monitoring, Data Sharing, Biospecimen Sharing, Onsite Auditing, and Clinical Trial Registration and Reporting). Describe the applicants' plan to ensure that results from clinical trials will be published in peer-reviewed manuscripts in a timely manner consistent with NCTN Program requirements.

NOTE: The applicants' capabilities and potential to conduct large-scale operations related to developing, activating, and conducting clinical trials is essential and will be a factor in the application merit evaluation. In this sub-Section, the applicants are expected to highlight their most relevant achievements over the past 5-6 years, in addition to details presented in summary tables to be included under "Resources", as indicated above.

The applicant’s key standard operating procedures for the conduct of clinical trials related to the following may also be provided in the Resource section of the application:

• Data and Safety Monitoring Policy for Phase 3 Trials and Randomized Phase 2 Trials
• Data and Safety Monitoring Plan for Phase 1 and Phase 2 Trials
• Conflict of Interest Policy
• Onsite Auditing Policy and Procedures
• Constitution & By-laws for Institution/Site Membership and Individual Participant/Investigator Membership (including Scientific and Administrative Committee Membership)
• Standard Template for the Informed Consent Document

Sub-Section D. Statistical Analysis and Data Management Program (up to 12 pages):

This functional component should consist of a well-defined organization, approaches, policies, and procedures for statistical analysis and data management of clinical trials led by the applicant (including any approved, multi-center Phase 2 and Phase 3 trials that originated from investigators outside the applicant's organization). The applicant should describe briefly the general approach to statistical trial design and analysis plans for multi-institutional clinical trials, including guidelines for interim monitoring and general procedures for sample size estimation and choice of testing and estimation procedures. Examples of robust statistical trial designs and statistical support should be described as well as how the organization provides statistical leadership in design and analysis, including incorporating new, integral and integrated, molecular and imaging biomarkers and laboratory studies into the overall evaluation of NCTN trials. The applicant should also describe how the organization ensures that final study analyses are performed in a manner to provide timely publication of study results and results reporting per NCI and federal regulations. The applicant should provide a brief description of the data management and study monitoring practices of the SDMC, including the flow and review of data following submission from individual institutions/sites and investigators. The applicant should describe the data management systems employed and how the SDMC would use standard NCTN tools including the NCTN Common Data Management System (CDMS) and use of NCTN-approved Common Data Element (CDEs) from the Cancer Data Standards Registry and Repository (ca-DSR), the NCTN Regulatory Support System (RSS), the NCTN Oncology Patient Enrollment Network (OPEN), the NCI/DCTD Clinical Data Update Systems (CDUS/CDS), the NCI Expedited Adverse Event Reporting System (AdEERs), the NCI Common Terminology Criteria for Adverse Events (CTCAE) for data management for NCTN trials, and trial registration in the NCI Clinical Trials Reporting Program (CTRP) and in the NIH National Library of Medicine (NLM) (www.clinicaltrials.gov) along with results reporting, as applicable.

Brief descriptions of training for investigators (including mentorship for junior investigators), Clinical Research Associates, and study chairs related to data management and study monitoring for clinical trials should be provided. The applicant should also describe procedures for study monitoring as well as for data quality control and accuracy verification, including how the organization conducts auditing activities. The applicant's method for active trial monitoring, including procedures for accrual and biospecimen collection tracking, assessing case, eligibility and evaluability, ensuring timely medical review and assessment of patient data, monitoring of data timeliness, and facilitating staff interactions with study chairs should be described briefly. The applicant should describe the organization's guidelines for institutions/sites for data timelines, including a summary of data quality and timeliness as an indication of its potential to operate efficiently within the NCTN Program.

