Part I Overview Information

Department of Health and Human Services

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

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

Title: Cancer Immunotherapy Trials Network (U01)

Announcement Type
New

Related Notices

Update: The following update relating to this announcement has been issued:

Request For Applications (RFA) Number: RFA-CA-10-007

Catalog of Federal Domestic Assistance Number(s)
93.395

Key Dates
Release Date: November 30, 2009
Letters of Intent Receipt Date: January 19, 2010
Application Receipt Date: February 19, 2010
Peer Review Date: April/May 2010
Council Review Date: August 2010
Earliest Anticipated Start Date: September 2010
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: February 20, 2010

Due Dates for E.O. 12372

Not Applicable
Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

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

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

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

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

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

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

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Purpose

This funding opportunity announcement (FOA) is designed to stimulate the conduct of multi-institutional Phase I and early Phase II clinical immunotherapy trials for cancer patients. The long-term objective is to bring promising combinations of immunotherapeutic modalities and agents to the clinic.

To accomplish this goal the NCI will support a Cancer Immunotherapy Trials Network (CITN). The CITN is designed to attract leading investigators in the immunotherapy field who are capable of and have a history of conducting clinical trials that utilize a variety of biologic agents and immunotherapeutic modalities.

The support of the CITN will be realized through a single award for a Central Operations and Statistical Center (COSC) of the CITN. This FOA solicits applications specifically for the CITN COSC, which will provide overall leadership, organizational infrastructure, and statistical and protocol coordination support for the CITN program.

COSC applicants must plan that the CITN will ultimately include the following additional elements for which COSC awardee will provide oversight:

  1. Member Sites (up to 25 institutions) that will conduct the clinical trials. Prospective candidates for Member Sites will be invited (through a separate NIH Guide Notice) to seek and compete for membership shortly after the COSC awardee is selected. Member Sites will be supported through subcontracts within the COSC award.
  2. Tumor immunology laboratories to conduct standardized immunomonitoring assays and biomarker and correlative studies related to the clinical trials. These laboratories must be associated with the Member Sites and will be supported through subcontracts within the COSC award

Note: A data coordinating service for the CITN will be provided by a unit operated by the NCI (therefore, this aspect remains beyond the scope of solicited applications).

Background

Cancer immunotherapies have demonstrated limited clinical success in spite of promising pre-clinical studies. For example, although single cancer immunotherapeutic agents and vaccines have been shown to induce significant cytotoxic T cell responses in vitro and provide cures in mouse models, these approaches have not consistently led to tumor regression and cure in patients. The reason for this lack of success is complex, reflecting a number of issues. First, the mouse immune system, and particularly the immunodeficient mouse model, which is used for many studies, does not replicate the complexities of the human immune system. Secondly, based on increased understanding of these complexities, it is now clear that a combination of immunotherapeutic modalities with other agents/modalities will be required for successful clinical trials. Thirdly, it remains generally unknown why some patients do respond remarkably well to certain therapies but most patients do not. Thus, markers of response to each therapy need to be developed in order to understand these differential responses before larger clinical trials can be conducted. Finally, limited numbers of eligible patients makes it difficult to accrue patients quickly and complete clinical trials in a timely way in order to inform the next clinical trial.

The need to intensify efforts towards clinical developments of immunotherapeutic modalities reflects also considerable progress in our understanding of biology of anti-tumor immune responses. These advances include an elevated appreciation of immune parameters characteristic of highly effective anti-tumor T cells as well as the identification of multiple immune suppressor mechanisms in the tumor microenvironment. Consequently, investigators understand now better the reasons for the failures mentioned above and may suggest new avenues for manipulating the immune response for a more favorable therapeutic outcome. A wide variety of studies are now in various stages of pre-clinical and clinical development that either enhance the immune response to tumor, provide ways to block inhibitory signals, or enhance the longevity of adoptively transferred T cells.

Taking advantage of the rapidly advancing field, the NCI organized an Immunotherapy Agent Workshop in July of 2007 (http://dcb.nci.nih.gov/newsdetail.cfm?ID=31) to gather leading investigators in tumor immunology/cancer immunotherapy. The group discussed the scientific value and clinical potential of a large number of immunotherapeutic agents that showed promise but were unavailable for clinical trials at that time. This workshop provided a ranked list of those agents (i.e., 20 of them listed in priority order for development as promising anti-cancer therapeutic agents), including cytokines, antibodies, and adjuvants. Since that list was developed, the NCI has promoted the production of some of these agents listed at or near the top of that list. In summary, it is now an opportune time to bring a new mechanism for the clinical translation of not only these agents but others as well that investigators in immunotherapy feel should be developed in appropriate combinations for optimized early phase trials.

Overall Goals

The overall goal of the CITN is to create a single network composed of the leading investigators and institutions in the field of cancer immunotherapy to design and implement early phase multi-institute clinical trials in this field. The network should consist of members capable of proposing trials that utilize a variety of immunotherapeutic modalities, e.g., cell-based approaches using T cells or dendritic cells, vaccines, antibodies, cytokines and suppressor blockers. The network is expected to initiate at least 15 Phase I or early Phase II trials over the course of the funding period. The most favorable approaches developed by the Network could hopefully be brought to the NCI Cooperative Groups for development of randomized Phase II and/or Phase III trials.

