Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Cancer Institute (NCI)
Funding Opportunity Title	Limited Competition: Adult Brain Tumor Consortium (ABTC) (UM1)
Activity Code	UM1 Multi-Component Research Project Cooperative Agreements
Announcement Type	Reissue of RFA-CA-08-504
Related Notices	May 16, 2014 - See Notice NOT-OD-14-091. Piloting Modified NIH Biosketches.
Funding Opportunity Announcement (FOA) Number	RFA-CA-13-501
Companion Funding Opportunity	None
Number of Applications	Only one application is permitted in response to this FOA (Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.395
Funding Opportunity Purpose	The purpose of this limited competition Funding Opportunity Announcement (FOA) is to continue the program of the National Cancer Institute (NCI) for the development of new anticancer therapies for adult patients with brain tumors, especially glioblastoma multiforme (GBM). This limited competition FOA solicits a single application from the current awardee of the Adult Brain Tumor Consortium (ABTC). The ABTC is a NCI-funded clinical trials group that performs clinical research on the treatment of patients with GBM. In this funding period, the ABTC is expected to remain focused on the early stage development of new agents for treatment of GBM. However, in addition to identifying agents with antitumor activity in patients participating in Phase I and II clinical trials, the Consortium will be expected to expand and enrich its translational research. These aspects include increased emphasis on the identification of the effects of anticancer agents on their intended targets and other studies to increase understanding of biological and molecular factors that may improve the response of GBM to new agents. ABTC must be capable of conducting comprehensive pharmacokinetic and pharmacodynamic evaluations, characterization of drug effects on relevant cellular targets (using appropriate biospecimens) and integrating such findings.

Posted Date	June 19, 2013
Letter of Intent Due Date(s)	August 16, 2013
Application Due Date(s)	September 16, 2013
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	November-December, 2013
Advisory Council Review	January 2014
Earliest Start Date	April 1, 2014
Expiration Date	September 17, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS 398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Looking ahead: NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. NIH will announce plans to transition the remaining programs in the NIH Guide to Grants and Contracts and on NIH’s Applying Electronically website.

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

The purpose of this limited competition Funding Opportunity Announcement (FOA) is to continue the program of the National Cancer Institute (NCI) for the development of new therapies for adult patients with brain tumors, especially glioblastoma multiforme (GBM). Only the current awardee of the Adult Brain Tumor Consortium (ABTC) is eligible to submit an application in response to this FOA.

The ABTC is a NCI-funded clinical trials group that performs clinical trial research for the treatment of patients with brain tumors with emphasis on GBM. In the current funding period, the ABTC is expected to remain focused on early stage development of new agents for the treatment of patients with GBM. However, in addition to identifying agents with antitumor activity in Phase I and II clinical trials, the ABTC will be expected to expand and enrich its translational research. These aspects include increased emphasis on the characterization of the effects of anticancer agents on their intended targets and other studies to increase the understanding of biological and molecular factors that may improve the response of patients with GBM to new agents. ABTC must be capable of conducting comprehensive pharmacokinetic/pharmacodynamic evaluations and imaging studies that may be needed to characterize drug effects on relevant cellular targets (using appropriate biospecimens).

The outcome for patients with high-grade gliomas, the most prevalent primary central nervous system (CNS) tumor in adults, remains dismal. Malignant primary gliomas are classified based on their histological presentation as anaplastic gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytomas; WHO grade III) and glioblastoma (WHO grade IV). Approximately 60-70% of primary brain tumors are glioblastomas. Annually, about 22,000 adults in the United States (U.S.) are diagnosed as having brain tumors and about 13,100 persons die as a result of those tumors.

The current standard of care for patients with GBM is maximal surgical resection followed by radiotherapy (RT) with concurrent temozolomide (TMZ) followed by adjuvant TMZ. Overall survival using this combination therapy is about 14 months. Glioblastoma growth is diffuse by nature and the vast majority of the patients eventually develop progressive disease. Median survival following disease progression is generally 6 to 9 months. Bevacizumab, which is Food and Drug Administration (FDA)-approved treatment for patients with recurrent glioma, produces a response rate of 30-40% with a median survival of 9 months in these patients. There are no other standards of care for patients with recurrent disease; therapeutic options include repeat surgery, re-irradiation, and experimental agents. Virtually no patients with GBMs are cured.

There are multiple challenges in the treatment of patients with glioma, including: 1) the diffuse infiltrating nature of the disease; 2) the impermeability of the blood-brain barrier to many anticancer agents; 3) poor tolerance of the surrounding brain tissue to therapeutic intervention; 4) the rapid proliferation of glioma cells, including a highly chemo-resistant cancer stem cell population; 5) malignant degeneration, in which the tumors become more aggressive when they recur; 6) the heterogeneous nature of the disease; and 7) the rapid development of resistance to conventional cytotoxic agents. Extensive testing of signal transduction modulators has not led to significant therapeutic advances, which is likely a reflection of the absence of a unique critical target.

Nevertheless, some progress has been made and the biology of the disease is becoming better understood. In particular, studies supported under The Cancer Genome Atlas (TGCA) have revealed that, although over 60 genetic mutations can be identified in GBM, deregulation of three interconnected pathways, the RTK/RAS/PI3K signaling pathway, and the p53 tumor suppressor and the Rb retinoblastoma pathways, have been implicated in the development of GBM. Gene expression analysis has subsequently revealed that GBM consists of four molecular subclasses: proneural, neural, classical, and mesenchymal. The rapid pace of evolving knowledge of GBM biology provides unique opportunities to identify new potential drug targets and design rational clinical trials. This situation underscores the need for comprehensive translational efforts and incorporation of various molecular, biological, and pathological characterizations in clinical trials with novel therapeutic agents for patients with GBM.

The NCI has long sponsored clinical trial groups dedicated to developing effective therapies for adults with brain cancer. ABTC, one of these groups, was formed in 2009 under RFA-CA-08-504. Given the limited therapeutic options for patients with brain tumor, there is a serious need to continue support for clinical trials and research in this area.

The overarching goal for ABTC, which remains the same for the coming funding period, is to develop more effective therapies for adult patients with brain cancer. This goal is to be achieved through the conduct of Pilot, Phase I, and Phase II clinical trials, with the incorporation of appropriate correlative auxiliary studies.

As this FOA addresses a unique niche in oncology, it is presented as a limited competition FOA that solicits a single application from the current awardee, the Adult Brain Tumor Consortium. The ABTC, in the previous funding period, created an efficient infrastructure with the appropriate capabilities to perform early phase, multi-center-clinical trials, with a strong emphasis on translational science. Accordingly, the ABTC represents the only NCI-supported enterprise able to sustain a comprehensive program involving the investigation and development of novel anticancer agents for adult patients with brain tumors. Additional support for drug development of adult brain tumors from the pharmaceutical industry is important. Such support, however, may not supplant the primary attributes of the NCI-sponsored Consortium.

To ensure both efficient functioning as well as scientific improvements, the ABTC needs to have the following general attributes:

• Capabilities to address required Scientific Objectives; and
• Appropriate Consortium structure.

Required Scientific Objectives:

• Clinical Trials Design. The ABTC must have all the necessary capabilities, expertise, staff, and infrastructure that will be needed for the full development of appropriate clinical trial designs.
• Timeliness of Clinical Trials Development and Activation. ABTC will be expected to develop and activate clinical trials to meet timeline requirements defined by the NCI Cancer Therapy Evaluation Program (CTEP) and to follow the Operational Efficiency Working Group (OWEG) Guidelines.
• Expected Number of Clinical Trials. ABTC is expected to conduct three-to-five Phase I and one-to-two Phase II trials, enrolling approximately 200 patients/year. However, the actual number of clinical trials performed in any given year will depend on integration with corresponding translational studies (see next item below).
• Translational Research. A priority in this funding period is on clinical trials that address translational (i.e., correlative) studies. Clinical trials with correlative studies would typically include, but are not limited to, pharmacokinetic, pharmacodynamic, pharmacogenomic, or imaging studies to predict outcome and/or response to treatment.
• Clinical Trial Data. The ABTC must have an effective quality control/quality assurance (QC/QA) program. ABTC will be required to utilize MediData Rave (http://www.mdsol.com/products/rave_overview.htm) as its clinical data management system and utilize the NCI-sponsored Cancer Trials Support Unit (CTSU) (https://www.ctsu.org/public/) for regulatory support.
• Productive Interactions with Other NCI-supported Programs. The Consortium will be expected to collaborate, as appropriate, with other NCI-supported clinical trials programs, such as researchers with investigator-initiated R01 grants, the NIH-sponsored research program at the Clinical Center (Opportunities for Collaborative Research at the NIH Clinical Center, http://grants.nih.gov/grants/guide/pa-files/PAR-13-029.html), the NCI-funded brain tumor SPOREs (http://grants.nih.gov/grants/guide/pa-files/PAR-12-296.html), or, if available and appropriate, by participation in the Drug-Development Teams in the NCI Experimental Therapeutics-Clinical Trials Network (ET-CTN, http://ctep.cancer.gov/investigatorResources/docs/ET-CTN_Program_Guidelines.pdf; http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-13-006.html).