NOTE: Appropriate summary documentation of the track record of the applicant team with respect to key statistical leadership staffing and timely data management and data collection for clinical trials over the past 5 to 6 years may be presented in summary tables to be included under "Resources", as indicated above. In addition, the applicant's key standard operating procedures for the conduct of clinical trials related to the following may also be provided in the Resource section of the application:

• Procedures for Statistical Analysis (e.g., guidelines for interim monitoring, general procedures for sample size estimation, accrual rate estimation, and choice of testing and estimation procedures)
• Data Management and Monitoring Policies & Procedures for Clinical Trials
• Procedures to Ensure Security and Confidentiality of Patient Data
• Conflict of Interest Policy
• Onsite Auditing Policy and Procedures
• Model Statistical Analysis Template for Clinical Trials
• Sample of Trial Reports (i.e., 5 trials) from the SDMC Report of Studies

The applicant should also describe the facilities and equipment available as well as the information technology (IT) support for central storage, security, analysis and retrieval of clinical data. The applicant should describe how it complies with guidelines for good clinical practice and with federal/DHHS/NIH/NCI regulations for clinical research involving human subjects as well as with NCI/NIH administrative requirements for conduct of clinical trials with respect to NCI/DCTD's Intellectual Property (IP) Option and NCI/DCTD's collaborative binding agreements for NCI/DCTD Investigational New Drug (IND) or Device Exemption (IDE) studies.

Sub-Section E. Program for Collaborations/Participation in Collective Management (up to 12 pages)

This functional component should consist of a well-defined plan for potential collaborations by the applicant with U.S. Network Groups and NCI-sponsored investigators and programs as well as how the applicant plans to participate in the collective management of the NCTN.

The applicant should address how it can contribute to the collective management of the NCTN Program through examples of participation in the NCI Scientific Steering Committees (SSC) and associated Task Forces and Working Groups, and Planning Committees for SSC Clinical Trials Planning Meetings, or examples of similar activities in other clinical trial network as indications of its potential to participate in the collective management of the NCTN. The applicant should also discuss its ability to complete development of study proposals and conduct future trials that may originate outside the NCTN Program if they are approved by the NCI disease-specific SSCs.

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS398 Application Guide with the following modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. An example of a Data Sharing Plan for Network Group Operations Centers and associated Network Group Statistics and Data Management Centers for the NCTN Program is provided in Part 4 - Appendices - Section VII in the Guidelines document for the NCTN Program.
• Generally, Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms if applicable, and GWAS Sharing Plan) are expected for this FOA.

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will not be reviewed.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by the NCI. Applications that are incomplete and/or nonresponsive will not be reviewed.

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI. "Award Administration Information. The applicant should review the Cooperative Agreement Terms and Conditions of Award prior to preparing the application as these terms include information and clarifications needed by the applicant to understanding the complete requirements of a Canadian Collaborating Clinical Trials Network award.

Information on the targeted/planned enrollment for minorities and members of both genders as well as children, if applicable, should be based on accrual summarized across all diseases for the planned project period, not on a study or disease-specific basis.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115. Note: Because applications submitted in response to this FOA have only one due date, applicants may submit materials per the exceptions list provided in NOT-OD-10-115 using the specified page limits.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, the emphasis is on the capabilities and experience of the applicant team in successfully developing, organizing, and coordinating large scale definitive clinical trials. As all applications submitted in response to this FOA will be new applications, those aspects will be largely evaluated based on the prior performance and productivity of the applicants. These capabilities and commensurate performance/productivity must be appropriate for the conduct of large-scale, multi-site clinical trials for NCTN in Canada and consistent with other specific requirements stated in this FOA. The required capabilities and experience are expected to reflect the properly documented successful performance of the applicant team under the former NCI National Clinical Trials Cooperative Group Program or equivalent large-scale NIH or other non-profit clinical trials networks or programs. Reviewers will be using this information as benchmarks in evaluating all aspects of the application, including plans for the specific components of the proposed Canadian Collaborating Clinical Trials Network and its overall scientific potential.

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the proposed Canadian Collaborating Clinical Trials Network to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the proposed Canadian Collaborating Clinical Trials Network proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a proposed Clinical Trials Network by its nature may not be innovative but it may be essential to advance a field.

