National Institutes of Health (NIH)
National Cancer Institute (NCI)
Limited Competition: Cancer Immunotherapy Trials Network (CITN)(UM1)
UM1 Research Project with Complex Structure Cooperative Agreement
Reissue of RFA-CA-10-007
The purpose of this limited Funding Opportunity Announcement (FOA) is to support the infrastructure to design and conduct multi-institutional Phase I and early Phase II clinical immunotherapy trials for cancer patients, using novel immunomodulatory agents. To realize these goals, the FOA will continue to support the research activities of the Cancer Immunotherapy Trials Network (CITN).
The CITN to be supported through this FOA will consist of:
The Central Operations and Statistical Office (COSC), which will provide overall leadership, organizational infrastructure, and statistical coordination support for the CITN; and
Clinical Member Sites (up to 25 institutions) as sites that will conduct the clinical trials, supported through subcontracts within the CITN award.
November 25, 2016
December 24, 2016
30 days prior to the application due date
New Date March 10, 2017, by 5:00 PM local time of applicant organization. All Application allowed for this funding opportunity announcement is due on this date.
No late applications will be accepted for this Funding Opportunity Announcement..
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
New Date March 11, 2017 per issuance of NOT-CA-17-017. (Original Expiration Date: January 25, 2017)
It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) 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. 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.
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
The purpose of this limited Funding Opportunity Announcement (FOA) is to continue to support the research activities of the Cancer Immunotherapy Trials Network (CITN), specifically to design and conduct multi-institutional Phase I and early Phase II clinical immunotherapy trials for cancer patients using novel immunomodulatory agents
The CITN to be supported through this FOA will consist of:
The original premise for the creation of the Cancer Immunotherapy Trials Network (CITN) was to bridge the gap between highly promising basic and pre-clinical studies in immuno-oncology, and the more limited success in translating immunotherapeutic approaches to the clinic. Hence, the CITN has provided a standing clinical network to conduct Phase I and II cancer immunotherapy trials.
The role of immunotherapy in oncology clinical trials, and increasingly in cancer standards of care, has grown substantially since the inception of the CITN in 2010. Indeed, with Food and Drug Administration (FDA) approval of monoclonal antibodies against immunomodulatory molecules that suppress the activity of anti-tumor T cells (specifically the “checkpoint blockade” antibodies, anti-CTLA4 and anti-PD1/ anti-PDL1) for treatment of several cancers, the era of immunotherapy as a common treatment modality has now arrived. Yet, even with broad effectiveness, high remission rates, and durable responses, not all patients and not all cancer types respond to currently available immunotherapies; additional immunotherapy approaches are needed to both broaden the activity and overcome resistance.
Some examples of specific agents with high potential for testing in future clinical trials that could be included in the portfolio of protocols in a renewal application include: 1) agonist antibodies to tumor necrosis factor/receptor superfamily molecules, such as: a) anti-4-1BB (CD137), which provides co-stimulatory signals, enhancing activity of cytotoxic T cells, with generation of a memory response, as well as enhanced NK-mediated cytotoxicity; b) anti-OX40 (CD134) and c) anti-GITR (CD357); 2) other agents besides anti-PD1/anti-PDL1 and anti-CTLA4 which reverse tumor immune evasion, such as anti -LAG3 and anti-TIM3; and 3 ) agents to reverse immunosuppressive cytokines, such as anti-IL-10 and anti-IL-6. Further control of the tumor microenvironment by control of the expression of immune-suppressive cells, specifically myeloid-derived suppressor cells and T regulatory cells, have also been explored by several laboratories and need further exploration for clinical application. Finally, because of the widespread use of FDA-approved anti-PD1 and anti-PDL1 antibodies, it will be important to understand the basis for non-responsive patients, and to devise combination strategies to overcome this resistance to therapy. In each of these areas, the CITN will be expected to contribute in a significant way in a new funding period.
Overall Goals for the CITN. The major goal of the CITN is to design and implement early phase multi-institutional clinical trials in cancer immunotherapies, via a single network involving the leading investigators and institutions in the field. The network should continue to be broad in scope, consisting of Clinical Member Sites capable of proposing appropriate clinical trials that would utilize a variety of immunotherapeutic modalities, e.g., antibodies, cytokines, vaccines, suppressor blockers and, potentially, cell-based approaches. Not only should the CITN will be composed of leaders in immunotherapy clinical research, but also the network should demonstrate that it has adopted procedures to evaluate, prioritize, and implement worthy clinical study proposals from non-CITN investigators.
The overall emphasis of CITN should be on utilizing combinations of immunotherapeutic agents or combination of immunotherapeutic agents with other treatment approaches (although clinical trials of promising single immunotherapeutic agents are also encouraged). It is expected that the most promising approaches developed by this Network would be brought forward for development of larger, randomized Phase 2 or Phase 3 trials via the NCI-supported National Clinical Trials Network (NCTN) or other related mechanisms.
Interactions with other NCI Clinical Trials Infrastructures/Services. To realize its overall goals, CITN will be expected to interact in various activities identified below with other NCI- or NCI-supported clinical trials infrastructures/units/programs/services. These entities include:
• The Cancer Therapy Evaluation Program (CTEP, https://ctep.cancer.gov/);
• The Experimental Therapeutics Clinical Trials Network (ETCTN, https://ctep.cancer.gov/initiativesprograms/etctn.htm);
• Cancer Trials Support Unit (CTSU, https://www.ctsu.org/Public/Default.aspx);
• NCI Central Institutional Review Board (IRB, https://ncicirb.org/); and
• A service that handles data management and audit support (currently through a contract to Theradex, http://theradex.com/).
Scientific Scope for the CITN Research. Examples of appropriate research topics include but are not limited to those listed:
Note: Novel immunotherapeutic agents to be studied are generally expected not to be included in the CTEP portfolio of INDs. If drug combinations are to be studied, other agents (e.g., non-immunotherapeutic agents), including, but not limited to, various molecularly targeted agents, may or may not be held in the CTEP IND portfolio.
Specific Expectations for the CITN
CITN applicants must have the following capabilities:
• Expertise and capabilities needed to introduce novel agents and/or agent combinations into clinical trials.
• Ability to initiate and complete sufficient number of Phase I and Phase II clinical trials: It is expected that three to four trials per year will be run in the network, for a total of 15-20 trials.