A second goal is to integrate several tumor immunology laboratories into the CITN to enable the network to utilize specimens obtained from patients on the clinical trials for: 1) immunomonitoring; 2) developing and credentialing biomarkers that assess pharmacodynamic effects or can serve as predictors of response; and 3) providing the experimental and analytical infrastructure to facilitate an understanding of the biological mechanisms underlying the results of the clinical trials. The resulting information and insights will be used to inform future clinical trial designs and to improve the understanding of the reagents, cell populations, and modalities under clinical investigation, whether the trials succeed or fail.

ORGANIZATIONAL REQUIREMENTS FOR CITN

A. Central Operations and Statistical Center (COSC, subject of this FOA): COSC will provide overall leadership and organizational infrastructure for the entire CITN. The COSC is expected to function as a central office, located at the lead Principal Investigator’s institution. It must provide: one or more protocol coordinators, finance and regulatory staff, biostatistical staff, and other administrative staff, as needed. The statistical unit of COSC will be coordinated by a Lead Biostatistician (who may not necessarily reside at the COSC institution).

The COSC will be responsible for the following specific aspects of CITN activities:

B. COSC Leadership: Applicants are encouraged to take advantage of the multiple PDs/PIs option and designate a lead PD/PI (based in the application submitting institution) and a second PD/PI, who would share the responsibilities but would also be capable of leading the entire COSC and CITN (in case the lead PD/PI is unable to continue serving in this role). If only one PD/PI is designated, COSC applicants must identify a PD/PI potential replacement candidate, i.e., a senior investigator who will be qualified to take over the PD/PIs responsibility for the entire CITN if such need arises.

C. Member Institutions: The CITN will include clinical immunotherapy Member Sites. It is expected that up to 25 institutions will be given Member Site status.

NOTE: Candidates for Member Site status will be evaluated by a panel of experts organized by the NCI/CTEP. Final selections of member sites will be made in consultation with the COSC awardee. The selected institutions will be supported through the U01 COSC award as consortium-subcontractual sites. The COSC awardee institution will be eligible to seek also the Member Site status.

The candidate institutions are expected to have the following attributes:

Member sites that are selected would be provided separate subcontract funding on a per protocol basis for the laboratory components selected to provide service for the protocol, specifically, for specimen collection, storage and distribution, for immune monitoring assay (e.g., flow cytometry, ELISA assay), or for biomarker assay (e.g., microarray). Alternatively, new biomarker correlates and other correlative studies could be submitted for approval by the Steering Committee using specimens collected for each protocol.

D. CITN Steering Committee: CITN will be governed by a Steering Committee. The Steering Committee will be chaired by the COSC lead PD/PI and will include other representatives of COSC as well as representatives of Member Sites.

The Steering Committee will be responsible for the evaluation of all potential treatment concepts as well as correlative science proposals, formally presented either by investigators from Member Sites or by investigators external to the CITN. Concepts approved by the Steering Committee will be forwarded by the COSC to the Cancer Trials Evaluation Program (CTEP) as a Letter of Intent (LOI). After CTEP approval, the Steering Committee will formulate a protocol writing team and will monitor the development of the protocol and approve for forwarding to CTEP for final review and approval. The Steering Committee will periodically review the performance of Member Sites.

The Steering Committee will also approve inclusion in CITN activities of Ancillary Sites , i.e., institutions conducting clinical trials that are external to the network. Ancillary Sites will be considered on a per protocol basis with the goal to enhance patient accrual and/or provide additional expertise.

The Steering Committee will be expected to establish appropriate subcommittees (as needed), including an External Advisory Panel as a sub-committee composed of leading immunotherapy clinicians and tumor immunologists.

For details on the composition and functions of the Steering Committee, see SectionVI2A4, Cooperative Agreement Terms and Conditions of Award, Collaborative Responsibilities.

E. NCI Cancer Trials Support Unit (CTSU, https://www.ctsu.org/): The NCI’s CTSU will be used as the regulatory support and data management center for the CITN, in order to rapidly begin and move trials from concept stage to enrolling patients as quickly as possible. The CTSU has experienced staff in place to manage trials and will be able to implement these trials using their automated data capture system(s) and regulatory support infrastructure.

The contribution of CTSU to CITN will include the following aspects:

SCIENTIFIC SCOPE OF CITN

Examples of appropriate research topics to include but are not limited to those listed below:

Specific Benchmarks for the CITN

The specific benchmarks for the CITN in the 2010 - 2015 funding period are listed below and will be used by the NCI to assess whether the CITN has satisfactorily contributed to the NCI’s clinical research program in immunotherapies:

1. The number of Phase I and Phase II clinical trials initiated and completed. It is expected that three to four trials per year will be initiated after a 1-year ramp-up period, or a total of 15-20 trials in the total funding period, and at least half of these trials will be completed during this time.

2. The introduction of novel agents and agent combinations into clinical trials, with particular emphasis on a significant number of the immunotherapy agents identified as high priority for translation to the clinic by the 2007 NCI Immunotherapy Agent Workshop, depending on availability.