Significance

Does the proposed Canadian Collaborating Clinical Trials Network address an important problem or a critical barrier to progress in the field? If the aims of the proposed Canadian Collaborating Clinical Trials Network are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the proposed Canadian Collaborating Clinical Trials Network? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? Given that the NCTN research projects/clinical trials are collaborative and the proposed Canadian Collaborating Clinical Trials Network will be involved in collaborative activities (and irrespective of whether the applicants choose to use the multi-PD(s)/PI(s) option), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the clinical research conducted by the proposed Canadian Collaborating Clinical Trials Network?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the proposed Canadian Collaborating Clinical Trials Network? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

Since the proposed Canadian Collaborating Clinical Trials Network will conduct

clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, , if applicable, , justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the clinical research conducted by the proposed Canadian Collaborating Clinical Trials Network benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the research that the Canadian Collaborating Clinical Trials Network applicant has proposed, reviewers will evaluate the following additional items A-D listed below while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Overall Research Strategy: Does the applicant articulate a clear, well-developed, overall research strategy to achieve the stated clinical research goals with respect to complementing the research of the U.S. Network Groups of the NCTN Program? Is the research strategy for complementing research activities of the NCTN Program practical and feasible? Are the disease areas included in the applicant’s overall research strategy appropriate and beneficial to the NCTN? How well would the applicant contribute to the development of and/or accrual to clinical trials in rare cancers?

Clinical Trial Quality: Based on the clinical trials currently being conducted as well as those proposed, what is the likelihood that the applicant's team can contribute meaningfully to the goals of the NCTN? Do the trials contain important integral and integrated translational science research questions that are appropriate and well justified? To what degree do their results reflect qualitatively new knowledge that advances the field and may inspire future clinical trials? Will (or have) the results lead (led) to meaningful practice changes for cancer care or other meaningful impacts (e.g., Phase 2 trials leading to Phase 3 trials conducted by government or private sector, provision of important toxicity or dosing information)? Does the applicant team have effective mechanisms for promoting timely presentation and publications of the results of clinical trials and associated studies?

Senior Group Leadership for Clinical Trials Development: How well can the PD(s)/PI(s) and the entire team of investigators assembled by the applicant provide scientific leadership for state-of-the-art early and late phase clinical trials? Will these investigators be able to work as a cohesive research team to efficiently and expeditiously develop and conduct NCTN clinical trials? Does the applicant have appropriate and clearly defined succession and transition plans for the senior leadership of the proposed Canadian Collaborating Clinical Trials Network?

Are the scope and authority of the senior leadership, Director of Operations position, and Executive/Advisory Committee for the organization clearly and appropriately addressed? Are the background and expertise of the proposed Director of Operations appropriate to oversee the operational management of the Group? Are the policies and procedures for institution/site membership (included in the Constitution and By-laws of the proposed Canadian Collaborating Clinical Trials Network) clear and appropriate for the NCTN Program?

If the application includes multiple PD(s)/PI(s) , are the proposed leadership governance, organizational structure, and decision-making processes and interactions among the members of the leadership team for the application optimal for achieving the goals of the application and the overall NCTN Program?

Do the research experience and qualifications of the leadership of the applicant's Scientific Research Committees provide multi-disciplinary representation (e.g., medical oncology, radiation oncology, imaging, surgery, pathology, translational science, patient advocacy) across a broad range of diseases appropriate to the stated research goals? Are the experience and qualifications of the leadership of the applicant's Administrative Committees appropriate for development and oversight of the administrative management categories needed for conducting both early phase and especially late phase, multi-institutional clinical trials (e.g., support functions for trials including involvement of patient advocates, support programs for enrollment of underserved patient populations, financial management)?

Training and Investigator Leadership Mentoring/Training: Does the applicant have appropriate training programs for study chairs and Clinical Research Associates (CRAs)? Does the applicant have a mentorship/training program for new and junior investigators that provides opportunities for leadership of clinical trials (e.g., developing concepts for trial proposals, serving as study chairs for trials, participating in scientific committees in support or leadership roles, participating in other clinical trial activities) at appropriate levels as well as the potential to provide opportunities to these investigators to participate in the future in NCTN activities or initiatives?