Approximately half of CITN clinical trials should be initiated utilizing agents that are not held by CTEP, thus outside of the CTEP IND process, with the remaining to be initiated using CTEP-held agents (CTEP/ETCTN trials).
• Ability to collect samples from patients on the CITN trials for testing potential biomarkers associated with these trials (actual testing will be done by a cancer immunology laboratory to be supported directly by the NCI as described below).
• Scientific rigor: ability to generate high quality outcomes data for both clinical and laboratory endpoints.
• An effective quality control/quality assurance (QC/QA) program with timely submission to the CTSU of required data elements.
• Effective use of the NCI Central IRB for all clinical trials.
CITN Organization and Functions
A. Central Operations and Statistical Center (COSC): The COSC, located at the awardee institution, will continue to provide overall leadership and organizational infrastructure for the entire CITN. In particular, the COSC will be responsible for the following aspects:
• Providing scientific leadership for overall direction of the CITN and implementation of CITN activities;
• Working on the design and implementation of clinical trials (in interaction with clinical trial protocol teams assembled from Member Site investigators), including: providing biostatistical input; preparing protocol letters of intent and other protocol documents for all clinical trials, as well as documents related to study activation and implementation; organizing training of Member Sites on protocol-specific requirements and monitoring; and managing reimbursements to Member Sites for trial enrollments; etc.;
• Providing oversight of all regulatory and quality control/quality assurance activities, including working with NCI CTEP staff regarding regulatory issues and contracts negotiated with outside vendors (i.e., pharmaceutical companies), submitting protocols to NCI Central IRB for review, and developing and implementing a data and safety monitoring plan as required for all NCI-sponsored trials;
• Coordinating communications/meetings of the Executive Committee and the Steering Committee, including developing agendas and minutes (logistical support will be provided by the NCI Cancer Trials Support Network, CTSU).
B. Member Institutions: The CITN will include clinical immunotherapy Member Sites operating under subcontracts to the awardee institution. The network will be limited to a maximum of 25 such Member Sites. The sub-contractual arrangements for Member Sites will include funding on a per protocol basis for managing the trial at the site and for the laboratory components essential for specimen collection and transfer to an immune monitoring laboratory associated with the CITN. In general, Member Sites will be expected to:
CITN will be required to establish a process for evaluating the performance of Member Sites. The process should have specific rules for removing under-performing Member Sites from the CITN and replacing them with new qualified Member Sites (to maintain a steady state of 25 sites).
C. Executive Committee: The Executive Committee will provide oversight of CITN trial development and implementation and will set the overall scientific agenda. For details of composition and responsibilities, see Section VI.2. Cooperative Agreement Terms and Conditions of Award.
D. Steering Committee: The CITN will have a Steering Committee as a self-governing body. For details, see Section VI.2. Cooperative Agreement Terms and Conditions of Award.
E. External Advisory Board: An External Advisory Board to the CITN will review the progress and overall agenda of the CITN and annually provide feedback to the Executive Committee. For details, which see Section VI.2. Cooperative Agreement Terms and Conditions of Award.
F. Services to CITN awardee to be supported directly by the NCI (i.e., beyond the scope of this FOA):
• A central tumor immunology laboratory, which will conduct standardized immuno-monitoring assays for the CITN trials, will be funded by the NCI through a different mechanism and is therefore not included in this award.
• All CITN clinical trial protocols will be reviewed by the NCI Central IRB, supplanting the use of local IRBs.
• A data monitoring and a regulatory support service for the CITN as well as audit support will be provided by separate entities operated by the NCI and thus beyond the scope of this award.
Specific trial management functions (including patient registration, data collection, and auditing, currently performed by the CITN COSC and ancillary contractors for trials that do not use CTEP-held INDs, will instead be performed via the mechanisms in the ETCTN funded via contract by CTEP. In order to expedite trial implementation, approved protocols will be sent to a Clinical Trials Monitoring Service (CTMS, currently, Theradex) and the NCI’s CTSU. The CTSU and the CTMS will coordinate studies with the CITN COSC to implement standards for timely data collection and transfer from sites, and participate in QA review of data collection and transfer performance (see Section VI.2. Cooperative Agreement Terms and Conditions of Award for details).
G. Participation of CITN Member Sites in non-CITN immunotherapy clinical trials:
CITN Member Sites will be able to participate in all early phase immunotherapy trials conducted by CTEP outside the CITN (specifically, by the ETCTN). Also, CITN investigators may participate in CTEP project teams for new immunotherapy agents being developed under CTEP IND. While CITN studies using agents in the CTEP IND portfolio will be made available to the entire ETCTN membership (as ancillary sites in the CITN), CITN studies not under CTEP IND will not be made available automatically to all ETCTN member sites. If an agent is not available via CTEP, then the CITN can contract for agents with companies and either the CITN or the company can hold the IND for the trial. In the event that a Letter of Intent (LOI) is submitted for clinical trials using a novel (non-CTEP held) agent to be used in combination with a CTEP-held agent and the LOI is approved, the CTEP Agent-CRADA (Cooperative Research and Development Agreement) mechanism may be used to bring the novel agent into the CTEP portfolio.
See Section VIII. Other Information for award authorities and regulations.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
NIH intends to fund one award, corresponding to a total of approximately $2.0 million, for fiscal year 2017. Future year amounts will depend on annual appropriations.
The applicant may request a budget of up to $1,500,000 annually in direct costs.
The applicant should request support for a project period of 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.
Only the current awardee of CITN COSC is eligible to apply.
Non-domestic (non-U.S.) Entities (Foreign Institutions) are
not 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 not allowed.
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
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 PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
Applicants are encouraged to take advantage of the multiple PDs/PIs option and designate two PDs/PIs. However, the contact PD/PI must be based in the application-submitting institution. A second PD/PI must be selected so that this individual would also be capable of leading the entire CITN (in case the corresponding PD/PI is unable to continue serving in this role
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.
For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.
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:
The letter of intent should be sent to:
William D. Merritt, Ph.D.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed with the following exceptions
The Research Strategy should consist of the following sub-sections with the indicated page limits:
Subsection A. CITN Overview: one required-12 pages
Subsection B. Central Operations and Statistical Office: one required-12 pages
Subsection C. Research Program: one required-6 pages
Subsection D. Member Institutions: one required-6 pages
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Facilities & Other Resources: Document available resources and facilities at the applicant institution that will be available to the COSC.