Structure of the Consortium:

The ABTC is required to have the following structural components and attributes:

• Leadership: The Consortium is encouraged to take advantage of the multiple PDs/PIs option and maintain the current joint PD/PI leadership structure, with joint PDs/PIs to be mutually in charge of the Consortium operations.
• Central Operations Office (COO): Consortium activities are expected to be centrally coordinated. The COO should have an integrated organization consisting of an Operations Unit and a Statistics and Data Unit.
• Clinical Trials Research Program: In order to perform scientific studies of the highest caliber, ABTC must be able to maintain a research team consisting of neuro-oncologists, neuro-surgeons, neuro-pathologists, radiation oncologists, and other experts as needed in order to a) safely and efficiently introduce novel anticancer agents into the treatment of high-grade primary brain tumors through the conduct of Phase I and Phase II clinical trials, b) develop scientifically appropriate clinical trials addressing increased needs for intensive translational efforts in accompanying studies, and c) incorporate PK and PD endpoints as appropriate into the clinical trials.
• Infrastructure for Coordination of Clinical Trials and Associated Activities: ABTC must have all the necessary capabilities, expertise, staff, and infrastructure necessary for the proper development and conduct of clinical trials, including monitoring and other activities needed to ensure compliance with all the applicable regulations.
• Member Institutions (clinical trials sites): The Consortium should include an appropriate number of institutions sufficient to complete the requisite number of clinical trials. Member institutions should have experience in participating in Phase I and II adult brain tumor trials and should have demonstrated the ability to accrue and monitor patients on Phase I and II trials, and have the ability and experience to report clinical data for central collection and review.
• Consortium Governance: The Consortium Coordinating Committee will be a body responsible for the overall direction and general operating strategies of the consortium. See Section VI. Cooperative Agreement Terms and Conditions of Award for details on the composition and roles of Coordinating Committee.

The ABTC will be subject to external evaluation near the end of the funding period (to be coordinated by the NCI Program Staff). Such evaluation is part of NIH efforts to optimize the efficiency of the funded research. The evaluation process will involve monitoring and assessing the progress of the ABTC toward achieving its goals. This aspect includes evaluating the quality, value, and scientific impact of the research conducted by the Consortium.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	Renewal The OER Glossary and the PHS 398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NCI intends to commit up to $2 million in total costs in FY 2014 to fund one award.
Award Budget	The application budget needs to reflect the actual needs of the proposed Consortium but must not exceed $2 million in total costs per year, with a total 5-year cost not to exceed $10,000,000. These amounts are inclusive of all Facilities and Administrative costs for both the awardee and consortium sites.
Award Project Period	A project period of 5 years must be proposed.

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

Only the current awardees of Adult Brain Tumor Consortium funded under RFA-CA-08-504 are eligible to apply.

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

Applicant organizations must complete the following registrations as described in the PHS 398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• System for Award Management (SAM) must maintain an active entity registration (formerly CCR registration), to be renewed at least annually. Use the Sam.gov Manage Entity function to manage your entity registrations. See the Grants Registration User Guide at SAM.gov for additional information.
• eRA Commons

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

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least6 weeks prior to the application due date.

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

More than one PD/PI (i.e., multiple PDs/PIs) may be designated in the application. For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS 398 Application Guide.

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

Applicant organizations may submit only one application in response to this FOA.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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

It is critical that applicants follow the instructions in the PHS 398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

William C. Timmer, Ph.D.
Clinical Grants and Contracts Branch
Cancer Therapy Evaluation Program
Division of Cancer Therapy and Diagnosis
National Cancer Institute
9609 Medical Center Drive, Room 5W542
Bethesda, MD 20892-9741 (U.S. Postal Service regular mail)
Rockville, MD 20850 (express delivery)
Telephone: 240-276-6130
Email: [email protected]

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

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

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

Referral Officer
Division of Extramural Activities
National Cancer Institute
9609 Medical Center Drive, Room 7W412
Bethesda, Maryland 20892-9750 (for Express mail, use Rockville, MD 20850)
Telephone: (240) 276-6390
Fax: (240) 276-7682
Email: [email protected]

All page limitations described in the PHS 398 Application Guide and the Table of Page Limits must be followed, in addition to the following page limitations to the Research Strategy subsections listed below:

A. Consortium Overview: 12 pages

B. Consortium Leadership and Central Operations Office: 12 pages

C. Clinical Trials Research Program: 12 pages

D. Infrastructure for the Coordination of Clinical Trials and Associated Activities: 12 pages

E. Member Institutions: 6 pages

The following section supplements the instructions found in the PHS398 Application Guide, and should be used for preparing a multi-component application.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions, as noted.

(Face Page)

All instructions in the PHS 398 Application Guide must be followed.

Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, Human Embryonic Stem Cells (Overall)

All instructions in the PHS 398 Application Guide must be followed with the modifications identified below.

The ABTC applicants are strongly recommended to name in the application an overall Consortium Chairperson, who will preside over the Consortium governing body, the Coordinating Committee (see Section VI. Cooperative Agreement Terms and Conditions of Award for details). The Consortium chairperson is expected to be one of the PDs/PIs based in the applicant institution. Applicants are also encouraged to identify a co-chairperson, who would share the overall leadership responsibilities with the chairperson, but would also be capable of leading the Coordinating Committee and the entire ABTC (in the event that the chairperson is unable to continue serving in this role). The individual designated as ABTC chairperson is also expected to serve as a contact PD/PI.

Table of Contents

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Modify Form Page 3 of the PHS 398 to replace standard sub-sections of "Research Strategy" with the following new sub-sections:

A. Consortium Overview (including Progress Report);

B. Consortium Leadership and Central Operations Office;

C. Clinical Trials Research Program;

D. Infrastructure for the Coordination of Clinical Trials and Associated Activities;

E. Member Institutions.

Detailed Budget for Initial Budget Period

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Use Additional Form Pages 4 and 5 to provide detailed separate budget information for initial budget period for the following individual application components:

• Consortium Leadership and Central Operations Office;
• Clinical Trials Research Program;
• Member Institutions.

The budget estimates provided below for the individual components should serve as guidelines, not strict caps. Nonetheless, substantial deviations from these guidelines should be justified.

Budget for Consortium Leadership and Central Operations Office: The budget for Consortium Leadership and Central Operations Office (COO) is expected not to exceed approximately $600,000 per year. This amount needs to be apportioned as necessary between the Operations Unit and the Statistics and Data Unit. The COO budget is expected to include costs of coordinating activities (specified in Subsection D of Research Strategy).

Applicants must also budget travel funds for appropriate number of ABTC investigators to attend ABTC semiannual meetings.

Budget for Clinical Trials Research Program: The Research Expenses Fund is expected to amount to approximately $800,000 per year. The expenses associated with this fund are principally for correlative studies that are associated with the individual clinical trials. These costs include expenses to support 1) pharmacokinetic and pharmacodynamic studies performed on specimens (e.g., blood, tumor tissue, etc.), 2) magnetic resonance imaging studies, and 3) pathology studies from adults enrolled on ABTC clinical trial. Costs associated with other correlative studies are also acceptable.

Budget for Member Institutions: The budget for member institutions is expected to mainly reflect a "Site Support Fund," intended to cover patient reimbursement costs. This "fund" is expected to be set at approximately $600,000 per year, assuming an enrollment of approximately 200 patients/year at a reimbursement cost of $3,000 per patient. The Site Support Fund may cover the research costs involved in evaluating, treating, and monitoring patients on a study, including costs for specimen/image collection. Excluded are costs of patient care, normally paid for by insurers for routine medical treatment. Additional funds may be requested to support institutional costs of research that must be met whether or not a patient is enrolled on a study (e.g., submission of clinical trial protocols for review by institutional review board (IRB), site training, pharmacy set-up, site administration and data collection).

Allocation of funds to participating member institutions must be planned through appropriate subcontractual arrangements.

Budget for Entire Proposed Period of Support

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Use Additional Form Pages 4 and 5 to provide detailed separate budget information (first year and cumulative budgets for the entire project period) using the same categories as described above for the initial budget period.

Biographical Sketch (Overall)

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions: except for the Biographical Sketch Format Page of all individuals listed as Senior/key Personnel and Other Significant Contributors, described below, must be followed in the order listed on Form Page 2.

The NCI is conducting a pilot of proposed changes to the PHS 398 Biosketch. The most important change replaces the request for applicants to provide a list of up to fifteen peer-reviewed publications (original section C). During this pilot, NCI peer reviewed submissions must describe up to five contributions to science, depending on length of post-graduate experience (see section C below). The intent is for applicants to be evaluated on the basis of better information than can be conveyed by a mere list of publications. The format of these contributions is described below. The instructions also explain how to include mention of other work closely related to the subject of the grant application. Additionally, to better clarify the intent of Section A, the Personal Statement, additional phrases have been included.