Accrual Potential: Given its past track record of accrual, does the applicant have the potential to provide accrual to clinical trials conducted across the NCTN as a whole, especially in the applicant's stated areas/diseases of research interest, given the patient population of Canada? Does the applicant have the potential to contribute to accrual of Canadian minority and underserved patient populations to trials? Do the applicant's member institutions/sites have the potential to contribute to accrual of patients to NCTN clinical trials in rare tumors as needed for the NCTN goals? Does the applicant demonstrate the ability to meet protocol-specified accrual goals in a timely manner for trials it conducts?

B. Operational Management Program

Operational Structure, Policies, and Procedures: Are the organizational structure and management policies of the proposed Canadian Collaborating Clinical Trials Network clear and appropriate, including appropriate sound financial management policies and procedures for grant administration, subcontracting with collaborating organizations, purchase service agreements for member institutions/sites, and other related activities (e.g., laboratory testing needed for specific clinical trials)? Does the applicant incorporate procedures and tools that enhance coordination and productivity of operational activities including protocol development?

If the applicant proposes to include international institutions/sites as full members of the Canadian Collaborating Clinical Trials Network participating in NCTN trials, does the applicant propose appropriate monitoring plans for these sites as well as performance assessment monitoring to ensure that the NCTN-supported activities meet the same requirements regarding conduct of clinical trials expected of full U.S. member institutions/sites? If the applicant plans to enrolls patients on clinical trials that are led by non-NCTN international clinical trials organizations, does the applicant propose appropriate policies and procedures to comply with the applicable regulations and requirements defined in the Terms and Conditions of the Award for a Canadian Collaborating Clinical Trials Network?

Clinical Trial Operations - Development & Conduct: Are the structure and composition of trial proposal and protocol development teams proposed by the applicant appropriate? How well does the applicant's proposed trial proposal and protocol development process mesh with NCI standard tools and services, including use of Common Data Elements and standard Case Report Form modules? How appropriate are the proposed Canadian Collaborating Clinical Trials Network policies and standardized procedures for development and monitoring of trial proposals and protocols (including its tracking and project management systems) for ensuring that the applicant would meet NCI-mandated trial activation timelines for operational efficiency (i.e., Operational Efficiency Working Group or OEWG timelines)?

Does the proposed Canadian Collaborating Clinical Trials Network have appropriate key standard operating procedures related to a Data and Safety Monitoring Board Policy for Phase 3 trials and randomized Phase 2 trials, Data and Safety Monitoring Plans for Phase 1 and Phase 2 trials, Conflict of Interest Policies, and a Model Informed Consent Document for clinical trials that address how it will assure compliance with NCI, NIH, and HHS policies and all U.S. federal regulations regarding the protection of human subjects in clinical research as well as how it will address study monitoring and reporting (e.g., explain how these aspects are covered by the applicant s policies on Data Safety and Monitoring, Data Sharing, Biospecimen Sharing, Onsite Auditing).

Does the applicant demonstrate that it can adhere to regulations regarding trial registration in the NCI Clinical Trials Reporting Program (CTRP) and in the NIH National Library of Medicine (NLM) (www.clinicaltrials.gov) along with results reporting, as applicable? Does the applicant demonstrate that it can publish results in peer-reviewed manuscripts in a timely manner consistent with NCTN Program requirements?

Compliance/Quality Assurance/Auditing: : How well do the applicant's policies and procedures proposed for the conduct of NCTN-supported clinical trials comply with good clinical practice, including all applicable NCI, NIH, and HHS policies and U.S. federal regulations related to clinical trial research with human subjects, as well as with NCI/DCTD requirements related to NCI/DCTD Intellectual Property (IP) policy, NCI/DCTD Cooperative Research and Development Agreements for clinical trials conducted under an NCI Investigational New Drug (IND) or Device Exemption (IDE) or other NCI binding collaborative agreement? How appropriate are the applicant's proposed policies and procedures in meeting the onsite audit requirements of the NCI National Clinical Trials Monitoring Branch Guidelines (CTMB) for its member institutions/sites? How appropriate are the applicant's plans to appropriately address issues with member institutions/sites noted at the time of audit, including non-compliance, data quality, data reporting requirement, and timeliness of audits and re-audits? Does the applicant propose a quality assurance program that is adequately proactive in terms of ensuring ongoing quality control of data during trial conduct?

