Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Cancer Institute (NCI)
Funding Opportunity Title	Limited Competition: Pediatric Brain Tumor Consortium (UM1)
Activity Code	UM1 Multi-Component Research Project Cooperative Agreements
Announcement Type	Reissue of RFA-CA-08-026
Related Notices	September 23, 2019 - This RFA has been reissued as RFA-CA-19-059. May 16, 2014 - See Notice NOT-OD-14-091. Piloting Modified NIH Biosketches. July 10, 2013 - See Notice NOT-CA-13-014. Clarifications for Applicants Responding to this FOA.
Funding Opportunity Announcement (FOA) Number	RFA-CA-13-502
Companion Funding Opportunity	None
Number of Applications	Only one application is permitted in response to this FOA. See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.395
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) is intended to continue support for the Pediatric Brain Tumor Consortium (PBTC). This limited-competition FOA solicits a single application from the current PBTC awardee. The PBTC was conceived as a dedicated clinical trials organization able to translate innovative therapies from the laboratory to early phase clinical testing so that treatment for primary brain tumors in children can be improved. The importance of the PBTC is highlighted by the continuing high mortality rate among some common brain tumor histotypes occurring in children [e.g., diffuse intrinsic pontine gliomas (DIPG), malignant supratentorial gliomas, and biologically high-risk medulloblastomas and ependymomas] and the functional impediments apparent in a large proportion of children surviving current therapies. The PBTC is designed to fill a unique niche in the NIH pediatric brain tumor research portfolio through its ability to translate multiple innovative therapies from the laboratory to early phase clinical testing.

Posted Date	June 19, 2013
Letter of Intent Due Date(s)	August 1, 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 support for the research activities of the Pediatric Brain Tumor Consortium (PBTC) so that more effective therapies for children with brain tumors can be developed. This limited-competition FOA solicits a single application from the current awardees of the PBTC.

The PBTC was conceived as a dedicated clinical trials organization able to translate innovative therapies from the laboratory to early phase clinical testing so that treatment for primary brain tumors in children can be improved. The Consortium was funded initially in 1999 under RFA-CA-98-007 and then funded for additional 5-year periods in 2004 under RFA-CA-04-501 and in 2009 under RFA-CA-08-026.

The molecular characteristics of childhood brain cancers are understood better today than when the PBTC was originally funded. This knowledge further underscores the distinctive biology of pediatric brain tumors and the need for a pediatric-focused clinical research program for these cancers.

The importance of the PBTC is further highlighted by the continuing high mortality rate among pediatric patients with some common brain tumor histotypes occurring in children [e.g., diffuse intrinsic pontine gliomas (DIPG), malignant supratentorial gliomas, and biologically high-risk medulloblastomas and ependymomas] and the functional impediments apparent in a large proportion of children surviving current therapies. As described below, the PBTC fills a unique niche in the NIH pediatric brain tumor research portfolio through its ability to translate multiple innovative therapies from the laboratory to early phase clinical testing.

The overarching goal for the PBTC remains the development of more effective therapies for children with brain tumors. The specific objectives for the PBTC in the coming funding period include:

• Evaluating novel treatment approaches based on research opportunities developed within PBTC institutions, within the NCI, by other academic institutions, or by the pharmaceutical/biotechnology sector.
• Conducting pilot studies and Phase 1 and 2 studies that require the specialized abilities of experienced neurosurgeons, neuro-oncologists, radiation oncologists and neuroimagers.
• Supporting laboratory studies related to PBTC clinical trials, to monitor or measure particular biological responses that may provide information relevant to the success or failure of therapy.

The PBTC is well-positioned to take advantage of expanding scientific knowledge for advancing treatment options for childhood brain tumors. Specifically, efforts are needed and expected from the PBTC in the new funding period to explore therapeutically-relevant leads made possible by the recently uncovered molecular characteristics of childhood brain cancers. Some examples (non-inclusive) of potentially promising areas that warrant exploration in this context are listed below.