Following the education block, complete sections A, B, C and D as indicated below:

A. Personal Statement. Briefly describe why you are well-suited for your role in the project that is the subject of the application. The relevant factors may include aspects of your training; your previous experimental work on this specific topic or related topics; your technical expertise; your collaborators or scientific environment; and your past performance in this or related fields (including mention of specific contributions to science that are not included in Section C). If you wish to explain impediments to your past productivity, you may here describe factors such as family care responsibilities, illness, disability, and active duty military service.

B. Positions and Honors. No Change in Instructions from PHS 398 Instruction Guide.

C. Contributions to Science. Describe your five most significant contributions to science. For each of these contributions, cite the peer reviewed publication (or set of no more than four publications) that present(s) the work, followed by a paragraph that includes the following elements:

• the historical background that frames the scientific problem;
• the central finding(s);
• the influence of the finding on the progress of science or on the application(s) of the finding to health and/or technology; and,
• the specific role you played in the described work.

Each scientific contribution, including any related figures, should occupy no more than half a page.

Publications pertinent to the current grant application that are not included among the Contributions to Science may be mentioned in the Background or Preliminary Results section of the application or in a preceding section of the Biosketch (Section A. Personal Statement) that asks why your experience and qualification make you particularly well-suited for your role in the project that is the subject of the application.

When citing articles that fall under the Public Access Policy, were authored or co-authored by the applicant and arose from NIH support, provide the NIH Manuscript Submission reference number (e.g., NIHMS97531) or the PubMed Central (PMC) reference number (e.g., PMCID234567) for each article. If the PMCID is not yet available because the Journal submits articles directly to PMC on behalf of their authors, indicate "PMC Journal - In Process." A list of these Journals is posted at: http://publicaccess.nih.gov/submit_process_journals.htm. Citations that are not covered by the Public Access Policy, but are publicly available in a free, online format may include URLs or PubMed ID (PMID) numbers along with the full reference (note that copies of publicly available publications are not acceptable as appendix material.)

At the end of section C, a link to a full listing of your published work as found in a public database such as PubMed may be included.

D. Research Support. No Change in Instructions from PHS 398 Instruction Guide.

All other components of the Biographical Sketch remain as described in the PHS 398 Instruction Guide.

NOTE: Site PDs/PIs at individual Member Institutions are considered Key Personnel. Accordingly, Biographical Sketches must be submitted for each PD/PI as per PHS 398 instructions.

Resources

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

In addition to standard information, provide in this section:

• Examples of the standard procedures developed and utilized by the applicants to support the timely development of Pilot, Phase I, Phase II, and pilot clinical trials for adults with brain cancer, including procedures, benchmarks, and a representative template for clinical trial protocols currently used.
• Documentation of important capabilities and available resources for Member Institutions. The documentation (synopses/summary tables) should not exceed two pages per institution and may include, but is not limited to, the following:
  • Documentation of the clinical and/or basic research experience, training, effort (in person-months) that key personnel will devote to ABTC activities, research competence, and commitment to the ABTC participation of the institutional (site) PDs/PIs (for example, as evidenced by past clinical research contributions and current research efforts relating to neuro-oncology drug development).
  • Documentation of the ability to meet the intensive data collection and regulatory requirements necessary for early phase clinical trials.
  • Documentation that institutional data management resources and procedures at the proposed member sites are adequate to ensure timely data submission for the ABTC clinical trials.
  • Documented ability to recruit patients for Pilot, Phase 1, Phase 2, and clinical trials for adults with brain cancer.
  • Scientific expertise (both clinical and laboratory) available at the member institution, along with a statement that the institution is willing to utilize this expertise for the conduct of the ABTC correlative studies (e.g., pharmacokinetic and pharmacodynamic monitoring or imaging research studies).
  • Availability of state-of-the-art imaging, such as magnetic resonance imaging (MRI), functional MRI, magnetic resonance spectroscopy (MRS), and positron emission tomography (PET). Include a statement indicating the institutional commitment for utilizing these techniques in the conduct of the ABTC studies when such imaging studies are required.

Research Plan

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Specific Aims: Identify general, strategic objectives for ABTC along with main benchmarks that would indicate accomplishment of these objectives.

Research Strategy: The Research Strategy must consist of the following sub-sections.

A. Consortium Overview

In this sub-section, applicants should include Progress Report and summarize their overall vision of the ABTC during the proposed funding period.

The Progress Report for the current ABCT funding period should address, but is not limited to, the following:

• Summarize the Consortium's current portfolio of agents and/or techniques. Information should be included (either tabular or written) explaining the scientific rationale for selecting the specific agent or technique chosen for study.
• A listing of the clinical trial protocol developments during the current funding period, including letters of intent (LOIs) submitted, clinical trial protocols submitted, and clinical trials activated, with timelines for specific steps in the clinical trial protocol development process.
• A table summarizing all of the clinical trials that the Consortium has opened during the current funding period (i.e., since 2009). The following information should be included about each trial: Trial Number; NABTT/NABTC Trial (Y or N); ABTC Designed Trial (Y or N); Agent Studied; Phase; Total Accrual; Open/Closed; Outcome (1 or 2 sentences). Copies of one or two representative protocols may be included in this section.
• Describe the main accomplishments and findings from each clinical trial that has been completed during the current funding period (e.g., indications of anti-tumor activity, dose levels evaluated and recommended dose for Phase II trials, important adverse events observed, pharmacokinetic findings).
• Key aspects of the past performance of current member institutions should be summarized in one or more tables to cover, for example, accrual to ABTC trials by year, enrollment of ineligible patients and lack of disease measurability when required, timeliness of data submission, timeliness of report submission for AdEERS Adverse Event Expedited Reporting System, compliance with specimen submission, etc.

Describe the scope and provide highlights of pharmacokinetic, pharmacodynamic, and neuroimaging research contributions, associated with each of the clinical trials; contributions from other disciplines (e.g., neuropathology) may also be included in this section.

B. Consortium Leadership and Central Operations Office

In this subsection, describe Consortium leadership structure and specific plans for the COO. Address the following aspects:

• Summarize the relevant qualifications, expertise, and experience of the leadership team, including: the chairperson and co-chairperson, directors of the Operations Unit and the Statistics and Data Unit, the PK/PD and neuroimaging research chairs, and other key personnel.
• Clearly identify chain of command and responsibilities for specific Consortium components. For example, define whether the Consortium chairperson will also be responsible for the COO oversight and will direct the Clinical Trials Research Program.
• Describe the organizational structure of the ABTC (an organizational chart(s) may be included). Lines of authority and decision-making process(es) should be described.
• Delineate the responsibilities of the Consortium chairpersons, PD(s)/PI(s), and senior investigators responsible for the activities in each of the participating member institutions. Leaders of individual member sites may be designated as PDs/PIs (if appropriate).
• Describe specific plans for COO and its Units for the coordination and facilitation of the key functions of the Consortium.
• Include a plan for transition of leadership.
• Outline plans and opportunities for the mentoring and career development of junior investigators.

The COO should consist of an Operations Unit and a Statistics and Data Unit.

In this subsection, describe plans for the organization of these units, addressing their roles as indicated below.

• Operations Unit: The Operations Unit will be responsible for developing clinical trial protocols, arranging Consortium meetings, following compliance with FDA and OHRP regulations, and monitoring the performance of institutional members of the Consortium. The Operations Unit will also collect data and prepare reports on the performance of the Consortium in meeting pre-specified time lines for Letter of Intent (LOI)/concept and clinical trial protocol development, study implementation, publication of Consortium studies, and member institution performance.
• Statistics and Data Unit: The Statistics and Data Unit will be responsible for all the statistical and the data management aspects of the Consortium. This center must ensure that clinical trials data are obtained directly from member institutions using a remote data entry (RDE) system. ABTC is required to use all appropriate services provided by the Cancer Trials Support Unit (CTSU; https://www.ctsu.org/public/)

NOTE: The COO and its units will be expected to assume responsibility for the various coordinating activities specified in Subsection D. Signal these responsibilities in general way in this subsection but avoid repetitions with Subsection D.

C. Clinical Trials Research Program

In this subsection, identify the leadership (Director) of the proposed Clinical Trials Research Program and outline strategic plans for this component.

In these plans, applicants need to focus on the following general goals:

a) Safe and efficient introduction of novel anticancer agents into the treatment of high-grade primary brain tumors through the conduct of Phase I and Phase II clinical trials;

b) Developing scientifically appropriate clinical trials addressing increased needs for intensive translational efforts in accompanying studies; and

c) Incorporating PK and PD endpoints as appropriate into the clinical trials.

Consortium is required to designate discipline-specific chairpersons, who will be responsible for leadership of the specified discipline. Discipline chairs should include, but are not limited to, PK/PD, neuropathology, neuroimaging, neurosurgery, radiation oncology, and biostatistics. Discipline chairs may be added or eliminated as appropriate, by the COO in concurrence with the Consortium Coordinating Committee.