How well has the proposed Canadian Collaborating Clinical Trials Network demonstrated its ability and track record to provide appropriately designed, robust, statistical analysis plans for early phase and especially late phase, definitive, multi-institutional clinical trials in oncology, including integral and integrated biomarker/correlative science studies? Does it appear that the applicant has the necessary expertise and experience to incorporate new molecular and imaging biomarkers into the overall evaluation of NCTN trials appropriately? Are the procedures for sample size estimation, end point selection, and monitoring plans adequately described and justified? Are analytical techniques, procedures, and policies adequate, appropriate, and consistent with accepted standards? Does the sample of trial reports from the Report of Studies indicated appropriate and timely data and study analyses?

Does the applicant describe well defined policies and procedures for data management of NCTN trials? How appropriate and robust are the data management and study monitoring practices of the organization? How well do the data management systems employed by the proposed SDMC use standard NCTN tools including the NCTN Common Data Management System (CDMS) and use of NCTN-approved Common Data Element (CDEs) from the ca-DSR, the NCTN Regulatory Support System (RSS), the NCTN Oncology Patient Enrollment Network (OPEN), the NCI/DCTD Clinical Data Update Systems (CDUS/CDS), the NCI Expedited Adverse Event Reporting System (AdEERs), the NCI Common Terminology Criteria for Adverse Events (CTCAE) for data management for NCTN trials, and trial registration in the NCI Clinical Trials Reporting Program (CTRP) and in the NIH National Library of Medicine (NLM) (www.clinicaltrials.gov) along with results reporting, as applicable?

Does the proposed Canadian Collaborating Clinical Trials Network have appropriate procedures in place to ensure compliance with federal/DHHS/NIH/NCI regulations for NCTN-supported clinical research involving human subjects as well as with NCI/NIH administrative requirements for conduct of clinical trials with respect to NCI/DCTD's IP Option and NCI/DCTD's collaborative binding agreements for NCI/DCTD IND and IDE studies?

Does the Canadian Collaborating Clinical Trials Network have clear guidelines for institutions/sites related to data timeliness and metrics for data quality for the clinical trial data and timely reporting to the institutions/sites of this information that indicate its potential to operative efficiently within the NCTN Program?

Do the facilities and equipment (including computer hardware and software) available as well as the information technology (IT) support for central storage, security, analysis and retrieval of clinical data for the proposed Canadian Collaborating Clinical Trials Network appear adequate for clinical trial research? Does the proposed Canadian Collaborating Clinical Trials Network have policies and procedures in place that are in compliance with federal regulations related to confidentiality of patient data, including Health Insurance Portability and Accountability Act (HIPAA) regulations for NCTN-supported activities?

Collaborations with NCTN Network Groups, NCTN Programs/Initiatives, and other NCI-sponsored Programs/Investigators: Does the applicant have a track record for collaborations with other trial organizations and NCI-sponsored programs and investigators on clinical trials and translational science studies that demonstrates its potential for collaboration within the NCTN Program?

Collective Management Activities: Does that applicant have a track record that demonstrates that the members of its scientific leadership teams (i.e., scientific research committee members) actively participate in or can actively contribute to NCI clinical trial activities (e.g., disease-specific and modality-specific Scientific Steering Committees and related task forces or working Groups, Clinical Trials Planning Committees for meetings supported by the NCI disease-specific Steering Committees, participation in other NCI programs and initiatives related to clinical research)?

As applicable for the clinical research that the proposed Canadian Collaborating Clinical Trials Network has proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

Since the proposed Canadian Collaborating Clinical Trials Network conducts clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources. Since this FOA is specifically designed to support a Canadian Collaborating Clinical Trials Network as a research partner for the NCTN Program, the reviewers will assess through the review criteria provided above how well the applicant addresses this research goal.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by an appropriate Scientific Review Group, convened by the NCI in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the NCI and will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statementas 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 and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) 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 HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, 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.