3. Sample collection from patients on trials with incorporation of appropriate standardized and centralized immunomonitoring assay and biomarker identification/discovery analysis on these samples.

4. Correlative studies proposals, either funded by the U01 or from alternative sources, to assess mechanism and thereby inform future trials.

5. Collaboration with industry partners to obtain biologic agents and to leverage NCI funds to cover costs not provided by the NCI.

6. Generation of high quality outcomes data for both clinical and laboratory endpoints.

7. An effective quality control/quality assurance (QC/QA) program with timely submission to CTEP/CTSU of required data elements.

8. Timely presentation of results at national meetings and publication in peer-reviewed journals.

9. Transitioning of successful new immunotherapy approaches and marker analyses in Phase II trials to the NCI cooperative groups for larger group studies.

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

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the NIH U01 cooperative agreement award mechanism.

The Project Director/Principal Investigator (PD/PI) or Project Directors/Principal Investigators (PDs/PIs) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

In the cooperative agreement mechanism, the PD/PI or PDs/PIs retain(s) the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

2. Funds Available

The estimated amount of set-aside funds available for the CITN is $1.6 million for fiscal year 2010 and $14 million total costs over a 5-year period of the award to fund one U54 CITN COSC award. Future support will depend on annual appropriations.

In addition to these funds, the NCI has allocated $3 million to support directly the CITN activities through the NCI Cancer Trials Support Unit (CTSU) during the first 2 years of the program (see details below).

The total project period for CITN COSC applications submitted in response to this FOA may not exceed 5 years. The budget requested must not exceed $1.6 million total costs in the first 2 years of the award and 3.6 million in years 3 - 5.

For years 1-2, applicants must take into account the direct allocation of the mentioned above $3 million for CITN support by CTSU for the costs of data management, per capita reimbursement of patient costs, and specimen collection for all clinical trials. This direct support through CTSU is estimated to suffice for the first eight trials of CITN.

For years 3-5, CITN COSC applicants must budget funds for the continuing CTSU support ($6 million will be needed by the CTSU for data management, reimbursement of patient costs, and specimen collection costs in years 3 - 5).

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of the award will also vary. Although the financial plans of the NCI provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

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

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.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

Foreign institutions are not eligible to apply in response to the FOA. COCS applications will be accepted only from eligible domestic institutions. Nonetheless, not only Domestic but also Canadian institutions will be eligible to seek Member Site status under subcontractual (consortium) arrangements (see the text for details on the Member Site selection).

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her institution 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.

More than one PD/PI (i.e., multiple PDs/PIs) may be designated on the application.

Applicants are encouraged to designate a lead PD/PI (based in the application submitting institution) and a second PD/PI, who would share the responsibilities but would also be capable of leading the entire COSC and CITN (in case the lead PD/PI is unable to continue serving in this role). If only one PD/PI is designated, applicants must identify a PD/PI potential replacement candidate, i.e., a senior investigator who will be qualified to take over the PD s/PI’s responsibility for the entire CITN if such need arises.

All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organization(s). Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills, and experience of the individual PD/PI will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. Additional information on the implementation plans, policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Resubmissions. Resubmission applications are not permitted in response to this FOA.

Renewals. Renewal applications are not permitted in response to this FOA.

Number of Applications. Applicants may submit only one application in response to this FOA.

Section IV. Application and Submission Information

1.Address to Request Application Information

The current PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance, contact GrantsInfo -- Telephone: (301) 710-0267; Email: GrantsInfo@nih.gov.

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

2. Content and Form of Application Submission

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

The title and number of this funding opportunity must be typed in Item (box) 2 only of the face page of the application form and the YES box must be checked.

Note: Exceptions from the standard PHS 398 instructions and details on application preparation are provided in Section IV.6. Other Submission Requirements.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a 3h for all PD/PIs. NIH requires one PD/PI be designated as the contact PD/PI for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the Contact PD/PI, et. al. The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PDs/PIs must be registered in the eRA Commons and must be assigned the PD/PI role in that system. Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name Field.

All projects proposing multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: A rationale for choosing a multiple PD/PI approach should be described. The governance structure and organization structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative and scientific responsibilities for the program should be delineated for PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of the award, the requested allocations may be reflected in a footnote on the Notice of Award

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

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

3.A. Receipt, Review, and Anticipated Start Dates
Letters of Intent Receipt Date: January 19, 2010
Application Receipt Date: February 19, 2010
Peer Review Date: April/May 2010
Council Review Date: August 2010
Earliest Anticipated Start Date: September 2010

3.A.1. Letter of Intent

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

William D. Merritt, Ph.D.
Clinical Grants and Contracts Branch
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN Room 7009, MSC 7436
Bethesda MD (for U.S, Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-8866
FAX: (301) 480-4663
Email: merrittw@mail.nih.gov

3.B. Sending an Application to the NIH

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

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

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

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

3.C. Application Processing

Applications must be received on or before the application receipt date) described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute. Incomplete and/or non-responsive applications will not be reviewed.

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

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

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of the award if such costs: 1) are necessary to conduct the project; and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of the award.

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

6. Other Submission Requirements

The COSC applicants must demonstrate in the application their ability to address the RESEARCH OBJECTIVES of the FOA (described in Section I) and the investigator responsibilities (described in Section VI.2.A.1).