The plans for Clinical Trials Research Program should include (but are not limited to) such aspects as:

• The general approach to study design and research plans for Pilot, Phase I, and Phase II clinical trials to evaluate new agents, particularly investigational agents, designed to affect specific molecular targets. Describe the criteria employed by ABTC for the prioritization of novel systemically administered agents for evaluation in clinical trials.
• A listing of new agents and/or techniques that are under consideration, along with their stage in the ABTC selection process (e.g., under ABTC review/discussion, awaiting regulatory status, etc).
• Procedures and plans for the conduct of correlative laboratory studies, as appropriate, should be addressed, including the incorporation of pharmacokinetic, pharmacodynamic, and pharmacogenetic endpoints into clinical trials evaluating new agents.
• Describe procedures and plans for ABTC to coordinate the collection of tumor specimens, biological fluids, and relevant clinical data and their distribution to the appropriate laboratories or tumor/specimen repositories.
• Describe plans for research studies that utilize 1) specialized neurosurgical expertise, 2) neuropathology expertise, and 3) radiation therapy.
• Plans for imaging should include plans to incorporate imaging endpoints and investigations on specific imaging research problems into the overall research program of ABTC. Briefly address the availability of adequate post-image storage, processing, and analysis capabilities, procedures and plans to coordinate with and engage imagers at each member institution, and plans to develop and implement common imaging protocols.
• Describe the procedures and plans for assuring timely publication of the results of clinical trials and laboratory studies to be conducted by ABTC.
• Collaborations, in effect or planned, between the Consortium and other brain tumor researchers or organizations, such as investigators holding R01 grants, or via NIH-sponsored research program at the Clinical Center (Opportunities for Collaborative Research at the NIH Clinical Center, http://grants.nih.gov/grants/guide/pa-files/PAR-13-029.html), or via the NCI-funded brain tumor SPOREs (http://grants.nih.gov/grants/guide/pa-files/PAR-12-296.html), or, if available and appropriate, participation in the Drug-Development Teams in the NCI Experimental Therapeutics-Clinical Trials Network (ET-CTN, http://ctep.cancer.gov/investigatorResources/docs/ET-CTN_Program_Guidelines.pdf; http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-13-006.html ).

In formulating the goals for the Clinical Trials Research Program and the entire Consortium, the applicants are expected to consider the following factors/benchmarks (which will also be used in the evaluation of the application merit):

• The number of Phase I and Phase II clinical trials initiated and successfully completed (two or three and four to five per year, respectively, are expected);
• The use of proper trial designs to determine appropriate doses in Phase I studies and appropriate endpoints in Phase II clinical trials;
• The incorporation of adequate pharmacokinetic and pharmacodynamic studies into Consortium trials;
• The incorporation of appropriate biomarkers to predict outcome and/or response to treatment, including the use of imaging studies;
• The timely presentation of results at national meetings and timely publication of results in peer reviewed journals;
• Appropriate clinical trial protocol development and activation (to meet timeline requirements defined by the NCI Cancer Therapy Evaluation Program, CTEP);
• The generation of high quality data as evidenced by an effective quality control/quality assurance (QC/QA) program and by review of data submitted to CTEP; and
• The number of clinical trial protocols/ancillary studies that result in interactions with NIH-funded investigators, SPOREs, the NIH Clinical Center, the Early Clinical Trial Network, and the National Clinical Trial Network.

Note: It is expected that integration of translational and PK/PD endpoints into clinical trials will receive elevated priority for the new funding period. Particularly relevant is the ability to obtain and analyze PK/PD and biomarker data in a large fraction of patients enrolled on all studies (or even all patients, if appropriate). These aspects will be assessed as one of the critical elements for responsiveness to this FOA as well as application merit.

D. Infrastructure for the Coordination of Clinical Trials and Associated Activities

It is expected that the COO and its Operations Unit and Statistics and Data Unit will be responsible for the actual coordination of clinical trials and associated activities. However, details about infrastructure for these activities are to be provided in this section. Describe here ABTC capabilities, expertise, staff, procedures, and other elements of infrastructure necessary for the proper development and conduct of clinical trials. Address the following aspects:

• Procedures for effective interaction and communication involving the leadership of ABTC and member institutions to facilitate the development of clinical trial protocols and conduct of clinical trials in safe and timely manner.
• Procedures for semiannual ABTC meetings to review progress, establish priorities, and plan future clinical trial research activities.
• Describe the data management, analysis, and standard procedures for Quality Control/Quality Assurance.
• Describe the statistical support for the ABTC clinical trials, and the general statistical approach to the design and analysis of Pilot, Phase 1, and Phase 2 clinical trials. Include a description of (a) facilities and data management resources and personnel; (b) procedures for ensuring the technical integrity and security of the data management systems; (c) procedures for development of data collection forms; and (d) procedures for data transmittal, data editing, and quality control/verification of submitted data.
• Describe the procedures for study monitoring, including establishing procedures for (a) assigning drug dose level; (b) assessment of patient eligibility and evaluability; (c) timely medical review and assessment of clinical trial data; (d) rapid reporting of treatment-related morbidity; and (e) interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice for Pilot, Phase 1, and Phase 2 clinical trials.
• 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/protocolDevelopment/templates_applications.htm). Describe procedures to ensure that claims of treatment agent activity (e.g., claims of objective responses) are accurate and reliable.
• Describe procedures for regulatory compliance, including following elements: Procedures for timely reporting of all serious and/or unexpected adverse events via (a) the Adverse Event Expedited Reporting System (AdEERS, http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adeers.htm) for investigational agents for which the status of Investigational New Drug (IND) has been sponsored by the NCI and (b) sponsor-specified methods for other agents bearing the IND status.
• Procedures to meet Office for Human Research Protections (OHRP) requirements for the protection of human subjects, including informed consent, institutional review board (IRB) review of protocols, and institutional assurances, should be addressed.
• Procedures for assuring that ABTC investigators performing clinical trials involving investigational agents sponsored by the NCI Division of Cancer Treatment and Diagnosis (DCTD) are NCI-registered investigators (Form 1572).
• Procedures for assuring that ABTC will comply with Cancer Therapy Evaluation Program (CTEP) requirements (as described in the DCTD Investigators' Handbook, http://ctep.cancer.gov/investigatorResources/investigators_handbook.htm) for storage and accounting for investigational agents (including NCI Drug Accountability Records [DAR] procedures (http://ctep.cancer.gov/protocolDevelopment/requisition_agents/docs/storage-03.pdf).

E. Member Institutions

The Consortium must include an appropriate number of member institutions that are capable of enrolling patients on brain tumor clinical trials. Member institutions must have experience in participating in Phase I and II adult brain tumor trials and should have demonstrated the ability to accrue and monitor patients on Phase I and II trials, and have the ability and experience to report clinical data for central collection and review. The selection of member sites does not have to be permanent for the entire funding period with the ultimate goal of retaining only well-performing sites.

In this sub-section, address the following aspects:

• Provide a brief description of how each member institution meets the criteria for appropriate research capabilities and for acceptable performance (do not exceed two pages per member institution).
• Highlight the relevant qualifications and experience of member institutions leadership (including PDs/PIs, if designated). In addition, note that leaders at member institutions are considered Senior/Key Personnel in the context of PHS398 instructions and appropriate documentation (such as biosketches) must be included for them.
• Describe the proposed procedures that the Consortium will be expected to develop and implement for interacting with member sites to maximize their performance.
• Describe plans for the evaluation of this performance on a regular basis for such elements as: adequate patient accrual, timely submission of required data, observance of clinical trial protocol requirements, contributions to clinical trial protocol development, authorship in ABTC publications, and participation in ABTC administrative and scientific committees.
• Describe procedures for dropping member institutions from the Consortium.
• Briefly outline any policy that would allow institutions that are not members of the Consortium to participate (via a guest membership) in selected Consortium clinical trials, provided they have the appropriate capabilities.

Progress Report Publication List: Publications during the previous funding period (including articles in press) should be listed as per PHS398 instructions. Address the timeliness and completeness of publications reflecting the conducted clinical trials.

Multiple PD/PI Leadership Plan: If multiple PD(s)/PI(s) are proposed, the application must include a Multiple PD/PI Leadership Plan. The plan is expected to identify who of the proposed multiple PDs/PIs will serve as an overall leader of the Consortium (or whether such leadership will be shared by more individuals).

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS 398 Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS 398 Application Guide.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS 398 Application Guide.

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

This initiative is not subject to intergovernmental review.

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

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

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

Upon receipt, application will be evaluated for completeness by the Center for Scientific Review and responsiveness by NCI, NIH. Application that is incomplete and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

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

For this FOA, a central aspect for the assessment of application merit is the extent to which the ABTC will be able to bring novel therapeutic strategies for adult patients with brain tumors, especially GBM into early clinical testing. Particularly important for the clinical development of current and next generation brain cancer therapeutics is the ability to integrate clinical trials with translational approaches.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Adult Brain Tumor Consortium to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

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

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?