The applicant must also document that each Member Site proposed has the infrastructure for the research, such as clinical, laboratory, pharmacy, computer, and available resources for routine laboratory testing; facilities for processing and storing blood and other clinical specimens; and institutional support for the conduct of clinical research under U.S., HHS, and NIH regulations and policies regarding human subjects.
Other Attachments: Applicants must provide the following additional materials specified below in support of their application. Each attachment should be uploaded in separate PDF files. The filename provided for each attachment will be the name used for the bookmark in the application image.
Attachment 1: Organizational Data. Provide the following information as a PDF file with the name “Organizational Data”, to include:
Attachment 2: Protocol development procedures and associated human subjects' protections documents. Provide the following information as a PDF file with the name “Protocol Development and Human Subjects Protection" to include:
Attachment 3: Summary Table of CITN Clinical Trials. Provide the following information as a PDF file with the name “Clinical Trials", to include:
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed. Additional guidance:
It is expected that the budget requested for the CITN COSC should include the items listed below. Use Budget Justification to provide budget breakdown by categories indicated below. The direct costs should include two main categories:
A. COSC (allocate approximately $600,000 per year)
B. Per-Patient Reimbursements to Member Sites (allocate approximately $900,000)
Applicants should include in the budget request patient per capita expenses costs for both the anticipated CITN and ETCTN clinical trials (see Section I, Specific Expectations for the CITN) as these will be reimbursed equally.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Specific Aims: Outline succinctly the overall strategic goals for the CITN and the plan to achieve these goals.
Research Strategy: Standard sub-sections of Research Strategy are replaced by the new sub-sections A-D .
Sub-Section A. CITN Overview
Sub-Section B. Central Operations and Statistical Office (COSC):
In this sub-section, describe the details of COSC functioning, noting that:
1. Main COSC Activities: Complying with the requirements stated above, outline main COSC activities, including plans, procedures, etc., for coordinating the timely development and implementation of Phase I and II clinical protocols in immunotherapy, describing the procedures below and adding benchmarks for their successful implementation:
2. Summary of standard procedures for assuring regulatory compliance:
Note: See other Attachments above for the required additional documentation pertaining to this subsection.
3. Data Analysis and Standard Procedures for Quality Control/Quality Assurance: Provide overview of the following elements and procedures:
Sub-Section C. Research Program:
Sub-Section D. Member Institutions.
Include a description of the following:
Letters of Support: Letters of collaboration from the leaders of each proposed Member Site must be included. The letters should clearly state the willingness of the Member Site investigators to participate in clinical activities of the CITN as well as serve a leadership role and participate in Steering Committee and protocol team activities. The letters should also specifically mention the site's capacity for enrolling patients on CITN clinical trial protocols (each letter should include numbers of patients projected for a given site in specific disease categories).
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:
Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.
All instructions in the SF424 (R&R) Application Guide must be followed.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
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 submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NCI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Applicants are required to follow the instructions for post-submission materials, as described in the policy.
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, note the following:
In assessing the merit of the application, reviewers will consider the overall abilities of the PD/PI and proposed member institution leaders, and the entire CITN team in the context of their past performance and the proposed new directions. Reviewers will consider whether the CITN, as proposed, is highly likely to bring novel, important trials in immunotherapy to the clinic. Reviewers will also assess whether these clinical trials can be expected to provide strong impetus to the field and provide the groundwork for pivotal larger trials in this area of cancer immunotherapeutics
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project 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 project 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 project that by its nature is not innovative may be essential to advance a field.
Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project 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?
Specific to this FOA: What is the likelihood that the CITN, as proposed, will bring novel, important trials in immunotherapy to the clinic that could provide the groundwork for pivotal larger trials in the area of cancer immunotherapeutics?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? 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)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Specific to this FOA: Are the qualifications, expertise, and experience of the PD/PI(s) appropriate to provide the scientific leadership necessary to lead a broad-based, multi-institutional network of investigators to develop and implement Phase I and II trials in cancer immunotherapy? Are there sufficient and appropriately named experienced personnel with the skills needed to develop, implement, and analyze Phase I and II trials in immunotherapy? Do the key investigators and support personnel have the needed experience in the collection, management, and analysis of data from multi-institutional clinical trials, including procedures for the technical integrity and security of the collected data?
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?
Specific to this FOA: Does the applicant propose novel or improved ways to conduct Phase I and II trials in cancer immunotherapy?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
Specific to this FOA: How do the applicant's general plans for clinical trials demonstrate an appropriate understanding of research opportunities and challenges in cancer immunotherapy? How will the applicant's general plans for clinical trials use agents determined to be "high priority" in the field? Are combination approaches for use of agents and various modalities appropriate and relevant? Will the CITN adequately provide for the timely development of the CITN’s next Phase I and Phase II clinical trials, and does the CITN have sufficient statistical support for the design of these trials? How strong are the specific Member Sites that are chosen for their potential to implement the clinical trials in the CITN, and are Member Site selection criteria appropriate? Does the applicant describe appropriate training to maintain the proficiency of Member Site personnel in the successful management of its clinical trials? Are plans for incorporating informative correlative/potential biomarker studies into clinical trials based on current technology and thinking surrounding immunomonitoring and biomarker studies for choosing patient populations most likely to respond to immunotherapy strategies? Are the plans and procedures described for quality control and quality assurance for multi-institutional clinical trials data, utilization of CTEP resources including procedures for timely reporting of data from CITN clinical trials to CTEP (using CDUS or alternative system that replaces it) appropriate? Are adequate processes described for complying with CTEP requirements for investigator registration and drug accountability, and for complying with the PHS Conflict of Interest requirements, included and appropriate? Are the mechanisms for the periodic review of quality control, quality assurance, data management procedures, and safety monitoring (including the procedures for the data safety and monitoring committees and on-site auditing programs), described and acceptable? Are acceptable procedures described for addressing regulatory compliance in the context of multi-institutional clinical trials?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed? Will the proposed CITN have suitable procedures for timely reporting of serious and unexpected adverse events during clinical trials using investigational agents?
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 project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
Specific to this FOA: How will specific elements in the overall institutional environment of the awardee institution impact the ability of the CITN/COSC to continue to manage the CITN?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
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 Guidelines for the Review of Human Subjects.
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
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.