Modifications to PHS398 Instructions for Preparation of COSC Application

For the COSC application submitted in response to this FOA, the standard PHS 398 Research instructions for application preparation are altered as follows:

Table of Contents (PHS 398 Form Page 3): Modify Form Page 3 of the PHS 398 to replace standard sub-sections of Section 3 Research Strategy of the PHS 398 Research Plan with the following new sub-sections A-G:

RESEARCH PLAN: The standard PHS398 Research Plan is altered as follows:

Other sections of the PHS398 Research Plan remain unmodified and should be completed following standard instructions.

A. Relevant Past Performance. In this section, applicants must summarize their past performance in the context of managing multi-institutional cancer clinical trials in the area of immunotherapies. Specific areas to address should be related to Research Objectives described in Section I. In particular, describe such aspects as:

a) Procedures for the oversight of clinical trials concept and protocol development, review and approval and successfully implementing these procedures;

b) Implementing approved study concepts at clinical collaborative sites in a timely way, including amendments to protocols;

c) Accrual planning, monitoring, and intervention, including the extent to which the center provides accurate accrual goals for trials, monitors accrual, and intervenes to provide direction for increasing accrual if accrual lags;

d) Providing biostatistical expertise in designing and managing Phase I and II studies;

e) Scheduling and coordination of face-to-face and teleconference meetings among collaborative site members to review progress and discuss goals;

f) Performance review of sites, including setting up of site performance guidelines and performance review parameters;

g) Fiscal planning and management activities: ability to develop and manage protocol budgets and generate financial reports; and

h) Negotiating contracts with outside sponsors, including the ability to successfully negotiate with pharmaceutical companies or foundations to provide agents and/or support for a clinical trial.

B. Investigators Qualifications.

a) For the lead Principal Investigator (i.e., the PD/PI designated to be in charge of the overall scientific direction of the CITN and head of the COSC) a description of the highlights of clinical trials management activities of multi-institutional immunotherapy clinical trials, including activities to coordinate communications among centers, accrual monitoring and intervention, and oversight over protocol development and implementation, with hiring of appropriate personnel. Include a synopsis of research accomplishments in the field of immunotherapy.

b) Provide analogous description for the second PD/PI (if multiple PD/PI option is used) or for the senior investigator designated as potential PD/PI replacement candidate (if one PD/PI option is used).

c) For all other key personnel, including Lead Biostatistician, Senior Administrator, Financial Analyst, Senior Protocol Coordinator, and a Human Subjects/ Regulatory Administrator, a brief description of qualifications and experience in the relevant areas of work.

C. Overall Research Strategies and Plans. Although no protocols or specific clinical trials to be developed by the CITN are required in this application, an overarching research strategy for the conduct of immunotherapy trials in the CITN is required.

a) The general approach to advance the field of cancer immunotherapy through implementation of Phase I and Phase II trials, particularly as it relates to the areas of research indicated in Section I, taking account the current status of the field and how the CITN and aspects of the COSC specifically would function to stimulate and optimize growth in this field. Include combination approaches and approaches to utilize high priority immunotherapy agents that would be considered to potentially provide highest clinical benefit. Include a prioritization of proposed studies.

b) A general plan for the use of standardized immunomonitoring of the clinical trials implemented by the CITN using patient samples, indicating key parameters to be measured. Include plans for sample collection for these assays.

c) A general plan for the use of patient samples for development of biomarkers in the clinical trials to choose the appropriate patient population for immunotherapy trials development. Include plans for sample collection to obtain appropriate data for biomarker studies.

d) Procedures and plans assuring timely publication of the results of the clinical trials and laboratory studies

D. Standard Procedure for the Development of Clinical Trial Protocols. A description of the standard procedures developed and utilized by the applicant to support the timely development of Phase I and II clinical trials in immunotherapy. Describe the procedures below and add benchmarks of their successful implementation.

a) Organizational structure and procedures for coordinating the timely development of clinical trials protocols, using the components of the CITN as specified in the Section I, including time lines for the steps in the process and actions taken when these time lines are not met.

b) Procedures for the effective interaction and communication involving leadership of the Member sites to develop concepts and protocols and conduct of trials in a safe and timely manner.

c) Procedures for at least semi-annual CITN meetings to review progress, plan future trials and establish priorities.

E. Data Analysis and Standard Procedures for Quality Control/Quality Assurance. Describe the following elements:

a) The statistical support for the CITN clinical trials, and the general statistical approach to the design and analysis of Phase I and Phase II clinical trials.

b) Procedures for study monitoring including establishing procedures for: a) assessment of patient eligibility and evaluability; b) timely medical review and assessment of clinical trials data; c) rapid reporting of treatment-related morbidity; d) interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice for Phase I and Phase II trials.

c) Procedures for on-site auditing including a description of how auditing will be coordinated with the CTEP Clinical Trials Monitoring Branch and the Clinical Trials Monitoring Service (http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_coop_ccop_ctsu.htm)

d) Procedures to ensure that claims of treatment agent activity are accurate and reliable

e) Procedures for timely reporting of data from the CITN clinical trials to CTEP using the CTEP s Clinical Data Update System (CDUS; http://ctep.cancer.gov/reporting/cdus.html).

f) Procedures for training and monitoring Member Site personnel to maintain proficiency and consistency in management of CITN trials.

g) The Data and Safety Monitoring Plan for the CITN (to be included in the Appendix of the application) which should be consistent with the NIH and NCI guidelines for data and safety monitoring in early phase clinical trials.