Specific for this FOA: Will the ABTC, as proposed, be able to introduce appropriate novel anticancer agents into brain tumor clinical trials in a timely, safe, and efficient manner?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific for this FOA: Have the PD(s)/PI(s) sustained high-level participation in the scientific leadership of early experimental therapeutics (e.g., serving as scientific committee or protocol/trial study chairs, contributing new trial ideas including participating in LOI development, co-authoring publications on clinical trials research)?

Do the PD(s)/PI(s) have adequate and appropriate experience in administering clinical trial research, including organization and management of the infrastructure required for patient recruitment/accrual, data collection, data reporting, and safety monitoring for patients enrolled on clinical trials? Will these investigators be able to work as a coherent research team to efficiently and expeditiously conduct clinical trials in brain cancer?

Does the Consortium have adequate biostatistical expertise to conduct and analyze complex clinical and molecular data?

How well do the research experience and qualifications of the PD(s)/PI(s) correspond to the need for multidisciplinary capabilities (e.g., neuro-oncology, radiation oncology, imaging, neuro-surgery)?

Are the other key personnel appropriately trained and well suited to carry out the work associated with clinical trials in brain cancer?

Does the Consortium provide sufficient training and mentoring opportunities for junior scientists?

Innovation

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

Specific to this FOA: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the treatment of adult patients with brain tumor? Do the applicants propose novel or improved ways and/or methods to enhance or better serve the goals of the Consortium?

Approach

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

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

Specific to this FOA: Do the Consortium’s research plans for Pilot, Phase I, and Phase II evaluations of new agents in adults with brain tumors demonstrate an appropriate understanding of research opportunities and challenges in drug development for brain tumors and of the methods and techniques available to exploit these opportunities?

Do the applicants propose novel or improved ways and/or methods to enhance or better conduct early clinical trials? Are the research plans for incorporating imaging endpoints into the Consortium s overall research program reasonable?

Are the plans for incorporating pharmacokinetic, pharmacodynamic, and pharmacogenetic endpoints into the Consortium’s clinical trials appropriate and sufficient? Are state-of-the-art approaches used to addressing these endpoints?

Have the applicants developed proactive plans for the Consortium’s collaboration with other NCI/NIH funded researchers working in the field (e.g., R01 awarded investigators, brain tumor SPOREs, Clinical Trials Cooperative Groups), and are there plans to both carry forward and hand-off clinical trials from and to other clinical trial investigators as appropriate?

Do these plans demonstrate an understanding of the contributions that imaging studies can make to the development of new drugs for brain tumors? Are there adequate plans for the interactions between the proposed Consortium and other NIH neuro-imaging initiatives and networks?

Environment

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

Specific to this FOA: How strong are the proposed Member Institutions in terms of ensuring their meaningful contributions to the Consortium's clinical trials?

As applicable for the Consortium proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

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. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

Reviewers will consider whether the budget for the required 5 year period of support is justified and reasonable in relation to the proposed research.

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

As part of the scientific peer review, application submitted in response to this FOA:

• will be discussed and assigned an overall impact score.
• Will receive a written critique.

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

Application will be assigned to the NCI. . Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

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

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

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

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

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

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

Awardee-selected projects that involve clinical trials or studies involving greater than minimal risk to human subjects require prior approval by NIH prior to initiation.

Specific requirements and procedures are defined below in Section VI.2 Cooperative Agreement Terms and Conditions of Award.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

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

The administrative and funding instrument used for this program will be the cooperative agreement (UM-01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• Defining the overall research goals and strategies for the Consortium and its components;
• Overseeing the development of Phase 1, Phase 2, and pilot clinical trial protocols for children with brain tumors in accord with the research interests, abilities and goals of the Consortium;
• Ensuring that these protocols are properly submitted to CTEP for review prior to their implementation; and
• Overseeing the planning and conducting of all other scientific, organizational, and administrative activities of the Consortium indicated below.

All the Consortium activities and specific activities of its components must be consistent with the guidelines contained in the following documents (and any subsequent modification to them) that are hereby incorporated as parts of the terms of award. These documents describe the programmatic responsibilities for the conduct of the research supported by this cooperative agreement:

• INVESTIGATOR'S HANDBOOK, a Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis, (DCTD), National Cancer Institute (http://ctep.cancer.gov/handbook/); and
• Intellectual Property Option to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).

COO Responsibilities

The COO and its components (the Operations Unit and the Statistics and Data Unit) will be responsible for coordinating clinical trial protocol development, protocol submission for review and approval, study conduct (including central data collection and analysis), quality control including study monitoring and subsequent associated quality assurance, 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 Operations Unit, with the guidance of the Consortium chairperson and the Coordinating Committee, will be responsible for development and maintenance of an organizational structure and Standard Operating Procedures for the Consortium.

2) Clinical Trial Protocol Development: It will be the responsibility of the Consortium to develop the details of the research design, including definition of objectives and approaches, planning, implementation, analysis, interpretations and conclusions of studies, and publication of results. The Operations Unit will be responsible, in accordance with the Consortium s SOPs, for the preparation and implementation of procedures for development and submission of Consortium clinical trial protocols to the CTEP Protocol and Information Office (PIO) in a timely fashion for review and approval by NCI.

• Clinical trial protocols must be developed, submitted, and implemented in accordance with the DCTD Investigator's Handbook" (http://ctep.cancer.gov/investigatorResources/docs/hndbk.pdf).
• Submission of Consortium clinical trial protocols for review and approval by NCI must 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/forms).
• The Operations Unit will be responsible for communicating the results of the CTEP Protocol Review Committee to relevant Consortium Committees and Consortium members.
• The Consortium will not expend NCI funds to conduct any study disapproved by CTEP unless CTEP's disapproval has been modified by the arbitration process (see Section VI.2.A.4 Arbitration Process).
• 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.cancer.gov/industryCollaborations2/intellectual_property.htm) and the NCI Standard Protocol Language for Cooperative Research and Development Agreements (CRADAs) and Clinical Trial Agreements (CTAs).
• The Consortium’s SOPs must 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 Operations Unit and Consortium members in meeting these time lines. The Consortium’s SOPs should also include corrective action plans outlining the steps to be taken when these time lines are not met. Data concerning the Consortium’s performance in meeting timelines for protocol development must be provided in the Annual Progress Report.

3) Study Monitoring: The Consortium must follow the general guidelines for study monitoring for CTEP-sponsored trials as described http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_multicenter.htm. The Consortium will be 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 intensive data requirements and the need for rapid reporting necessary for Pilot, Phase I, and Phase II studies. Standard procedures include (but are not necessarily limited to):

• Precise tracking of patient accrual and adherence to accrual goals defined by clinical trial protocol-defined accrual goals. If the Consortium wishes to continue accrual to a study beyond the total accrual goal for eligible and ineligible patients specified in the clinical trial protocol, the Consortium will have to obtain approval from CTEP prior to continuing patient accrual;
• Procedures for assigning dose level (for Phase 1/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;
• Ongoing assessment of patient eligibility and of disease measurability;
• Adequate measures to ensure timely medical review and assessment of individual patient data;
• Adequate measures to ensure timely submission of clinical trials data (e.g., adverse events, anticancer response, etc.) from Member Institutions. These measures should include procedures for monitoring compliance with Consortium’s guidelines for data timeliness on an institution and a study basis, including summary reports of data submission timeliness to be used for Institutional Performance Review and to be used for study monitoring (e.g., as specified by the Data and Safety Monitoring Plan)]. These summary reports should also be included in the Annual Progress Report;
• 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 the Adverse Event Expedited Reporting System (AdEERS) according to CTEP guidelines specified in each protocol (http://ctep.info.nih.gov/adeers.html);
• 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 semiannual reports for Consortium meeting agendas, and reports as required to comply with the Consortium’s Data and Safety Monitoring Plan; and
• Adequate policies and procedures for closure of studies. If the Consortium 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 the 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 and Safety Monitoring Plan regarding notification of CTEP must be followed.

4) Data Management Policies and Practices: The responsibilities of the Statistics and Data Unit for data management related to study monitoring will include the following:

• Providing for central storage, security, processing, and retrieval of study results;
• Incorporating security features consistent with the guidelines of the U.S. Department of Health and Human Services (DHHS);
• Implementing procedures for backing up the Consortium’s clinical and administrative data, including intermittent duplication of the database with storage at a remote facility;
• Protecting patient confidentiality at all steps in the submission and analysis of clinical trials data and ensuring the technical integrity and security of the data management systems; and
• Providing NCI in a timely manner, upon the request of the Grants Management Officer, true copies of data files and supporting documentation for all NCI-supported protocols that have a major impact on patterns of care, as determined by the NCI.

5) CTRP/clinicaltrials.gov Registration and Outcomes Reporting: All ABTC trials must also be registered and appropriate information updated in the NCI Clinical Trials Reporting Program (CTRP) as described at: http://www.cancer.gov/clinicaltrials/conducting/ncictrp/main as well as registered in the U.S. National Library of Medicine clinical trials database (i.e., at www.clinicaltrials.gov). Changes in the trial design and accrual as well as results reporting from NCTN trials are also required to be reported in clinicaltrials.gov as required under the Food and Drug Administration Amendments Act (FDAAA), Section 801.