For Renewals, the committee will consider the progress made in the last funding period, including specific aspects below.
Has the CITN developed and implemented sufficient, high-quality clinical trials in the current funding period that have made an impact to the overall progress in the field? Has the CITN team demonstrated appropriate expertise in biostatistical design? How well did the applicant document their ability to manage timely protocol implementation, fiscal planning and management of budgets, patient accrual monitoring, performance review of member sites, and planning and coordination of meetings among sites over the course of the award?
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 score.
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).
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) Genomic Data Sharing Plan (GDS).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
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(s) convened by the NCI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications 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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.
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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
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 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.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
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 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 awardee is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipient's activities by involvement in and otherwise working jointly with the award recipient 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 awardee for the project as a whole, although specific tasks and activities may be shared among the awardee and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
The CITN awardee will be responsible for developing the CITN clinical and laboratory research program, including definition of objectives and approaches, planning, implementation, analysis, interpretations and conclusions of results. The awardee will continue to develop Phase I and Phase II clinical trial protocols in accord with the research interests, abilities and goals of the CITN, and submit these protocols to CTEP for review prior to their implementation.
The following documents (and subsequent modification to them) are hereby incorporated by reference as terms of award. These documents describe the programmatic responsibilities of the conduct of the research supported by this cooperative agreement.
INVESTIGATOR’S HANDBOOK, a Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm).
Intellectual Property Option to Collaborator (https://ctep.cancer.gov/industryCollaborations2/default.htm).
The awardee must comply with the NCI Clinical Terms of Award as required by the NCI policy http://deainfo.nci.nih.gov/grantspolicies/index.htm) for clinical studies and trials when they are a component of any research being funded by the NCI. The PD(s)/PI(s) must ensure that clinical studies and trials conducted under CITN award are monitored commensurate with the degree of potential risk to study subjects and the complexity of the studies. The PD(s)/PI(s) must also ensure compliance with reporting of all clinical trials to ClinicalTrials.gov per NIH policy on Dissemination of NIH-funded Clinical Trials Information (see NOT-OD-16-149).
Responsibilities of the Central Operations and Statistics Center:
The Central Operations and Statistics Center (COSC) is responsible for coordinating the development of clinical trial protocols, submission of these protocols for review and approval, study conduct (including data analysis) quality assurance/quality control and study monitoring, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations and protocol and performance reporting. Specific responsibilities are:
1) Organizational Structure and Standard Operating Procedures (SOPs): The COSC, with the guidance of the PD/PI, as Director of the COSC (or a head of the COSC, if different) and the Steering Committee, are responsible for development and maintenance of an organizational structure and SOPs from the CITN.
2) Clinical Trials Protocol Development: It is the responsibility of the CITN to develop the details of the research design, including definition of objectives and approaches, planning, implementation, analysis, interpretation and conclusions of studies, and publication of results, using the NCI approved Letters of Intent (LOI) and protocol templates and standardized language for trial logistics and administrative issues. The COSC is responsible, in accordance with the CITN SOPs, for the preparation and implementation of procedures for development and submission of CITN clinical trial concepts and protocols to the CTEP Protocol and Information Office (PIO) in a timely fashion for review and approval by NCI. Concepts will be submitted in the form of LOIs.
Specific issues are:
a) Clinical trial protocols should be developed, submitted, and implemented in accordance with the DCTD “Investigator’s Handbook” (https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm). The CTSU will provide logistical support for protocol submissions.
b) Submission of CITN clinical trial protocols for review and approval by NCI should be preceded by a written Letter of Intent (LOI) to the CTEP LOI coordinator declaring interest in conducting a particular study. LOIs should be submitted using the LOI template (https://ctep.cancer.gov/protocolDevelopment/lois_concepts.htm). LOIs should be submitted to CTEP for review at the very earliest stage possible in order to coordinate timely trial development.
c) The COSC is responsible for communicating the results of the CTEP LOI and protocol review to relevant CITN committees and members.
d) The CITN will not expend funds to conduct any study disapproved by CTEP unless CTEP’s disapproval has been modified by the arbitration process (see Section VI. 2. Dispute Resolution)
e) All clinical trials utilizing NCI-sponsored investigational agents shall be conducted in accordance with the terms of the “Intellectual Property Option to Collaborators” (https://ctep.cancer.gov/industryCollaborations2/default.htm)
and the NCI Standard Protocol Language for Cooperative Research and Development Agreements (CRADAs) and Clinical Trial Agreements (CTAs).
f) The CITN SOPs should include timelines for the steps involved in the development of Concept Proposals, LOIs, and clinical trial protocols, and should include mechanisms for monitoring the performance of the COSC and Member Sites in meeting these time lines. The CITN’s SOPs should also include corrective action plans outlining the steps to be taken when these times are not met. Data concerning the CITN’s performance in meeting timelines for protocol development should be provided in the Annual Progress Report.
3) Member Site participation: The COSC will engage immunotherapy sites, both current Member Sites and those outside the CITN, to participate as Members in the renewal period. Applications for membership should include:
a) past performance on immunotherapy trials (a minimum of at least 20 patients in total to all NCI-sponsored trials testing immune modulatory agents including 5 patients accrued to current CITN trials if a current Member);
b) synopsis and accrual status of any on-going early phase trial using a novel immune modulatory agent alone or in combination with other immune-modulatory or targeted cell pathway-specific agent, and/or radiation, that could potentially be brought into the CITN, with any agreement with pharma to supply the drug and/or funds to run the trial;
c) a 1-3 page concept to test a novel immune modulatory agent either alone or in combination as in 2 above that could feasibly be run in the CITN, separate from point 2;
d) requirement for agreement to use the NCI Central IRB; and e) agreement to submit all accrual and results data and adverse events, etc., to the COSC (see Responsibilities of Member Sites, below).