• BRAF Targeting. The role of BRAF genomic alterations, and particularly the KIAA1549-BRAF fusion, in pediatric low-grade gliomas has been defined. Cells expressing the KIAA1549-BRAF fusion display paradoxical activation and resistance to first-generation BRAF-specific inhibitors that are effective against BRAF V600E mutated melanoma.
• Children-specific Variants of High Grade Gliomas. Pediatric high-grade gliomas rarely show the IDH1/IDH2 mutations associated with secondary glioblastomas in adults or other genomic alterations associated with primary glioblastomas in adults, but instead show specific mutations in histone H3.3 genes (e.g., K27M and G34R in H3F3A), with K27M H3.3 mutations observed in 70% or more of DIPG patients and with G34V-H3.3 occurring in tumors in the cerebral cortex.
• Molecularly Distinctive Medulloblastoma Subtypes. Medulloblastoma has been redefined as four relatively distinctive molecular entities, each with its own constellation of genomic alterations, age distribution, and prognostic significance.

Additional examples of scientific opportunities that the PBTC will be expected to address include, but are not limited to, the following:

• Studies of brain tumor patient populations with specific molecular characteristics. The juxtaposition of increased biological understanding and expanded numbers of novel therapeutic strategies creates clinical research opportunities for the PBTC to exploit for identifying new effective treatments for subsets of patients with molecularly characterized tumors. Accordingly, the PBTC will be expected to conduct studies of patient populations selected for specific molecular characteristics.
• Immunotherapeutic Interventions. Immunotherapy is another area of scientific opportunity for the PBTC. Specific potential research areas include tumor vaccines such as the glioma peptide vaccine, for which the PBTC is currently developing a clinical trial, agents that enhance the activity of the immune system such as antibodies directed against CTLA-4 and PD1, and oncolytic viruses able to stimulate antitumor immune responses.
• Clinical Research on Diffuse Intrinsic Pontine Glioma (DIPG). The PBTC will be expected to continue its clinical research to improve outcome for children with DIPG. Children with this diagnosis continue to have an extremely poor prognosis, with long-term survival of no better than 10%. The PBTC is uniquely positioned to pursue local administration of immunotoxins and other novel agents using convection enhanced delivery for children with DIPG. This capability will equally apply to local therapeutic approaches to supratentorial high-grade gliomas, should such research opportunities arise.

In the new funding period, the PBTC will be expected to establish a closer collaboration with the Children's Oncology Group (http://www.childrensoncologygroup.org/), in particular with the COG Brain Tumor Committee. The goal for this interaction is to facilitate seamless transition of studies initiated by the PBTC to evaluations in larger numbers of institutions within COG. To facilitate collaboration, the PBTC 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. The Consortium is also strongly encouraged to further leverage resources by collaborating with other brain tumor researchers or organizations, including researchers with investigator-initiated R01 grants, the NIH-sponsored research program at the Clinical Center (PAR-13-029, Opportunities for Collaborative Research at the NIH Clinical Center), and the NCI-funded brain tumor SPOREs (Specialized Programs of Research Excellence).

The PBTC must include the following components that meet the requirements specified below:

• Clinical Research Program. Clinical Research Program is expected to cover the most important scientific roles and serve as functional operations center of the Consortium. The Clinical Research Program needs to include strong scientific leadership, which is essential for prioritizing new agents and new therapeutic approaches for evaluation and for directing the development and implementation of scientifically and clinically sound Phase 1, Phase 2, and pilot studies in children with brain tumors. Expertise in early phase clinical trials, pharmacology, translational research, and imaging is required for the PBTC's scientific leadership team. The Clinical Research Program must comprehensively address developing and managing clinical trial protocols (and managing related documentation), monitoring study conduct, assuring compliance with FDA and OHRP regulatory and patient protection requirements, coordinating manuscript development, and monitoring performance of institutional members. The activities of the Clinical Research Program must also include reporting on the performance of the Consortium in meeting pre-specified timelines for LOI/concept and protocol development, for study implementation, and for publication of studies. The Clinical Research Program additionally encompasses responsibility for the administrative and financial management of the Consortium.
• The Statistics and Data Management Core. This Core will be responsible for data management and data analysis as well as for meeting the overall statistical needs of the Consortium.
• The Pharmacokinetic/Biology/Genomics Core. A dedicated component is needed to integrate pharmacokinetic and biological studies into the Consortium’s clinical trials. This integration is expected to allow for the comparison of key pharmacokinetic parameters between adult and pediatric patients receiving analogous treatment to identify evidence of age effects and to determine how data from adult studies relating systemic exposure to target modulation can be applied in the pediatric setting. This component must have appropriate leadership, staff, and technical capabilities to design and conduct correlative studies to determine relationships between doses, pharmacokinetic parameters, and biological effects of the administered agents. One area of a particular focus is expected to be the identification of patients with tumors bearing specific genomic/pathway alterations for eligibility for clinical trials of agents targeting these alterations or their downstream effects. Additional restricted funding will be provided to support comprehensive genomic analysis of a subset of patients enrolled on PBTC clinical trials. These funds will allow the PBTC to assess the relationship between genomic alterations detectable by exome sequencing and response to therapy for patients enrolled on selected clinical trials. See Note below on initiating and funding Pharmacokinetics/Biology studies.
• The Neuroimaging Core. This component will be responsible for the incorporation of appropriate imaging studies into Consortium clinical trials and for the central collection, review, and archiving of the results of such studies. The anticipated research activities of the Core include utilizing state-of-the-art imaging to non-invasively assess tumor and normal tissue biological responses to experimental therapies. The Neuroimaging component will also be responsible for confirming that claims of agent activity (e.g., claims of objective responses) are accurate and reliable, as well as for relating imaging findings to pharmacokinetic, pharmacodynamic, and clinical parameters as evidence of agent effect. See Note below on initiating and funding these studies.
• Member Institutions (Sites of Clinical Trials). The Consortium should have approximately 10 member institutions. This number of Member institutions should allow the PBTC to complete approximately 3-4 trials per year and to enroll 100-150 patients onto clinical trials. Member institutions should have documented experience in participating in early phase clinical trials and should have the requisite highly qualified medical, nursing, and pharmacy staff. Member Institutions should have demonstrated ability to carefully monitor patients treated during Phase 1 trials and pilot studies, to report clinical data in a timely manner for central data collection, to contribute to the scientific leadership of the Consortium, and to employ state-of-the-art imaging studies in the early phase clinical trial setting. Institutions that are not PBTC Members will be able to participate in selected Consortium clinical trials if they have unique capabilities needed to complete a particular trial or if they have contributed significant scientific leadership in the development of the treatment strategy under investigation.

The PBTC is expected to have procedures for initiating and funding auxiliary studies to accompany its clinical studies. The PBTC should provide plans to establish a process for soliciting and reviewing applications from researchers to perform pharmacokinetic and correlative studies.

For this purpose, the Consortium must have two dedicated budget items:

• Patient Study Research Funds that will support the collection of blood and tissue specimens as appropriate for the conduct of correlative studies and the performance of imaging studies when such studies are necessary for research purposes to meet study endpoints; and
• Biology/Pharmacokinetic/Genomic Studies Funds that will support performance of pharmacokinetic and correlative laboratory studies and genomic analysis using collected biospecimens.

The Consortium applicants are also encouraged to seek additional funds for auxiliary studies from other sources to supplement those expected in the Consortium award.

The PBTC 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 PBTC toward achieving its goals. This aspect includes evaluating the quality, value, and scientific impact of the research conducted by the Consortium. For the efficient evaluation of the Program, cooperation of the Consortium awardee will be important and expected.

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 $2.59 million in total costs in FY 2014. One award is planned under this FOA.
Award Budget	Application budget needs to reflect the actual needs of the proposed Consortium but must not exceed $2.59 million in total costs in the first year with a total 5-year total cost not to exceed $13,100,000. These amounts are inclusive of all Facilities and Administrative costs for both the awardee and consortium sites.
Award Project Period	Project period of five 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 Pediatric Brain Tumor Consortium funded under RFA-CA-08-026 are eligible to apply under this Limited Competition FOA.

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.

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 more than one application, provided that each application is scientifically distinct.