6) Quality Control of Consortium Clinical Trials: Quality Control and Quality Assurance (QC/QA): The Consortium is responsible for establishing and implementing mechanisms to assure the accuracy and reliability of the Consortium clinical trials data. Key items that should be addressed in this regards include:

a) Study Monitoring: The Clinical Trials Research Program is responsible for overall organization and oversight of study teams that monitor data from specific clinical trials and with appropriate coordination with the Statistics and Data Management Component.

b) Evaluation of the performance of member institutions in terms of:

• Accrual of adequate number of eligible patients onto Consortium trials;
• Timely and accurate submission of required data;
• Conscientious observance of protocol requirements;
• Participation in study development, leadership, and publication; and
• Participation in Consortium administrative and scientific committees and/or other Consortium activities.
• Summary reports of the results of performance evaluations should be submitted with the annual progress reports.

c) Procedures for placing Member Institutions on probation for inadequate performance and for removing such institutions from the Consortium if performance is not adequate during the probationary period or at any time that the institution (or participating site) does not meet Consortium standards for institutional performance.

d) Training functions that address data collection, data management, and overall data quality. These aspects include, but are not limited to, the following elements:

• Training for new Clinical Research Associates (CRAs) in the Consortium’s data submission policies and ongoing training for all CRAs concerning changes to Consortium procedures and instructions for data submission in new protocols;
• Instruction for Study Chairs on their responsibilities for study monitoring;
• Instruction for responsible site investigators at Member Institutions and other participants in the clinical trials on their responsibilities in complying with the Consortium’s SOPs and Federal regulations at their institution; and
• Training/guidance should also be provided to all participants on how to comply with NCI/NIH policies and procedures (e.g., Ethics, Conflict of Interest, etc.) in addition to the policies and procedures of other governmental agencies important to the conduct of clinical trials (e.g., Office for Human Research Protections, FDA).

e) Procedures for central review of the reliability of the key elements defining the outcome of clinical trials, including such aspects as: imaging studies on which claims of therapeutic responses are based; pathology; surgery; and compliance with protocol-prescribed dosing and dose modification.

e) On-site Auditing of Consortium Member Institutions: The ABTC’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 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 ABTC is responsible for maintaining its on-site auditing program in compliance with the Clinical Trials Monitoring Branch (CTMB, CTEP) guidelines (http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_coop_ccop_ctsu.htm) and for submitting the results of audits to the NCI in accordance with the guidelines. In the event that the NCI determines that a ABTC Member Institution failed to comply adequately with NCI guidelines for conduct of clinical trials, the accrual of new patients to ABTC protocols at the affected institution shall be suspended immediately upon notice of the NCI determination. The suspension will remain in effect until the ABTC conducts the required audit and the audit report or remedial action is accepted by the NCI. The Operations Center 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.

7) Timely reporting of data to CTEP using the Clinical Data Update System (CDUS): The ABTC is responsible for the timely reporting of data from ABTC clinical trials to CTEP using the Clinical Data Update System (CDUS) or its successor application as described at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/cdus.htm. For clinical trials that do not use CTEP IND agents, reporting to CTEP will generally consist of CDUS abbreviated procedures (primarily demographic data). For studies using CTEP IND agents, CDUS complete reporting procedures may be required to capture demographic, adverse event information (by course), and response data. CDUS complete reporting is required for Phase 1 studies and Phase 2 studies using CTEP IND agents, while abbreviated CDUS reporting is usually used for Phase III studies; however, complete reporting of CDUS data on adverse events may be required for Phase III trials by CTEP under certain circumstances.

8) Publications: Timely publication of major findings is central to the ABTC’s mission and is a primary means by which the ABTC s accomplishments can be evaluated.

a) The ABTC 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 ABTC’s components in meeting these timelines. Corrective action plans will be implemented when these timelines are not met.

It is expected that preliminary results of major Phase III trials will be presented at a scientific meeting within 6 to 8 months of completion of the study analysis (if not sooner based on the relevance of the results). It is a requirement under the Terms of Awards that a full manuscript on the study results be prepared and submitted for publication in the peer-reviewed literature (not as an abstract) within one year of the availability of the primary study results based on the completion date of the study recorded in the U.S. National Library of Medicine database, clinicaltrials.gov. Exceptions to this policy must be approved in writing by the ABTC Program Director (e.g., an exception may be made for results that are being analyzed for a marketing/licensing application to the FDA by a company partner). Also, these timelines may be modified in the future by NCI institute-wide requirements that are in development.

It is also a requirement of these Terms of Award that the results of all NCTN studies be submitted as required by the Food and Drug Administration Amendments Act (FDAAA) Section 801 to comply with the rules defined for inclusion of clinical trial information in clinicaltrials.gov

b) Publication or oral presentation of work conducted under the ABTC’s Cooperative Agreement requires appropriate acknowledgment of NCI support.

c) For any study using agent(s) supplied under CTEP Collaborative Agreements (e.g., CRADA, CTA, or CSA), both CTEP and the NCI pharmaceutical/biotechnology collaborator(s) will have a 30-day period in which to review any manuscripts for informational purposes as well as for comment (as per the NCI Standard Protocol Language for CTEP Collaborative Agreements) prior to submission of the manuscript by the Group for publication. An additional 30 days may be requested in order to ensure that confidential and proprietary data, in addition to the intellectual property rights of the Collaborator(s), are protected. In addition, the NCI pharmaceutical/biotechnology collaborator(s) will have courtesy review of any abstracts as soon as possible (preferably at least 3 days prior to submission), but in any case, prior to presentation or publication. Manuscripts and abstracts should be provided to CTEP for delivery to the NCI pharmaceutical/biotechnology collaborator(s). Pre-review timing for publications other than abstracts or manuscripts for studies involving agents supplied under CTEP Collaborative Agreements should be discussed with appropriate CTEP staff in the Investigational Drug Branch and the Regulatory Affairs Branch.

d) For Consortium publications associated with NCI-support that do not involve agent(s) supplied under CTEP Collaborative Agreements (except as noted below for press releases), the ABTC Program Director must receive a copy of the manuscript or abstract 30 days in advance of publication and a copy of abstracts should be provided three days in advance of publication. Unlike the situation for agent(s) supplied under CTEP Collaborative Agreements, however, no review or comments will be provided by CTEP unless specifically requested by the Consortium. This is simply a confidential notification. Review timing for publications other than abstracts or manuscripts should be discussed with appropriate NCI/DCTD staff.

e) All press releases issued by the NCI and/or the Consortium on primary study findings and results require review by NCI, NIH, and DHHS. Pre-review timing for press releases on study finding and results must be discussed with and approved by the ABTC Program Director. The ABTC is encouraged to send drafts of press releases on other topics to NCI for pre-review and/or pre-release notice.

f) The ABTC will comply with the NIH Public Access Policy that ensures that the public has access to the published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. To help advance science and improve human health, the Policy requires that these papers are accessible to the public on PubMed Central no later than 12 months after publication. More information about this policy or the submission process is available on the NIH Public Access Policy website at: http://publicaccess.nih.gov/.

9) ABTC Meetings: The Central Operations Office is responsible for the organization of semiannual meetings to review the ABTC’s progress, establish priorities, and plan future activities. Additional meetings between ABTC members and meetings with NCI staff may be held as needed. Relevant responsibilities for meeting organization include:

a) Arranging for appropriate meeting space and accommodations for attendees;

b) Developing and distributing meeting agendas;

c) Providing the Report of 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. The Operations Unit and Statistics and Data Unit are responsible for ensuring that copies of the report (electronic and/or hard copy) are distributed to ABTC members and NCI program staff.

d) Preparing summaries as appropriate after each meeting to be sent to ABTC members and NCI program staff.

10) ABTC Communications: The Central Operations Office must establish routine electronic communication with member institutions to facilitate clinical trial protocol development and study monitoring and to facilitate the work of the ABTC’s Study and Scientific Committees. Relevant communication methods include web site postings, e-mail, teleconferences, and web/video conferences.

11) Compliance with Federal Regulations Concerning Clinical Research: The ABTC PD(s)/PI(s) will be responsible for ensuring that the ABTC 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 ABTC must assure that each member has a current, approved Federal wide Assurance (FWA), on file with OHRP. Information on assurances is available on the OHRP website at: http://www.hhs.gov/ohrp/. In addition, federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to 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.

b) IRB Review of ABTC Protocols: The Central Operations Office must assure that each ABTC clinical trial protocol is reviewed and approved by each member institution’s IRB prior to patient entry, and must ensure that each clinical trial protocol undergoes continuing review no less than once per year by the IRB so long as the clinical trial is active.