4) Study Monitoring: The CITN must follow the general guidelines for CTEP-sponsored trials. The CITN is responsible for assuring accurate and timely monitoring of the progress of each study, and therefore must have standard procedures for timely data collection and data management consistent with the data requirements for Phase I and Phase II trial in collaboration with CTEP’s Cancer Trials Support Unit (CTSU). Patients shall be enrolled through the CTSU’s Oncology Patient Enrollment Network (OPEN). Standard procedures for monitoring should include (but are not necessarily limited to):
a) Precise tracking of patient accrual and adherence to accrual goals, with development of corrective action plans if accrual goals are not achieved; if the CITN wishes to continue accrual to a study beyond the accrual goal for eligible and ineligible patients specified in the clinical trial protocol, the CITN must seek approval from CTEP prior to continuing patient accrual;
b) Procedures for assigning dose level (for Phase I "dose escalation studies") at the time a new patient is enrolled in a study, and assuring that the required observation period has elapsed before beginning a higher dose level;
c) Ongoing assessment of patient eligibility and evaluability;
d) Adequate measures to ensure the timely medical review and assessment of individual patient data, in conjunction with the CTSU as responsible for data collection and management;
e) Adequate measures to ensure timely submission of clinical trials data (e.g., adverse events, anticancer responses) to the CTSU from Member Sites;
f) Rapid reporting of treatment related morbidity information and measures to ensure communication of this information to all relevant parties; for investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP, according to CTEP guidelines specified in each protocol (https://ctep.cancer.gov/branches/pio/reporting_guidelines.htm)
g) Preparation of study monitoring reports describing patient accrual and demographics, data timeliness, toxicity, and other items as appropriate; examples of study monitoring reports include reports prepared for study chairs, the reports needed for CITN meeting agendas, and reports as required to comply with the CITN’s Data and Safety Monitoring Plan;
h) Adequate policies and procedures for closure of studies; if the CITN 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 NCI staff for review and concurrence prior to implementation of that decision. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the clinical trial protocol in order to facilitate these decisions. In the event that the study is recommended for early closure for safety reasons, procedures in the Data Safety Monitoring Plan regarding notification of CTEP must be followed.
5. Quality Control of CITN Clinical Trials: Quality Control and Quality Assurance (QC/QA) Programs are inherently linked. The Clinical Trials Monitoring Branch (CTMB) of CTEP provides direct oversight of NCI-sponsored Consortia and cooperative group QC/QA programs. The CITN is responsible for establishing and implementing mechanisms to assure the accuracy and reliability of its clinical trials data. Quality control is a complex topic spanning the entire range of diagnostic and therapeutic modalities employed by the CITN. Key items that should be addressed concerning quality control procedures include:
a) Institutional performance evaluations. Performance factors to be considered include:
b) Procedures for placing Member Sites on probation for inadequate performance and for removing such institutions from the CITN if performance is not adequate during the probationary period or at any time that the institution does not meet CITN standards for institutional performance.
c) With assistance from the CTSU, the awardee will implement educational functions that address data collection, data management and overall data quality. These aspects include, but are not limited to, the following elements:
i) Training for new Clinical Research Associates (CRAs) in the CITN’s data submission policies and ongoing training for all CRAs concerning changes to CITN procedures and instructions for data submission in new protocols;
ii) Instruction for appropriate Member Site participants and study chairs on their responsibilities for study monitoring;
iii) Instruction for Member Site Leaders and all members at participating sites on their responsibilities in complying with the CITN’s SOPs and Federal regulations at their institution; and
iv) Training/guidance should also be provided to all participants on how to comply with NCI/NIH policies and procedures (e.g., ethics, conflict of interest, etc.) in addition to policies and procedures of other governmental agencies important to the conduct of clinical trials (e.g., Office for Human Research Protections, FDA).
d) Training of Clinical Sites on protocol-specific requirements for trial implementation, procedures, and monitoring.
e) Procedures for central review of major elements that impact on the outcome of clinical trials. This will include central review of claimed clinical responses and adequacy of biomarker studies that serve as predictors of response, as well as central review of submitted data with determination of protocol compliance in dose administration and dosage modification, and additional review as necessary.
f) On-site auditing: CITN is expected to work closely with NCI and a Clinical Monitoring Service (CTMS, currently Theradex) to ensure proper completion of all actions and steps associated with on-site auditing. In the event that the NCI determines that a CITN Member site failed to comply adequately with NCI guidelines for the conduct of clinical trials, the accrual of new patients to CITN protocols at the affected institution shall be immediately suspended upon notice of the NCI determination. The suspension will remain in effect until the NCI conducts the required audit and the audit report or remedial action is accepted by the NCI. The COSC will be responsible for notifying any affected participating institution of the suspension. During the suspension period, no funds from this award may be provided to the participating institution for new accruals, and no charges to the award for new accruals will be permitted.
6) Timely reporting of data to CTEP using the Clinical Data Update System (CDUS) or any systems that replace it, which includes:
a) For most CITN studies using NCI-sponsored investigational agents, CDUS Complete reporting procedures (or a replacement alternative) will be used, which capture demographic, adverse event information (by course, and response data;
b) For clinical studies that do not use NCI-sponsored investigational agents, reporting to CTEP will generally use the CDUS Abbreviated Procedures (demographic data only);
c) Reporting of serious and unknown adverse events requirements shall be reported using NCI reporting mechanisms (currently AdEERS); and
d) Reporting and accounting for program Income as described in the NIH Grants Policy Statement (https://grants.nih.gov/grants/policy/nihgps/HTML5/section_8/8.3_management_systems_and_procedures.htm?Highlight=program%20income#). The method to be used would be included in the NOA.
6) Publications: Timely publication of major findings is central to the CITN’s mission and is a primary means by which the CITN’s accomplishments can be evaluated.
a) The CITN will have timelines for the development of abstracts for meeting presentations and manuscripts for submission for publication in scientific journals based on its clinical trials, and it should have mechanisms for monitoring the performance of the CITN’s components in meeting these timelines. Corrective action plans will be implemented when these timelines are met.
b) Publication or oral presentation of work conducted under the CITN’s Cooperative Agreement requires appropriate acknowledgement of NCI support.
c) For investigations using an agent supplied under a CRADA or Clinical Trials Agreement (CTA), the NCI pharmaceutical collaborator will have an opportunity to review manuscript drafts prior to their submission for publication as per the NCI Standard Language for CRADAs and CTAs. The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies.