F. Standard Procedures for Regulatory Compliance. Describe the following elements:

a) Procedures for timely reporting of all serious and/or unexpected adverse events via the Adverse Event Expedited Reporting System (AdEERS; http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/newadverse_2006.pdf) for investigational agents for which the status of Investigational New Drug (IND) has been sponsored by the NCI, and sponsor-specified methods for other agents bearing IND status.

b) Procedures to meet Office of Human Research Protections (OHRP) requirements for the protection of human subjects, including informed consent, institutional review board (IRB) review of protocols, and institutional assurances.

c) Procedures for assuring that CITN investigators performing clinical trials involving investigational agents sponsored by the NCI Division of Cancer Treatment and Diagnosis (DCTD) are NCI-registered investigators (Form 1572).

d) Procedures for assuring that the proposed CITN will comply with CTEP requirements (as described in the DCTD Investigators Handbook, http://ctep.cancer.gov/handbook/index.html) for storage and accounting for investigational agents (including NCI Drug Accountability Records [DAR] procedures, http://ctep.cancer/gov/form/storage-03.pdf).

Note: Conflict of Interest (COI) Policy to be used by the proposed CITN must be included in the Appendices of the application. This policy and associated procedures must be consistent with U.S. Public Health Service (PHS) requirements for ensuring that there is no reasonable expectation that the design, conduct, and/or reporting of research conducted by the proposed CITN will be biased by any conflicting financial conflict of interests of an investigator.

G. Member Institutions: General Policies and Procedures. Include a description of the following aspects:

a) Procedures for performance monitoring of institutions (addressing for example, accrual of adequate number of eligible patients to the CITN clinical trials, timely submission of required data, observance of clinical trial protocol requirements, contributions to clinical trial protocol development and conduct, authorship of CITN publications, and participation in CITN administrative and scientific committees);

b) Procedures for responding to inadequate performance of institutions, with removal policies for lowest ranking underperforming institutions (for instance, use of warning letters, grace period to allow corrections, and a policy and mechanism for replacing unresponsive institutions;

c) Procedures for inclusion of additional sites participate with the CITN on a per protocol basis as Ancillary Sites , and inclusion of other institutions that might wish to interact with the CITN and conduct correlative studies research on a collaborative basis (i.e., using their own funding outside the support for the CITN).

Notes on Budget: The budget of the CITN COSC should include the items listed below. Use the provided direct costs estimates for individual categories as guidelines.

a) Central Operations and Statistical Center (COSC): Funds should be allocated for support of the administrative and regulatory activities to support the CITN, and communication activities with Member Sites and with CTEP (CTSU and Regulatory Affairs Branch [RAB] in particular) for protocol development and implementation (include protocol coordinators, administrative staff, regulatory and human subjects protections personnel, finance staff; up to approximately $200,000 direct costs).

b) Scientific Leadership: Include funds allocated for the lead PD/PI designated to be in charge of the overall scientific direction of the CITN and head of the COSC. An additional leader of the COSC may be identified as second or PD/PI under the multiple PDs/PIs framework. Within the framework of the COSC, include also an individual to serve as the Lead Statistician in charge of the Statistics unit. Each of these individuals at the COSC is expected to have a substantial commitment to the program (at least 1.2 - 2.4 months effort per year).

c) Statistical support for data management and analysis activities: Funds required for biostatistical support staff to support data analysis and clinical trials development and monitoring ($100,000 direct costs).

d) Immunomonitoring, biomarker assessment, banking, and correlative studies support: Funds to support subcontracts to tumor immunology laboratories located either at clinical Member Sites or non-affiliated sites for personnel and supplies for banking of specimens, biomarker identification/discovery studies, standardized immunomonitoring assays, as well as for key correlative studies to inform future trials ($500,000 direct costs). Note that outside the U01 CITN award, additional NIH resources may potentially augment this aspect of CITN (e.g. by separate contracts to government laboratories for some CITN-related work). The CITN and NCI will develop a review process for how the laboratory for a specific assay will be selected.

e) Travel: Support for one or two representatives for all Member Sites (up to 25) to travel to Washington, DC, for up to three Steering Committee meetings per year ($100, 000 direct costs).

f) Cancer Trials Support Unit (CTSU): For years 3 - 5 include subcontract costs to the CTSU to support data monitoring activities, COSC support activities, and patient reimbursement and specimen collection costs ($2 million/year, includes F&A costs). These costs will reflect $300,000/trial for patient reimbursement and specimen collection costs and $200,000/trial for data management and COSC support costs, for 4 trials, which includes F&A costs). For years 1 and 2 these costs would be 0 dollars, as they will be covered by the direct allocation to CTSU ($3 million; see Section II.2. Funds Available). The portion of costs that reflects patient reimbursement and specimen collection costs should be listed as Consortium/Contractual Costs as per PHS 398 instructions.