The ABTC must assure that each protocol for a ABTC clinical trial is reviewed and approved by the appropriate Institutional Review Board (IRB) of the member institution prior to patient entry via the Regulatory Support Services (RSS) of the CTSU, and assure that each protocol is reviewed annually by the IRB so long as the protocol is active. The ABTC must ensure that each member site of the Group forwards its regulatory documents to RSS, otherwise the site will not be allowed to enroll patients on ABTC trials.

c) Assuring Appropriate Informed Consent: The ABTC must have procedures in place to ensure that each member institution is trained and understands the policies and procedures relevant to ensuring that patients are enrolled on studies with appropriate informed consent per NCI/NIH policy and federal regulations.

d) IRB Review of the Clinical Research Program and Statistics and Data component: (http://archive.hhs.gov/ohrp/humansubjects/guidance/engage08.html): An IRB should review and approve the research activities related to the receipt and processing of the identifiable private information by the Clinical Research Program and Statistics and Data component. The IRB should ensure that there are sufficient mechanisms in place to adequately protect the privacy of subjects and maintain the confidentiality of the data.

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

12) Data and Safety Monitoring Policy: The ABTC must establish a Data and Safety Monitoring Policy for the clinical trials conducted by the Group in compliance with NIH and NCI guidelines for data and safety monitoring for clinical trials. Data and Safety Monitoring Boards (DSMBs) or Data Monitoring Committees (DMCs) must be established that comply with the NCI NCTN Program Data Monitoring Committee Policy as provided in Part 4 Appendices Section VIII of the National Clinical Trials Network Program Guidelines. For the purposes of these Guidelines, the terms DSMB and DMC are used interchangeably to refer to committees established under with this policy. The ABTC's DSMB/DMC policy and membership roster, as well as any changes/modifications to the policy or membership roster, must be submitted to and approved by the ABTC Program Director.

Data and Safety Monitoring plans developed for other ABTC studies (e.g., Pilot, Phase I, and Phase II studies) must comply with the NIH policy for data and safety monitoring, posted on the NIH website at: http://grants.nih.gov/grants/guide/notice-files/not98-084.html, with additional description at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Further information concerning essential elements of Data and Safety Monitoring Plans for clinical trials funded by the NCI is available at: http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines.

13) Clinical Specimens Management: The ABTC will be responsible for 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 laboratory studies, as appropriate.

14) Conflict of Interest: The ABTC will be responsible for establishing a Conflict of Interest Policy that is in compliance with all of the DHSS regulatory requirements for conflict of interest as outlined by NIH grants policy available at http://grants.nih.gov/grants/policy/coi. This policy should ensure that there is no reasonable expectation that any investigator or staff member of the ABTC's central offices or at any of its member institutions/sites involved in the design, conduct, or reporting of research will be biased by any conflict of interest (using the definition of investigator provided in the NIH grants policy).

15) Fiscal management of the Consortium, including:

a) Establishment of consortium arrangements with member institutions to support ABTC-related activities at each member institution;

b) Administration of the Clinical Trials Research Program, including the process for selecting laboratories to perform specific studies (a competitive process is encouraged when feasible); and

c) Distribution of funds from the Member Institutions Fund to member institutions to support special clinical research costs for patients accrued onto ABTC clinical trials. Funds will be disbursed on a capitation basis upon documentation that the test(s) have been performed. It is anticipated that for each ABTC protocol, the capitation formula for institutional reimbursement required to offset specific research expenses will be reviewed and approved by the Steering Committee.

16) Annual Progress Reports: Submission of annual progress reports to the NCI that describe activities and accomplishments during the previous year of the ABTC. These report are expected to include:

a) A summary of the overall performance of the Clinical Research Program and Statistics and Data component in meeting their responsibilities to the ABTC for clinical trial protocol development, study monitoring, and complying with Federal regulations;

b) Summary data on performance of each ABTC Member Institution, 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 and/or staff, and the proposed budget for the coming year.

17) Member Institutions:
a) Membership Roster: The ABTC Clinical Research Program is responsible for having a comprehensive and consolidated membership roster of all its sites and associated investigators and research staff and for maintaining the roster for both auditing and financial management purposes with real-time status of all members within the Regulatory Support System (RSS) of the NCI Cancer Trials Support Unit (CTSU). All member institutions/sites must have appropriate and accurate NCI institutional codes approved by NCI.

b) Member sites are expected to prioritize ABTC clinical trials for enrollment at their institutions.

c) Member sites are required to collect and transmit clinical data, biospecimens, neuroimaging studies, and other research results and/or specimens as specified in ABTC protocols.

d) Investigators at member sites are expected to participate in ABTC scientific and administrative committees as appropriate and necessary to forward the research objectives of the ABTC.

e) See the Quality Control/Quality Assurance section for requirements for the evaluation of the performance of member institutions.

18) Participation by non-Consortium Institutions: Procedures to allow non-ABTC institutions to participate in the development and conduct of ABTC trials in those limited situations in which an institution has distinctive expertise or capabilities that would contribute to successful conduct of a ABTC study.

19) Re-competition for Institutions: The ABTC will be responsible for conducting a competition in year three of the project period in which those institutions rated in the lower tertile of performance in the first 2 years of the award must compete with non-ABTC institutions to maintain their position in the ABTC.

20) Correlative Science Studies: Correlative science studies embedded in ABTC clinical trial studies at the time of initial proposal submission should be appropriately designed as integral and/or integrated studies with robust statistical designs and analysis plans that address specific and important scientific hypotheses. Although optional collection of biospecimens without an approved research plan may be approved for a trial, use of the specimen must be approved by CTEP and must be based on studies with specific hypotheses and statistical analysis plans (i.e., biospecimens cannot be reserved for future unspecified research without a subsequent study proposal being reviewed and approved).

The PD(s)/PI(s) assumes responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the Consortium research in accordance with terms and conditions of the award.

The Consortium will be subject to periodic external evaluation (coordinated by the NCI). The CRN awardee and member institutions will be expected to participate in such evaluations.

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

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

A designated NCI Program Director, acting as a Project Scientist, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The NCI Project Scientist will be the main NCI contact for all facets of the scientific interaction with the awardees and will provide advice to the awardee on specific scientific and/or analytic issues in addition to programmatic issues. As needed, additional NCI scientific staff members with relevant expertise may also become substantially involved in the Consortium activities as Projects Scientists or Coordinators. NCI Program Staff Responsibilities will include:

Specific responsibilities of NIH Program Staff will include the following:

1) Coordination of National Priorities: NCI/DCTD staff are responsible for maintaining a clear set of national priorities for treatment research, based upon substantial consultation with experts in the field. In relation to adult brain tumors, this follows from input from experts in the ABTC, and the Brain Malignancies Steering Committee.

2) Monitoring Consortium progress: Actions necessary for monitoring may include, but are not limited to, the following: regular communications with the PD(s)/PI(s)and staff, periodic site visits for discussions with awardee research teams, response audits to confirm activity reported from a Consortium clinical trial, observation of field data collection and management techniques, fiscal review, review of clinical trial reports submitted by the Consortium to NCI, review of the Consortium’s annual progress report, and attendance at Consortium meetings. The NCI retains, as an option, the right to conduct periodic external reviews of progress.

2) Scientific Liaison: Serving as a resource with respect to other ongoing NCI activities that may be relevant to the Consortium 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 protocol development process for ABTC studies begins with proposals that are evaluated as either Letters of Intent (LOIs) or Concepts depending on the whether the proposal is reviewed/evaluated by the NCI/DCTD Cancer Therapy Evaluation Program (CTEP) Protocol Review Committee (PRC) or by the NCI Brain Malignancies Steering Committee. The LOI mechanism is designed to allow for the rapid preliminary review of study concept, facilitate agreement on study priority and design, and expedite the development and implementation of optimized clinical trial protocol (for further details of these mechanisms, see the DCTD Investigator's Handbook at http://ctep.cancer.gov/handbook/). Submission of protocols for Phase II clinical trials will be preceded by a written Concept Proposal. This will be reviewed by the Brain Malignancy Steering Committee following procedures outlined in the Cooperative Group Guidelines (http://ctep.cancer.gov/investigatorResources/default.htm#guidelines_policies).

Clinical trial concept proposals prioritized by the BMSC undergo expedited review by CTEP before final approval is given in order to ensure significant safety, feasibility, and regulatory issues are adequately addressed, including ensuring that there are adequate resources available for the trial given the resource allocation constraints for the disease area, and to prevent duplication. However, it is expected that this final review/approval by CTEP can be accomplished in an expedited manner in most cases as designated NCI/DCTD staff participate as full members on the various NCI and significant issues in these areas are incorporated into the evaluation/prioritization discussion.

NCI/DCTD staff (approximately four representatives including biostatistical staff and medical staff) are full members on the disease-specific and Clinical Imaging Scientific Steering Committees. The Clinical Investigations Branch physician responsible for adult brain tumors has special responsibilities on the NCI BMSC, including developing meeting agendas with the BMSC co-Chairs, preparing the Consensus Evaluations for pediatric brain tumor proposals evaluated by the committees, and working with the BMSC Co-Chairs on the scientific direction of the committee.