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:

Malcolm A. Smith, MD, PhD
National Cancer Institute
9609 Medical Center Drive
RM 5-W414, MSC 9737
Bethesda, MD 20892 (for United States Postal Service) or
Rockville, MD 20850 (for non-USPS delivery)
Phone: (240) 276-6087
FAX: (240) 276-7892
Email: Malcolm.Smith@nih.gov

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

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

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

Referral Officer
Division of Extramural Activities
National Cancer Institute
9609 Medical Center Drive
Room 7W412, MSC 9750
Bethesda, Maryland 20892-9750 (for Express mail, use Rockville, MD 20850)
Telephone: (240) 276-6390
Fax: (240) 276-7682
Email: ncirefof@dea.nci.nih.gov

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:

• Consortium Overview: 12 pages
• Clinical Research Program: 12 pages
• Biostatistics and Data Management Core: 6 pages
• Neuroimaging Core: 6 pages
• Pharmacokinetics/Biology/Genomics Core: 6 pages
• 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 (Overall)

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 following modification:

The PBTC applicants are strongly recommended to name in the application an overall Consortium Chairperson, who will preside over the Consortium governing body, the Steering Committee (see Section VI. Cooperative Agreement Terms and Conditions of Award for details). Consortium chairperson is expected to be a PD/PI based in the applicant institution. The individual designated as Consortium chairperson is also expected to serve as a contact PD/PI.

It is also expected that:

• A Contact PD/PI will commit at least 2.4 person months effort and all other PD(s)/PI(s) (if designated) at least 1.8 person months effort to the Consortium. These commitments are expected to be maintained through the entire funding period.
• The overall Consortium chairperson(s) will be expected to serve as Director(s) of the Clinical Research Program.

Table of Contents (Overall)

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:

• Consortium Overview
• Clinical Research Program
• Biostatistics and Data Management Core
• Neuroimaging Core
• Pharmacokinetics/Biology/Genomics Core
• Member Institutions

Detailed Budget for Initial Budget Period (Overall)

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) for the following individual application components:

• Budget pages for Clinical Research Program;
• Budget pages for Statistics and Data Management Core;
• Budget pages for Pharmacokinetic/Biology/Genomics Core;
• Budget pages for Neuroimaging Core; and
• Budget pages for Member Institutions.

Important Note on Budget: The budget for the PBTC should include (in addition to support for scientific leadership, administrative and regulatory activities, data management and analysis, meeting support and travel, etc.) the following items:

• Funds for Per Capita Reimbursement. For the purposes of budget preparation for per capita reimbursement, an annual accrual rate of 120 patients should be assumed. Funds for per capita reimbursement should be included within the Clinical Research Program budget pages.
• Funds for Member Institutions (independent of per capita reimbursement for patients enrolled in clinical trials) to support the non-accrual responsibilities associated with participating in the Consortium’s clinical trials (e.g., IRB submission and continuing review, site training, pharmacy set-up, and site administration) that must be met whether patients are ever enrolled on a study at an institution.
• Patient Studies Research Funds (minimum $100,000 direct costs per year) to be allocated to support institutional costs of research that are not considered a cost of treatment by medical insurers, and therefore are not reimbursed by insurers (e.g., blood and urine collection and shipping for pharmacokinetic studies, tumor tissue handling and shipping to the tissue bank or Biopathology Center, and performance of research imaging studies). Include this within the Clinical Research Program budget pages.
• Biology/Pharmacokinetics Research Funds (minimum $300,000 direct costs per year, with $200,000 of this restricted for the genomics component) for laboratory studies (e.g., pharmacokinetic and pharmacodynamic studies and genomic studies) performed on specimens (e.g., blood, tumor tissue, buccal cells, etc.) obtained from children enrolled on PBTC clinical trials. Include this within the Pharmacokinetic/Biology/Genomics budget pages.

Budget for Entire Proposed Period of Support (Overall)

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, 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 PHS398 instructions.