The PD(s)/PI(s) will have the primary responsibility for:

• Development of an overall research strategy for the development of clinical trials for the NCTN Program as well as all key components related to the conduct of approved clinical trials. The awardees programmatic responsibilities for the conduct of the clinical research supported under the Cooperative Agreements are described in the documents listed below and subsequent modifications of these documents. These documents are incorporated by reference as program-specific Terms and Conditions of Award:
  • NCI National Clinical Trials Network (NCTN) Program Guidelines available at: http://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policies with the "Specific Awardee Rights and Responsibilities for the Canadian Collaborating Clinical Trials Network" described in detail in Part 1 - Section IV.B.6. of the Guidelines document.
  • NCI CTEP Investigator’s Handbook (Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis, NCI) available at: http://ctep.cancer.gov/handbook/index.html
  • NCI-CTMB Guidelines for Monitoring of Clinical Trials for Cooperative Groups, CCOP Research Bases, and the Cancer Trials Support Unit (CTSU) available at: http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_coop_ccop_ctsu.htm
• Throughout these Terms and Conditions of Award, Canadian Collaborating Clinical Trials Network refers to the organizational structure which is composed of the key personnel (including the scientific and administrative leaders of the organization and its scientific research and administrative committees) and the member institutions/sites (including the institution/site physicians and clinical research associates), responsible for implementing clinical trials and collaborating on research goals of the NCTN Program. In addition, throughout these Terms and Conditions of Award, Canadian Collaborating Clinical Trials Network refers to all of its member institutions/sites as well.
• 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, NIH, and NCI policies and within the limits of any accepted binding NCI/NIH collaborative agreements with biotechnology and pharmaceutical partners and as governed by NCI-approved Data Sharing Plans and NCI-approved review for use of biospecimens collected in association with NCTN trials.
• Awardees are allowed to accept funds from non-governmental sources to support NCTN research that is not supported in part or in full by the NCI. These funds are considered Program Income (e.g., additional per case data management funding supplementing the NCI/DCTD per case data management funding, support for correlative science studies that use biospecimen or image collections funded by the NCI/DCTD for trials under the NCTN Program) and must be reported under the Terms and Conditions of Award for the NCTN Program unless they are associated with an exempted category under the NIH grant policy for program income, available at: http://grants.nih.gov/grants/policy/nihgps_2011/nihgps_ch8.htm#_Program_Income.
• All key components of the NCTN Program must report these funds to the NCI on an annual basis (in the non-competitive Type 5 application the annual progress report) and must indicate the clinical trial that the funds are being used to support (or other functional component if the funds are not provided to support specific trials). The Terms and Conditions of Award for all the Cooperative Agreements under the NCTN Program define the operational principles under which the awardees must function to ensure the independence of the research conducted regardless of whether program income is or is not available for any of the awards.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

An NCI Program staff member(s) acting as a Project Scientist(s) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members may be designated to have substantial involvement (e.g., in the role of Project Coordinators). The NCI Project Scientist(s)/Coordinator(s) will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is deemed essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict of interest.

Additionally, an NCI program director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Some Program Officials may also have substantial programmatic involvement (as Project Scientists/Coordinators). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications or will seek NCI waiver as stated above.

The main NCI responsibilities are related to research efforts of the Network and include but are not limited to the following activities:

• responsibilities as a drug sponsor for investigational agent or device development for NCI-sponsored or co-sponsored IND and/or IDE clinical trials;
• serving as scientific liaisons to awardees of key components of the NCTN Program and participation in scientific meetings of the key components;
• informing Network investigators of scientific opportunities resulting from NCI-supported clinical research programs;
• oversight of data and safety monitoring plans and boards for NCTN clinical trials;
• oversight of data management and monitoring programs for NCTN trials as well as onsite auditing programs and quality assurance programs for the NCTN Program, including oversight of core services for radiotherapy and imaging supporting NCTN trials;
• facilitating coordination of the clinical trial activities and collaborations between the Network and other NCI-sponsored programs and investigators;
• facilitating the evaluation of clinical trial concepts and protocol development as well as review of correlative science study requests for use of biospecimens collected in association with NCTN trials;
• ensuring compliance with FDA requirements for investigational agents and ensuring compliance with OHRP and other federal requirements and regulations for research involving human research subjects;
• advising awardees concerning mechanisms established by the awardees for quality control of therapeutic and diagnostic modalities; and
• monitoring the progress and performance of this key component of the NCTN Program.