4) CTEP Review of Proposed Clinical Trial Protocols: All Consortium clinical trial protocols, including protocols utilizing agents not sponsored by NCI, will be reviewed by the PRC. Ad hoc reviewers external to NCI (who could be staff members of other NIH ICs and/or non-NIH scientists), 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 Consortium with a consensus review that describes recommended modifications and other suggestions, as appropriate (see the DCTD Investigator's Handbook, for further information regarding protocol review at CTEP).

If a proposed clinical trial protocol is disapproved, the specific reasons for lack of approval will be communicated in writing by the NCI Program Director to the Consortium 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 protocol that it has not approved. The NCI Program Director will be available to assist the Consortium in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the Consortium and of the NCI.

5) CTEP Protocol Amendment Review: Any change to the protocol document subsequent to its approval by CTEP must be submitted in writing for review and approval prior to implementation. For full details of the required procedure, see The Investigator’s Handbook at http://ctep.cancer.gov/handbook/).

6) CTEP Involvement in Auditing of Member Institutions: The Clinical Trials Monitoring Branch (CTMB) of CTEP will coordinate with the Consortium the performance of on-site audits at Consortium Member Institutions, which are to occur at approximately 2-3 year intervals. CTMB will review audit results and the corrective plans developed by the Consortium in response to the audits.

7) CTEP Involvement in Neuroimaging Research: Members of the NCI Cancer Imaging Program will advise the Consortium Steering Committee and the NCI Program Director with respect to ongoing NCI activities and research opportunities related to the application of imaging in drug development. They will participate in CTEP review of Consortium protocols with neuroimaging components and will assist the NCI Program Director in the overall review of Consortium neuroimaging research activities and accomplishments.

8) CTEP Involvement in Radiation Oncology Research: The NCI Radiation Oncology Research Coordinator will advise the Consortium Steering Committee and the NCI Program Director with respect to ongoing NCI activities and research opportunities related to radiation therapy for pediatric cancers. He/she will participate in CTEP review of Consortium protocols with radiation therapy components and will assist the NCI Program Director in the overall review of Consortium radiation oncology research activities and accomplishments.

9) CTEP Involvement in Clinical Trial Protocol Closure: Protocol closure is primarily the responsibility of the Consortium and the specific Protocol Committee. The NCI Program Director will also monitor clinical trial protocol progress and may request protocol closure to further patient accrual for the following reasons: (a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol performance; (d) patient safety or regulatory concerns; (e) study results are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. NCI will not provide investigational agents or permit expenditures of NCI funds for a study after requesting closure (except for patients already on study).

10) Data Management and Analysis Review: NCI Biometrics Research Staff will review mechanisms established by the Consortium for data management and analysis. When deemed appropriate, NCI staff will make recommendations to ensure that data collection and management procedures are adequate for quality control and analysis and as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense. The NCI will have access to all data, although they remain the property of the awardee institution. Data must also be available for external monitoring as required by NCI's agreement with the FDA relative to the NCI's responsibility as drug sponsor.

11) Data and Safety Monitoring Plan: The NCI Program Director, assisted by the Biostatistical Research Branch (BRB) staff, will assess Consortium compliance with NCI and NIH established policies on Data and Safety Monitoring Plans. The NCI Program Director must review and approve the Consortium’s Data and Safety Monitoring Plan. One or more CTEP staff will serve as non voting members on the Consortium’s Data and Safety Monitoring Committee (DSMC), should the Data and Safety Monitoring Plan (DSMP) specify a DSMC.

12) Participation in the Activities of the Consortium Steering Committee and its Scientific Meetings: The NCI Program Director will be a member of the Consortium Steering Committee (see below) and will attend the Consortium meetings (twice a year) to discuss relevant scientific information, to discuss progress in the clinical trials, and to discuss the status of newly available investigational agents and other research opportunities in order to plan future activities. Other NCI staff (e.g., from the Investigational Drug Branch, Radiation Research Program, and Cancer Imaging Program) will attend as needed.

13) CTEP Involvement in Investigational New Drug Applications: The NCI Program Director, assisted by the Chief, Regulatory Affairs Branch (RAB), CTEP, will advise investigators of specific requirements and changes in requirements concerning IND sponsorship that the FDA may mandate. Investigators performing trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents.

14) CTEP Review of Federally Mandated Regulatory Requirements: The Chief, Clinical Trial Monitoring Branch (CTMB), through the NCI Program Director, will advise the Consortium regarding mechanisms to meet FDA regulatory requirements for studies involving DCTD sponsored investigational agents and OHRP requirements for the protection of human subjects by Consortium institutions.

15) 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 Consortium for onsite auditing of clinical trials data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies. The awardee will comply with the data access provisions of applicable CTAs and CRADAs, and when these agreements are in place the Industry Sponsor will have complete access to the data for any and all regulatory filings.

16) 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).

17) CTEP Review of Progress: Performance of each Consortium will be reviewed at least annually by the NCI Program Director and other CTEP representatives based on the information provided at the twice-yearly Consortium Scientific Meetings and other meetings, as well as information in the annual progress reports and in the CDUS reports submitted to CTEP for each of the Consortium’s clinical trials. Insufficient patient accrual or progress, or noncompliance with the terms of award, including these Terms and Conditions of Award, may result in a reduction of budget, withholding of support, suspension or termination of the award.

NCI staff members who are substantially involved in the Consortium activities will not attend peer review meetings of renewal and/or supplemental applications. If such participation is essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict interest.

In addition, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the award, and will be named in the award notice. If this individual becomes substantially involved in the Consortium activities, he/she will not attend peer review meetings of renewal and/or supplemental applications or will seek NCI waiver if such participation is essential.

Areas of Joint Responsibility include:

The Consortium will have a Coordinating Committee as a governing body. Coordinating Committee will consist of the following voting members:

• Consortium chairperson and co-chairperson, who will preside over the Coordinating Committee;
• Rotating four to six senior representatives of the Member Institutions (e.g., other PDs/PIs or site leads, who are not designated as PDs/PIs, no more than one person from any Member Institution);
• Director of the Operations Unit;
• Director of the Statistics and Data Unit; and
• NCI Project Scientist.

Initial rotating representatives of Member Institutions may be invited from those Members who have contributed most significantly to the clinical trials in the current funding period. Rotation of these members may be conducted depending on the contributions of the Member Institutions to the Consortium Clinical trials in the new funding period.

Each member of the Coordinating Committee will have one vote. Additional NIH representatives may participate as advisors and observers in the Coordinating Committee meetings as needed but will not have voting rights.

The Coordinating Committee will be responsible for the following aspects:

• Approval of any changes to the Consortium organizational structure and Consortium Standard Operating Procedures;
• Establishing priorities for clinical trials and preliminary approval of clinical trials protocols (prior to submission to NCI and final NCI approval);
• Reviewing Consortium progress on a regular basis, including the performance of the Operations Unit and Statistics and Data Unit and the performance of the ancillary scientific activities (imaging, pharmacology, and biologic studies);
• Assuring that deficiencies identified during these reviews are adequately addressed in a timely manner.
• Reviewing Member Institutions for adequate performance, with the authority to place on probation or to suspend an insufficiently performing Member Institutions as well as to add new institutions to replace any Institutions whose membership in the Consortium is suspended.
• Establishing a process for the selection of the laboratories to perform laboratory studies associated with individual clinical trial protocols; and
• Authorize the spending of funds from the Clinical Trial Research Program Fund.

The Coordinating Committee may form subcommittees as needed. NIH representatives may serve on these subcommittees as they deem appropriate. One subcommittee that is expected to form include an Advisory Panel.

Advisory Panel: This panel should consist of brain tumor experts recruited from other relevant NIH Programs, including Brain Tumor Disease Chairs from RTOG [Radiation Therapy Oncology Group], NCCTG [North Central Cancer Treatment Group], HUB [High Priority Undertakings in Brain Tumors], Brain Tumor SPOREs [Specialized Program of Research Excellence]) as well as relevant NIH staff members with key roles in those programs.

The Advisory Panel should meet at least twice per year, with at least one of the meetings being in person. The Advisory Committee should assist the Coordinating Committee in reviewing Consortium overall research plan and strategic goals. At a minimum, the Advisory Committee should review all Consortium clinical trials protocols that are pending CTEP approval and should advise the Consortium regarding gaps/opportunities in their portfolio of studies. Additionally, the Advisory Committee should discuss potential collaborations between the Consortium and SPOREs, as well as other NCI-sponsored clinical trials, translational research, or neuro-imaging groups.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Coordinating Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590 or RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]

William C. Timmer, Ph.D.
Division of Cancer Therapy and Diagnosis
National Cancer Institute
Telephone: 240-276-6130
Email: [email protected]

Referral Officer
Division of Extramural Activities
National Cancer Institute
Telephone: 240-276-6390
Fax: 240-276-7682
Email: [email protected]

Shane Woodward
Office of Grants Administration
National Cancer Institute
Telephone: 240-276-6303
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92).