Resources (Overall)

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 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 the PBTC activities, research competence, and commitment to the PBTC 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 Site are adequate to ensure timely data submission for the PBTC clinical trials;
  • Documented ability to recruit approximately 10 patients per year to Phase 1, Phase 2, and pilot clinical trials for children with brain tumors;
  • Scientific expertise (both clinical and laboratory) that is available at the institution and applicable to the development of new drugs for pediatric oncology. Include a statement that the institution is willing to utilize this expertise for the conduct of the PBTC 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 methodologies in the conduct of the PBTC studies when such imaging studies are required; and
  • Arrangements that will be available to families of patients who live some distance from the institution to facilitate participation of these patients in PBTC clinical trials.

Research Plan (Overall)

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

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

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

A. Consortium Overview

In this section address the following aspects:

• Brief overview of Consortium formation and evolution
• Progress accomplished during the current funding period, including:
  • Clinical trial protocol development: A listing of clinical trial protocol development activities, 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 brief summary of each clinical trial that has been initiated during the current funding period, addressing the important facets of the study (e.g., the rationale for evaluating the agent, schedule of administration, target patient population, etc.) and salient findings (e.g., dose levels evaluated and recommended dose for Phase 2 trials, important adverse events observed, and anti-tumor activity, if observed). Note that pharmacokinetic/biology accomplishments and imaging comments can be referred to in this section, but should be described in more detail in the sections that detail these activities.
  • A table should be included (within the page limits for this Section) that enumerates accrual by year for each study; and
  • Other significant accomplishments.
• Scientific Leadership, including
  • Leadership structure for the Consortium in the new funding period and a plan for replacement of key leadership positions should leadership transitions be required; and
  • Lines of authority and decision-making processes for the Consortium; and
  • An overview of how the Consortium components will interact and work together to accomplish high quality Phase 1, Phase 2, and pilot studies.

Note: To fulfill the objectives of the FOA, all leadership individuals designated as PD(s)/PI(s) will be expected to engage meaningfully in Consortium activities.

B. Clinical Research Program

Clinical Research Program is expected to cover all the strategic aspects of planning clinical trials and auxiliary studies and serve as the operations center for the conduct of these activities. Below the title of this sub-section, provide the name(s) of the Program Leader(s). In the narrative, address the following aspects:

• The Consortium’s strategy for prioritizing new agents for evaluation and examples of agents (or classes of agents) that are planned for prioritization for the new funding period;
• The general approach to study design and research plans for Phase 1, Phase 2, and pilot clinical trials to evaluate systemically administered new agents, particularly investigational agents designed to affect specific molecular targets with direct relevance to the pediatric brain tumor population. For such agents, describe and document the ability to select patients for study based on specific molecular characteristics of their brain tumors.
• Research plans for evaluating agents administered either by the intraventricular, intratumoral, or intrathecal routes;
• Plans for research studies that utilize the specialized neurosurgical expertise required for the proposed PBTC;
• Plans for studies focused on radiation therapy, including the use of systemically administered chemotherapy to potentiate the effectiveness of radiation;
• Research plans for developing disease-specific pilot studies for defined pediatric patient populations (e.g., children with diffuse intrinsic brain stem gliomas, pilocytic astrocytomas, etc.).
• The Consortium’s plans and procedures for coordinating its research program with the COG Brain Tumor Committee.
• Organizational structure and procedures for coordinating the development of clinical trial protocols in a timely manner, including timelines for key steps in this process and actions to be taken when these timelines are not met;
• Plans for training activities to maintain the proficiency of Member Institution personnel in the management of Phase 1 and pilot clinical trials;
• Plans for maintaining effective interaction and communication between Consortium Leadership, Study Committees and Member Institutions to facilitate clinical trial protocol development and safe and timely conduct of clinical trials;
• Procedures for timely reporting of all serious and/or unexpected adverse events via the AdEERS (Adverse Event Expedited Reporting System) system for investigational agents sponsored by the NCI and via sponsor-specified methods for other agents bearing the status of Investigational New Drug (IND);
• Procedures for semiannual PBTC meetings to review progress, establish priorities, and plan future clinical trial research activities; and
• Plans and procedures for assuring rapid publication of the results of clinical trials and laboratory studies conducted by the Consortium.