7) CITN meetings: The COSC is responsible for the organization and conduct of meetings of the Executive Committee (monthly), the External Advisory Board (annually), and up to two face-to-face as well as bi-monthly conference call Steering Committee meetings to discuss and approve concepts and protocols, as well as the CITN’s progress, establish priorities, and plan future activities. Additional meetings between CITN members and meetings with NCI staff may be held as needed. The CTSU can provide logistical support for these meetings such as arranging space and accommodations and distribution of invitations and meeting materials. Relevant responsibilities of the COSC include:
a) Developing meeting priorities and agendas;
b) Providing the report of ongoing studies to include information detailing patient accrual and demographics, data timeliness, toxicities experienced by study participants, and other items (e.g., outcome data) as appropriate;
c) Preparing summaries as appropriate after each meeting to be sent to CITN members and NCI program staff members.
8) CITN communications: The COSC must establish routine electronic communication with Member Sites to facilitate clinical trial development and study monitoring and to facilitate the work of the CITN’s committees. Relevant communication methods include web site postings, email, teleconferences and web/video conferences. The COSC must also establish communications with NCI’s CTSU for data transfer (see role of CTSU, section 2.A.2., and Fiscal management, section 2.A.1.12).
9) Compliance with Federal Regulations Concerning Clinical Research. The PD/PI and the COSC will be responsible for ensuring that the CITN is in compliance with all applicable federal regulations concerning the conduct of human subjects research. Policies and guidelines to be addressed include:
a) OHRP assurances: The COSC must assure that each participant site has a current, approved assurance of file with OHRP.
b) Assuring appropriate Informed Consent: The COSC must assure that each patient (or legal representative) gives written informed consent prior to entry on study.
c) IRB Review of CITN protocols: The NCI/CTEP-managed Central IRB will provide centralized review of all protocols, and thus timely submission of protocols to the CIRB is mandatory.
d) Registration of CITN investigators: The COSC is responsible for assuring that CITN investigators performing trials involving DCTD Investigational Agents are NCI-registered investigators (Form 1572).
e) Adverse Event Reporting: The COSC is responsible for assuring timely reporting of all serious and/or unexpected adverse events. Adverse events should be reported using the Common Terminology Criteria for Adverse Events (CTCAE), which is the NCI’s standard language for reporting adverse events in clinical trials (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm ). For investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP, via the Adverse Event Expedited Reporting System (AdEERS), or its successor application, according to CTEP guidelines specified in each clinical trial protocol (https://ctep.cancer.gov/branches/pio/reporting_guidelines.htm.)
f) Assuring that the CITN is in compliance with CTEP requirements described in the DCTD Investigators’ Handbook for storage and accounting for investigational agents (including NCI/DHHS Drug Accountability Records [DAR] procedures), and is in compliance with FDA requirements for investigational agents.
10) Managing and coordinating the acquisition and shipping of protocol-specified tumor specimens and biological fluids (with relevant clinical data) to the appropriate laboratories for testing and to a tumor/specimen repository for storage of specimens for correlative studies.
11) The COSC will be responsible for establishing a Conflict of Interest policy for the CITN. This policy should ensure that there is no reasonable expectation that the design, conduct, or reporting of research conducted by the Group will be biased by any conflicting financial interest of an investigator. The policy should be in compliance with the general policies with the NCI and the NIH.
12) Fiscal management of the CITN, including:
a) Establishment of consortium arrangements with any new Member Sites to support CITN-related activities at each member institution;
b) Assure distribution of funds to Member Sites to support costs of patients accrued onto CITN clinical trials.
13) Submission of annual progress reports to the NCI to describe activities and accomplishments during the previous year of the CITN.
14) Procedures to allow non-CITN institutions to participate in the development and conduct of CITN trials in those situations in which an institution has distinctive expertise, capabilities, or ability to add to accrual of a specific protocol.
Responsibilities of Member Sites:
Participation of Member Site investigators in CITN activities, as evidenced by the following:
1) Offering participation in CITN studies to eligible patients and entering a sufficient number of patients to meet accrual targets;
2) Participating in research design and clinical trial protocol development, including:
a) Serving as clinical trial protocol Chairs or as members of protocol study teams;
b) Participating in the Scientific and Administrative Committees (such as Steering Committee and Executive Committee) needed to support the CITN’s research objectives;
c) Participation in meetings: appropriately participating in the regular meetings of the Steering Committee of the CITN, and in other meetings as deemed necessary for performance of CITN activities;
d) Following the CITN’s SOPs for the conduct of clinical research.
3) Implementing the core data collection method and strategy of the CITN: It is the responsibility of each Member Site to ensure that the procedures for data submission for each CITN clinical trial protocol are understood by investigators at the site and that protocol-specific data are submitted accurately and in a timely manner to the COSC.
4) Complying with mechanisms for quality assurance and quality control of therapeutic and diagnostic modalities employed in CITN trials. Institutional responsibilities for quality control include, but are not limited to, submission of appropriate data to allow determination of clinical trial compliance in dose administration and dose modification of immunotherapy agents used in the clinical trials.
5) On-site auditing: Participation in the on-site monitoring program established by appropriate NCI-associated CTMB (currently Theradex).
6) Human Subjects Protections: Each institution must comply with OHRP and FEA regulations concerning protection of human subjects. Member institutions must implement the procedures established by the CITN to meet OHRP and Federal requirements for the protection of human subjects.
6) Participating in the NCI Central IRB for review of all protocols.
7) Adverse Event Reporting: Implementing the procedures established by the CITN for assuring timely reporting of all serious and/or unexpected adverse events.
8) Investigational agent responsibilities: Implementing the procedures established by the CITN for assuring that CITN investigators performing clinical trials involving DCTD Investigational Agents are NCI registered investigators (Form 1572).
9) Submission of Specimens: Acquisition and submission of protocol-specified tumor specimens, biological fluids, and relevant clinical data to the appropriate laboratories where these specimens will be tested and/or stored for future studies.
10) Participating in CITN procedures for the timely publication of major findings.
11) Conflict of Interest: Complying with the Conflict of Interest Policy of the CITN to ensure that there is no reasonable expectation that the design, conduct, or reporting of research conducted by the CITN will be biased by any conflicting financial interest of an investigator.
CITN awardee institution and Members Sites institutions will be required to accept and implement policies approved by the Steering Committee to the extent consistent with grant regulations.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
The NCI will coordinate and facilitate various activities of the CITN. The NCI staff members will have substantial programmatic involvement that is above and beyond the normal stewardship role in cooperative agreement awards. NCI Program staff members, acting as Project Scientists will provide oversight, advice to the awardee on scientific and/or analytic and programmatic issues as outlined below. The NCI Program Official may also have a role of a Project Scientist. In that case, the individual involved will not attend peer review meetings of renewal or revision applications or will seek NCI waiver as stated above.