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

Do not use the Appendix to circumvent the page limitations. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition. For further information, see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National Cancer Institute and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact: Reviewers will provide an overall priority/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 five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria: Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each.

Significance: Does the project address an important problem or a critical barrier to progress in the field? 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?

Approach: Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, are issues of feasibility and management of particularly risky aspects addressed? Are the plans for: 1) protection of human subjects from research risks; and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Innovation: Is the project innovative? For example, 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 for this area of research? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

In addition, specific to this FOA: Do the applicants propose novel or improved ways to conduct Phase I and II trials in cancer immunotherapy?

Investigator(s): Are the PD/PIs, collaborators, and other researchers appropriately trained and well suited to the project? Have they demonstrated an ongoing record of accomplishments that has advanced the field, and is the work proposed appropriate to the experience level of the Principal Investigator and other Key Personnel? If the project is multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

In addition, specific to this FOA:

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

In addition to the above NIH-wide review criteria, the following FOA-specific criteria will be applied to applications in the determination of scientific merit and the impact/priority score.

Relevant Past Performance:

Overall Research Strategies and Plans:

Data Analysis, Quality Assurance and Data and Safety Monitoring:

Regulatory Compliance:

Additional Review Criteria.

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

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

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption; 2) human subjects involvement and characteristics; and 3) sources of materials.

Inclusion of Women, Minorities, and Children: When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

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

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

Additional Review Considerations

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

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

Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

Selection Process

The following will be considered in making funding decisions:

NIH considers the following in evaluating Center grant applications:

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information

1. Award Notices

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

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

2. Administrative and National Policy Requirements

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

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

2.A. Cooperative Agreement Terms and Conditions of Award

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

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

Throughout these Terms and Conditions of Award, CITN refers to the organizational structure which is composed of the CITN PDs/PIs and other key personnel, the members of the Central Operations and Statistical Center, and involved investigators at Member Institutions, all of whom agree to collaborate on the research goals of the CITN.

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

The CITN is responsible for developing the details of its clinical and laboratory research program, including definition of objectives and approaches, planning, implementation, analysis, interpretations and conclusions of results. The CITN 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. Specific Rights and Responsibilities for the Central Operations and Statistical Center and Member Institutions are described below.

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.

All awardees must comply with the NCI Clinical Terms of Award (http://deainfo.nci.nih.gov/grantspolicies/ClinicalTrials/Clinical%20Trial%20Terms%20of%20Award.pdf) 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 Principal Investigator must ensure that his/her clinical studies and trials are monitored commensurate with the degree of potential risk to study subjects and the complexity of the studies.

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 listed below.

1) Organizational Structure and Standard Operating Procedures (SOPs): The COSC leadership, together with the Steering Committee, will be 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 CTIN 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. The CTSU will provide the COSC NCI-approved 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 Letters of Intent (LOIs).

Specific issues are:

a) Clinical trial protocols should be developed, submitted and implemented in accordance with the DCTD Investigator’s Handbook (http://ctep.cancer.gov/handbook/index.html). 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 (http://ctep.cancer.gov/guidelines/index.html).

c) The COSC is responsible for communicating the results of the CTEP-coordinated Concept Review Committee for LOI review and the CTEP Protocol Review Committee 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 dispute resolution process (see Section VI.2.A.4 Dispute Resolution Process).

e) All clinical trials utilizing NCI-sponsored investigational agents shall be conducted in accordance with the terms of the Intellectual Property Option to Collaborators (http://ctep.info.nih.gov/industry/ipo.html) 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 LOIs, Concept Proposals, 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) Study Monitoring: The CITN must follow the general guidelines for NCI 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 as described at http://ctep.info.nih.gov/monitoring/section2.html#2.2.2 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 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, via AdEERS according to CTEP guidelines specified in each protocol (http://ctep.info.nih.gov/reporting/adeers.html).

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 and Monitoring Plan (DSMP) regarding notification of CTEP must be followed.

4. Quality Control of CITN Clinical Trials: Quality Control and Quality Assurance (QC/QA) Programs are inherently linked. The Clinical Trials Monitoring Branch (CTMB, http://ctep.cancer.gov/branches/ctmb/default.htm) 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 must be addressed concerning quality control procedures include:

a) Institutional performance evaluations. Performance factors to be considered include:

i) Accrual of adequate number of patients onto CITN trials;

ii) Timely and accurate submission of required data;

iii) Rigorous adherence to clinical trial protocol requirements;

iv) Participation in study development and in timely publication of study findings; and

v) Participation in CITN administrative and scientific committees and/or other CITN activities;

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, will develop and 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 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 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, COI, 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, U.S. Food and Drug Administration [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: The CITN’s on-site monitoring program will be coordinated with the Clinical Trials Monitoring Branch (CTMB) of CTEP. As a sponsor for investigational agents and the funding agency for other cancer clinical trials, FDA regulations require NCI Division of Cancer Treatment and Diagnosis (DCTD) to maintain a monitoring program. The on-site audit will address issues of data verification, protocol compliance, compliance with regulatory requirements for the protection of human subjects and investigational agent accountability. The CITN is responsible for maintaining its on-site auditing program in compliance with the CTMB guidelines (http://ctep.info.nih.gov/monitoring/guidelines/html) and for submitting the results of audits to the NCI in accordance with the guidelines. 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 CITN 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.