The programmatic responsibilities for the NIH staff are completely described in NCI National

Clinical Trials Network (NCTN) Program Guidelines available at http://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policieswith the "NCI/DCTD Responsibilities" described in

detail in Part 1 - Section IV.C. of the Guidelines document.

The NCI will have access to all data (including imaging data) collected and/or generated under this Cooperative Agreement and may periodically review the data. The NCI may also review all records related to awardees performance under the award for appropriate collection, review, and distribution of biospecimens collected in association with NCTN trials. In case of insufficient patient accrual per the protocol specified timelines and/or NCI/DCTD slowly accruing guidelines for trials, inability to meet the scientific aims of the Cooperative Agreement, or noncompliance with the Terms and Conditions of Award, the NCI reserves the right to reduce award budget, withhold support, suspend or terminate the award.

Areas of Joint Responsibility include:

• General aspects of collaboration on study development and conduct especially with respect to compliance with federal regulations for clinical trial research (and with respect to ensuring that when new avenues of cancer therapy involving investigational drugs are pursued, trials are designed, when appropriate, such that the clinical information obtained would be acceptable to the FDA for inclusion in a potential licensing application), conduct of Data and Safety Monitoring Boards for Phase 3 trials and randomized Phase 2 trials, development of collaborative trials and international trials, collective management of the NCTN including participating in the NCTN Leadership Management Committee that makes recommendations to NCI for modifications to the Program as well as to standard NCTN common tools and services.
• Review of recommendations from the NCI Clinical Trials and Translational Research Advisory Committee (CTAC) on strategic directions for the NCTN Program.
• The joint programmatic responsibilities for the awardees of the key components of the NCTN and the NIH staff are completely described in NCI National Clinical Trials Network (NCTN) Program Guidelines available at: http://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policies with the "Collaborative Responsibilities (Awardees of NCTN Key Components and NCI/DCTD)" described in detail in Part 1 - Section IV.D. of the Guidelines document.

Dispute Resolution:

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 Dispute Resolution, except for areas of dispute that are already addressed by the appeal process within the Terms and Conditions of Award for decisions regarding approval of NCTN study proposals and the types of studies supported by the NCTN Program as described in detail under "Appeals Process for Decisions Regarding Study Proposals & Types of Studies Performed by NCTN Program" in Part 1 Section IV.E. of the NCI National Clinical Trials Network (NCTN) Program Guidelines.

For other scientific and programmatic matters that are not covered by the appeals process, a Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Network Group representatives on the NCTN Leadership Management Committee chosen by them 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.

The appeals process and this special dispute resolution procedure do not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement. Additional required reporting by the Canadian Collaborating Clinical Trials Network awardee is described in detail in the section on the "Specific Awardee Rights & Responsibilities for the Canadian Collaborating Clinical Trials Network" under the Terms and Conditions of Award in the Guidelines document for the NCTN Program in Part 1-Section IV.G.1.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in theNIH Grants Policy Statement .

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

General Research Scientific and Programmatic Information:

Meg Mooney, MD
National Cancer Institute
Telephone: 301-496-2522
Email: ncictepanalyst@mail.nih.gov

Information on Scientific Program for Statistics and Data Management:

Ed Korn, PhD
National Cancer Institute
Telephone: 301-402-0635
Email: Korne@ctep.nci.nih.gov

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 regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: 301-496-3428
FAX: 301-402-0275
Email: ncirefof@dea.nci.nih.gov

Crystal Wolfrey
Deputy Director
Office of Grants Administration
National Cancer Institute
6120 Executive Blvd., Suite 243
Bethesda, MD 20892 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: 301-496-8634
Email: wolfreyc@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

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 Part 52 and 45 CFR Parts 74 and 92.