Specific responsibilities of Project Scientist(s) will include the following:
1) Monitoring CITN progress: Actions necessary for monitoring may include, but are not limited to, the following: regular communications with the PD/PI and CITN staff members, confirmation and review of CITN and CTSU data sharing and associated management responsibilities, audits to confirm activity reported from a CITN clinical trial, fiscal review, review of clinical trial reports submitted by the CITN to NCI, review of the CITN’s annual progress report, and participation in the CITN Steering Committee, Executive committee, and other meetings. The NCI retains, as an option, the right to conduct periodic external review of progress.
2) Scientific liaison: Serving as a resource with respect to other ongoing NCI and other NIH activities that may be relevant to the CITN research efforts to identify promising new leads, to facilitate compatibility with other NCI research projects and to avoid unnecessary duplication of effort.
3) CTEP assistance in clinical trial protocol development: The clinical trial protocol must be a detailed written plan of a clinical experiment mutually acceptable to the CTEP Protocol Review Committee (PRC). Communication at the early stages of protocol development is encouraged as necessary to promote protocol development and implementation. Protocols should be preceded by a written Letter of Intent (LOI) from the CITN declaring interest in conducting a particular study. The PRC will formally review the LOI.
Following LOI review, the NCI Project Scientist will provide a Program response to the CITN and will address the following issues:
(a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort;
(b) information including relevant pharmacokinetic, pharmacodynamic and immunologic data concerning the investigational agents;
(c) availability of investigational agents;
(d) the PRC’s assessment of the scientific rationale and value of the proposed study, its design, and statistical requirements;
(e) appropriate inclusion of NCI Standard Protocol Language for CRADAs and CTAs in the protocol; and
(f) the implementation of the study, if indicated.
The LOI mechanism is designed for preliminary review and is required to expedite clinical trial protocol development and implementation and to facilitate agreement on study priority and design (for further discussion of these mechanisms, see the DCTD Investigator’s Handbook https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm
4) CTEP review of proposed clinical trials protocols: All protocols, including protocols utilizing agents not sponsored by the NCI, will be reviewed by the PRC, which meets weekly and is chaired by the DCTD Associate Director, CTEP. Ad hoc reviewers, external to the PRC, will be utilized when deemed appropriate by the PRC chairperson. Following the review of the clinical trial protocol by the PRC, the NCI Project Scientist will provide the CITN with a consensus review that describes recommended modifications and other suggestions, as appropriate (see DCTD Investigator’s Handbook, for further information regarding protocol review at CTEP).
The major considerations relevant to protocol review by CTEP include:
a) The strength of the scientific rationale supporting the study;
b) The clinical importance of the question being posed;
c) The avoidance of unnecessary duplication with other ongoing studies;
d) The appropriateness of study design;
e) Consistency with development plans for particular IND agents;
f) A satisfactory projected accrual rate and follow-up period;
g) Patient safety;
h) Compliance with federal regulatory requirements;
i) Adequacy of data management;
j) Appropriateness of patient selection, evaluation, assessment of adverse events, response to therapy and follow up; and
k) Methods of monitoring and reporting to NCI to be used.
If a proposed clinical trial is disapproved, the specific measures for lack of approval will be communicated in writing by the NCI Project Scientist to the CITN as a consensus review within 30 days of protocol receipt by the NCI. NCI will not provide investigational agents or permit expenditure of NCI funds for a clinical trial that is not approved. The NCI Project Scientist will be available to assist the CITN in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the CITN and the NCI.
5) CTEP protocol amendment review: Any change in the protocol document subsequent to its approval by CTEP must be submitted in writing and approval prior to implementation (see Section 8.6 – The Investigator’s Handbook for further discussion of these procedures).
6) CTEP involvement in auditing member sites: The Clinical Trials Monitoring Branch (CTMB) of CTEP will coordinate with the CITN the performance of on-site audits at CITN Member Sites, which are to occur at approximately 2-3 year intervals. The CTMB will review audit results and the corrective plans developed by the CITN in response to the audits.
7) CTEP involvement in clinical trial closure: Protocol closure is primarily the responsibility of the CITN and the specific protocol committee. The NCI Project Scientist and Program Director will also monitor clinical trial progress and may request protocol closure to further patient accrual for the following reasons: (a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol performance; (d) patient safety or regulatory concerns; (e) study results are already conclusive, and (f) emergence of new information that diminishes the scientific importance of the study question. NCI will not provide investigational agents or permit expenditures of NCI funds for a study after requesting closure (except for patients already on study).
8) CTEP involvement in data management and logistical support activities. The Cancer Trials Support Unit (CTSU) and a Clinical Trials Monitoring service (CTMS, currently, Theradex), as CTEP contact organizations, will be utilized as the CITN’s data management, audit support, and regulatory support. The CTSU will provide:
a) a system to operate, and maintain a comprehensive, fully electronic system for management of all clinical trials data (OPEN), including logistical support for and templates for data submission;
b) a Regulatory Support System, to include an IRB database to track approval, an investigator and site credentials database, and a document management system;
d) posting of CITN trials on the CTSU website menu;
e) training of clinical sites on general clinical trial procedures with preparation of related training materials, and interface with the CTSU;
f) coordination with the COSC to develop data transfer and quality control procedures;
g) logistical support for CITN meetings such as distribution of materials to investigators and other ancillary support as needed including arranging for appropriate meeting space and accommodations for attendees;
h) contracting services with industry partners.
A Clinical Trials Monitoring Service (CTMS, currently through contract to Theradex) will:
a) Develop the case report forms in MediData RAVE;
b) Provide a comprehensive, fully electronic system for management of all clinical trials data;
c) Audit support
9) Data Management and Analysis Review: NCI Biometrics Research Staff will review mechanisms established by the CITN for data management and analysis. When deemed appropriate, staff will make recommendations to ensure that data collection and management procedures are adequate for quality control and analysis, and as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense. Data must also be available for external monitoring as required by NCI’s agreement with the FDA relative to the NCI’s responsibility as drug sponsor.