5) Timely reporting of data to CTEP using the Clinical Data Update System (CDUS, http://resresources.nci.nih.gov/database.cfm?id=1209)

a) For most CITN studies using NCI-sponsored investigational agents, CDUS Complete reporting procedures 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).

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 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 Cooperative Research and Development Award (CRADA) or CTA, the pharmaceutical collaborator [to the NCI?] 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 U.S. Department of Health and Human Services (HHS), PHS, and NIH policies.

7) CITN meetings: The COSC is responsible for the overall organization of two to three face-to-face Steering Committee meetings each year to review 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, toxicity experienced by study participants, and other items (e.g., outcome data) as appropriate; and

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 and payments to sites (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 PI(s) 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) IRB Review of CITN protocols: Although IRB approvals are collected by the CTSU, the COSC is responsible for assuring that each CITN clinical trial protocol is reviewed and approved by each Member institution’s IRB prior to patient entry, and must assure that each clinical trial protocol undergoes continuing review no less than once per year so long as the clinical trial is active.

c) Assuring appropriate Informed Consent: The COSC must assure that each patient (or legal representative) gives written informed consent prior to entry on study.

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 (http://ctep.cancer.gov/reporting/ctc/html). 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 (http://ctep.info.nih.gov/reporting/adeers.html).

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 future correlative studies.

11) The COSC will be responsible for establishing a COI 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 Member Sites to support CITN-related activities at each member institution;

b) Administration of the Immunomonitoring/Biomarkers/Correlative Science Fund, including procedures for selecting laboratories to perform specific studies on a per protocol basis (a competitive process is encouraged, when feasible). Funds will be disbursed to laboratories on a capitation/per sample basis after receipt of samples from the sample repository. It is anticipated that for each CITN protocol, the capitation formula for institutional reimbursement required to offset specific research expenses will be reviewed and approved by the Steering committee.

c) Assure distribution of funds to Member Sites from the CTSU 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. The report will use the PHS 2590 and 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.

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, and/or ability to add to accrual of a specific protocol.

15) Contingent on availability of funds, the NCI may release during the CITN project period an FOA for competitive supplements to expand the scope of the CITN award by innovative clinical trials or correlative studies to be conducted in collaboration with CITN by non-CITN institutions. The CITN will be responsible for identifying appropriate candidate non-CITN institutions and working jointly with them to prepare applications for such competitive supplements. These applications will undergo regular NIH peer review process by an NCI-managed peer review committee. Supplemental funds will be awarded only if one or more of the applications (and the proposals within them) are determined to be of sufficiently high scientific merit through peer review and through the NCI’s programmatic decision making process. If one or more supplements are funded, then the CITN would make subcontract(s) to the selected member institutions.

Responsibilities of Member Sites:

1) Participation of Member Site investigators in CITN activities, as evidenced by the following:

a) Offering participation in CITN studies to eligible patients and entering a sufficient number of patients to meet accrual targets;

b) Participating in research design and clinical trial protocol development, including:

i) Serving as clinical trial protocol Chairs or as members of protocol study teams;

ii) Participating in the Scientific and Administrative Committees 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.

2) 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.

3) 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.

4) On-site auditing: Participation in the on-site monitoring program established by the CITN.

5) 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 FED requirements for the protection of human subjects.

6) Adverse Event Reporting: Implementing the procedures established by the CITIN for assuring timely reporting of all serious and/or unexpected adverse events.

7) 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).

8) 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 tested and/or stored for future studies.

9) Serving as a resource for conduct of protocol-specified laboratory assays and studies (specifically related to conduct of immunomonitoring assays and biomarker studies). The CITN steering committee will establish a process for the selection of the laboratories to perform these studies. These projects may be supported using the Immunomonitoring/Biomarkers/Correlative Sciences Fund of the CITN or by independent funding.

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 institutions and Member Sites institutions will be required to accept and implement policies approved by the Steering Committee to the extent consistent with grant regulations.

2.A.2. NIH Responsibilities

The NCI will coordinate and facilitate various activities of the CTIN. The NCI staff members will have substantial programmatic involvement that is above and beyond the normal stewardship role in cooperative agreement awards. The NCI Program Director in CTEP, serving as Project Coordinator, will be the main NCI liaison and coordinator for all facets of the scientific interaction with the awardees and will provide oversight and advice to the awardee on specific scientific and/or analytic issues in addition to programmatic issues. Additional substantially involved NCI program staff members serving as Project Coordinators will include representatives from both the Division of Cancer Biology, Immunology and Hematology Branch, and the DCTD Cancer Diagnostics Program. These individuals will provide additional oversight and advice related to the laboratory/tumor immunology aspects of CITN studies.