10) Data and Safety Monitoring Plan: the NCI Program Official, assisted by the Biostatistical Research Branch (BRB) staff, will assess CITN compliance with NCI and NIH established policies on Data and Safety Monitoring Plans. The NCI Program Officer must review and approve the CITN’s Data and Safety Monitoring Plan. One or more CTEP staff will serve as non-voting members on the CITN’s Data and Safety Monitoring Committee (DSMC), should the DSMP specify a DSMC.
11) CITN meetings: The NCI Program Officers will attend CITN Steering Committee and other CITN meetings to participate in the discussion of relevant scientific information, progress in the clinical trials, and the status of newly available investigational agents and other research opportunities in order to plan future activities. Other NCI staff members from CTEP (e.g., from the Investigational Drug Branch) as well as Program Directors from other programs in the Division of Cancer Treatment and Diagnosis (DCTD, e.g., from the Cancer Diagnosis Program) will attend as needed.
12) CTEP involvement in Investigational New Drug (IND) applications: The NCI Project Scientist or Program Director, assisted by the Chief, Regulatory Affairs Branch (RAB), CTEP, will advise investigators of specific requirements and changes in requirements concerning IND sponsorship that the FDA may mandate. Investigators performing trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents.
13) CTEP Review of Federally Mandated Regulatory Requirements: The Chief, Clinical Trials Monitoring Branch (CTMB), through the NCI Program Officer, will advise the CITN regarding mechanisms to meet FDA regulatory requirements for studies involving DCTD-sponsored investigational agents and OHRP requirements for the protection of human subjects by CITN institutions.
14) Access to data: The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. Data must also be available for external monitoring as required by NCI’s Drug Master File Agreement with the FDA relative to the responsibility of the NCI as an IND agent sponsor. Data from studies of non-NCI-sponsored agents must be available for external monitoring as described in the policies and procedures established by the CITN for on-site auditing of clinical trials data. The awardee will comply with the data access provisions of applicable CTAs and CRADAs, and when these agreements are in place the Industry Sponsor will have complete access to the data for any and all regulatory findings.
15) Access to agents for pre-clinical testing: For NCI-sponsored IND agents, NCI will facilitate transfer of material to investigators with a Materials Transfer Agreement (MTA).
16) CTEP review of progress: Performance of the CITN will be reviewed at least annually by the NCI Project Officer on the basis of the information provided at the semi-annual and other meetings, in the annual progress reports and in the CDUS reports submitted to CTEP for each of the CITN’s clinical trials. Insufficient patient accrual or progress or progress, or non-compliance with the terms of the award, including these Terms and Conditions of Award, may result in a reduction of budget, withholding of support, suspension, or termination of the award.
17) Potential expansion of CITN scope: Contingent on the availability of funds, NCI staff members will be responsible for developing an RFA for competitive supplements to expand the scope of the CITN award by innovative clinical trials conducted in non-CITN institutions.
The substantially involved NCI staff members (i.e., Project Scientists) will not attend peer review meetings of renewal and/or revision applications. If such participation is essential, these individuals will seek NCI waiver according to NCI procedures for management of conflict of interest.
Additionally, the 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.
Areas of Joint Responsibility include:
The CITN will have a Steering Committee as a governing body. The Steering Committee will include the following voting members the CITN:
Each Member will have one vote except for NCI representatives, who will collectively have one vote for NCI.
Other NCI representatives such as NCI-designated biostatistician may participate as advisors and observers in the Steering Committee meetings as needed but will not have voting rights. The CITN liaison to the appropriate Immunomonitoring Core laboratory and lead statistician will participate in Steering Committee meetings but will not be voting members.
The awardee will be required to accept and implement policies approved by the Steering Committee.
The Steering Committee will be chaired by a Member Site Clinical Leader, elected by the members after nomination by the Executive Committee. The Chair-elect and past chair will also sit on the Steering Committee.
The Steering Committee will also be responsible for the following aspects of CITN activities:
primary responsibility to establish priorities, develop and provide preliminary approval of LOIs and protocols (prior to submission to NCI and final NCI approval), and to review progress;
Be responsible for any changes to the CITN organizational structure and CITN Standard Operating Procedures, including reviewing on a regular basis the performance of the Central Operations and Statistical Center;
Approving inclusion of Ancillary Sites external to the network to the network.
The steering committee will include Subcommittees, as needed. The subcommittees must include:
Executive Committee (EC). This committee will be composed of: the CITN PD/PI, (or PDs/PIs, if multiple PD/PI option is used), the Steering Committee chair, the chair-elect, the past-chair, senior administrator, the lead statistician as well as a senior administrator from the Operations/Statistical office, a liaison to the appropriate Immunomonitoring Core, and the NCI Program Officers (Program Director and Project Scientist).
The committee will prioritize letters of intent from investigators for bringing forward for steering committee presentation and approval, and organize the concept working groups for concept development, as well as prioritize concepts that are approved by the Steering Committee for moving to protocol development.
The Executive Committee will also be responsible for:
Nominating chair and co-chair (chair-elect) of the Steering Committee (annually);
Providing initial review and approval of concepts for bringing forward for presentation to the Steering Committee;
Review status of all protocols and discuss any logistical concerns of protocol implementation;
Review Member Sites for adequate performance, approve plans for review of corrective action plans, and review these plans when submitted by the site, and then place on probation or suspend Members and add new Members suspended by the Steering Committee.
External Advisory Board (EAB). The EAB should be formed (under the auspices of the SC) to provide external review on the scientific progress of the CITN, and recommendations for future directions. The EAB will be expected to include, as members, at least four leading clinical immunotherapists and/or tumor immunologists. EAB membership may be renewed during the award period (i.e., members could serve for 2-3 year periods). The members of the EAB will periodically receive updates on the CITN progress (including the CITN annual progress report). EAB will be expected to meet face-to-face or by teleconference at least once per year. The EAB should prepare written evaluations and recommendations for future directions. These evaluations should be provided to the EC and the Steering Committee at least 1 month before the annual in-person Steering Committee meeting.
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. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the 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 dispute resolution procedure does 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.
The progress report should specifically include:
a) A summary of the overall performance of the COSC in meeting their responsibilities to the CITN for clinical trial development, study monitoring, and complying with Federal Regulations;
b) Summary data on performance of each CITN Member Site, including clinical trial accrual, quality and timeliness of submitted data, and involvement in clinical trial protocol development activities; and
c) Research plans, changes in procedures or staff, and the proposed budget for the coming year.
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 the NIH 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.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.
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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 Part 75.
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