Specific responsibilities of substantially involved NCI Program Staff Members 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(s) and CITN staff members, periodic site visits to the COBC for discussion with awardee team, 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 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 CITN Protocol Review Committee (PRC). Communication at the various 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 review, the NCI Program Director 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 if designed for preliminary review and is recommended 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 (http://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 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 Program Director 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 win writing by the NCI Program Director 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 Director 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-year to 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 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, (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, patient reimbursement, and logistical support activities. The Cancer Trials Support Unit (CTSU) of CTEP will be utilized as the CITN’s data management and regulatory support center. The CTSU will provide:

a) a Clinical Trials Management System, which will provide, 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;

c) per-protocol payment of patient capitation and specimen collection costs to Member Sites;

d) use of the CTSU website for posting of Network trials on its menu;

e) training of clinical sites on general clinical trial procedures and interface with the CTSU;

f) coordination with the COSC to develop data transfer and quality control procedures;

g) logistical support for CIITN meetings such as distribution of materials to investigators and other ancillary support as needed including arranging for appropriate meeting space and accommodations for attendees.

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 members 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 NCI DCTD Biometric Research Branch (BRB) staff, will assess CITN compliance with NCI and NIH established policies on Data and Safety Monitoring Plans. The NCI Project Coordinator 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 Official will attend CITN Steering Committee and other CITN meeting 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 (e.g., from the Cancer Diagnosis Program) and from the Division of Cancer Biology (e.g., from the Cancer Immunology and Hematology Branch) will attend as needed.

12) CTEP involvement in Investigational New Drug (IND) applications: The NCI Program Official, 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 retain 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 he CTIN’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 FOA for competitive supplements to expand the scope of the CITN award by innovative clinical trials conducted in non-CITN institutions.

The NCI Project Coordinator as well as other NCI staff members acting as Collaborators or Coordinators will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is essential, the NCI Project Coordinator will seek NCI waiver according to NCI procedures for management of conflict of interest if such participation is deemed necessary.

Additionally, an NCI Program Director, acting as Program Official, will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The NCI Program Official and Project Coordinator may be the same person. In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications or will seek NCI waiver as stated above.

2.A.4. Collaborative Responsibilities

The CITN will have a Steering Committee as a governing body. The Steering Committee will include the following voting members:

Representative from the Member Site can be either the lead investigator from the clinical trials team from this institution OR the lead investigator from the laboratory component of this institution, but each site can have only one voting representative on the Steering Committee.

Each voting member will have one vote. The NCI Project Coordinator will serve as an advisory (non-voting) member to the Steering Committee. Other NCI representatives may participate as non-voting advisors and observers in the Steering Committee meetings.

The Steering Committee will be chaired by the COSC lead PD/PI. In the absence of lead PD/PI, the second COSC PD/PI (or a designated senior investigator) will chair Steering Committee meeting. The Steering Committee will conduct two or three face-to-face meetings a year with additional teleconference meetings as needed.

The Steering Committee will be responsible for any changes to the CITN organizational structure and CITN Standard Operating Procedures. The Steering Committee will have primary responsibility to establish priorities, and to develop and provide preliminary approval of protocols (prior to submission to NCI and final NCI approval, and to review progress.

The Steering Committee will be responsible for the following aspects of CITN activities:

The Steering Committee may create subcommittees as needed.

These subcommittees must include External Advisory Panel, composed of at least four leading immunotherapy clinicians and tumor immunologists. The External Advisory Panel will be expected to meet at least once per year to provide external input on the scientific program and progress of the CITN, with subsequent written evaluations and recommendations for the Steering Committee.

The Steering Committee will also establish a CITN Executive Committee (EC). The EC will be composed of the COSC PD/PI (or two COSC PDs/PIs, if the multiple PD/PDI option is used), the Lead Biostatistician, the Lead Protocol Coordinator from the COSC, the CTSU project manager, and the NCI Project Coordinator. The EC will be responsible for bringing issues and the scientific agenda before the steering committee.

2.A.4. Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. 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 in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A suggested format for CITN-specific information relevant to the progress summary section of the Form PHS 2890) will be provided. Performance of the CITN in developing new LOIs and protocols should be discussed, as should the performance of Member Sites in participating in CITN studies and the performance of the appropriate reference tumor immunology laboratories. An update on clinical trials that were approved, activated, closed and/or completed during the relevant budget period should be discussed in the progress summary. Plans pertaining to clinical trial activities for the next budget period should be addressed as well.

Clinical trials reporting requirements will be in agreement with FDA regulations and NCI procedures. Interim reports of each activated and ongoing clinical trial should be prepared for each CITN Steering Committee meeting and shall include specific data on patient/participant accrual as well as detailed reports of treatment-related morbidity. Quarterly accrual reports must be provided as appropriate to CTEP for all active trials through the NCI’s Instructions and Guidelines for CDUS reporting are at http://cancer.gov/reporting/cdus.html.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

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

1. Scientific/Research Contacts:

William D. Merritt, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN Room 7014, MSC 7436
Bethesda, MD 20892-7436 (for U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-8866
FAX: (301)
Email: merrittw@mail.nih.gov

2. Peer Review Contacts:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

3. Financial or Grants Management Contacts:

Eileen M. Natoli
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, EPS 243, MSC 7150
Bethesda, MD 20892-7150 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-8791
FAX: (301) 496-8601
Email: natolie@mail.nih.gov

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

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

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

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

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/.

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

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

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

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

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

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

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-116.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

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

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

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

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

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

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

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

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NIH Funding Opportunities and Notices


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