C. Biostatistics and Data Management Core

Below the title of this sub-section, provide the name(s) of the Core Leader(s). In this section, address the following aspects:

• Expertise of the leadership of the statistical and data management components. General organizational structure and workflow for data collection and management from multi-institutional early phase and pilot clinical trials;
• The Consortium’s proposed statistical approach to the design and analysis of Phase 1, Phase 2, and pilot studies;
• Procedures for ensuring the technical integrity and security of the data management systems;
• Procedures for development of data collection forms, and procedures for data transmittal, data editing, and quality control and verification of submitted data. Include a description for how the Consortium will utilize the clinical data management system (Medidata RAVE) that has been adopted for the NCI Clinical Trials Network;
• 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 Phase 1, Phase 2, and pilot clinical trials;
• Procedures for on-site auditing and a description of how the on-site auditing program will be integrated into the overall Quality Assurance/Quality Control (QA/QC) program for Consortium clinical trials data;
• Procedures for training of Member Institution personnel to maintain their proficiency in the management of Phase 1, Phase 2, and pilot clinical trials; and
• General Characteristics of the Data and Safety Monitoring Plan for PBTC, which should be consistent with NIH and NCI guidelines for data monitoring in early phase clinical trials.

D. Neuroimaging Core

Below the title of this sub-section, provide the name(s) of the Core Leader(s). In this section, address the following aspects:

• Highlights of imaging studies and accomplishments in the current funding period;
• The research strategy for the Consortium’s Imaging Core addressing the incorporation of imaging endpoints into the overall research program of the Consortium;
• The availability of adequate post-acquisition image storage, processing, and analysis capabilities.
• The plans of the Imaging Core for coordinating efforts of radiologists at each Member Institution to develop and implement common imaging protocols;
• Procedures for ensuring that claims of treatment agent activity based on imaging approaches (e.g., claims of objective responses) are accurate and reliable; and
• The availability at Consortium Member Institutions of state-of-the-art imaging, such as magnetic resonance imaging (MRI), functional MRI, magnetic resonance spectroscopy, and positron emission tomography (PET). A table is recommended for presenting these data and can be included in the "Resources" section.

E. Pharmacokinetics/Biology/Genomics Core

Below the title of this sub-section, provide the name(s) of the Core Leader(s). In this section, address the following aspects:

• Highlights of pharmacokinetic and biology studies and accomplishments in the current funding period;
• The general approach that is proposed for the new funding period for the conduct of pharmacokinetic studies and biology/pharmacodynamic studies in Consortium clinical trials within the constraints that apply to research involving children;
• The decision-making process for use of funds restricted to Biology/Pharmacokinetics;
• The approach to identifying patient populations with specific biological characteristics (e.g., specific tumor gene mutations) when needed (e.g., to determine eligibility for enrollment in clinical trial); and
• Plans for the coordination of the acquisition and shipping of tumor specimens, biological fluids, and relevant clinical data to the appropriate laboratories within the Consortium and/or outside biospecimen repositories (as required by specific clinical trials protocols).
• Identify the Genomics Scientific Leader(s) and describe plans for exome sequencing (or comparable methods supplying global genomic results) of the tumors and matching constitutional DNA of a subset of patients enrolled on PBTC studies (approximately 50 per year).

F. Member Institutions

In this section, address the following aspects:

• Include a list of the Consortium Member Institutions and identify the lead investigator at each site who will be responsible for PBTC activities;
• Describe the Consortium’s procedures for Institutional Performance Monitoring (addressing, for example, accrual of adequate number of eligible patients to Consortium trials, timely submission of required data, observance of clinical trial protocol requirements, contributions to clinical trial protocol development and conduct, authorship in Consortium publications, and participation in Consortium administrative and scientific committees);
• Describe Consortium procedures for responding to inadequate performance of Member Institutions and for removing institutions from the Consortium if performance is not adequate.
• Describe the procedures that will be used for competing the membership slots for the lowest ranking Member Institutions during Year 3 of the award - list criteria proposed to be used for selecting among candidate Member Institutions; and
• Include a table(s) that summarizes key aspects of the performance of Member Institutions (e.g., accrual to Consortium trials by year, enrollment of ineligible and inevaluable patients, timeliness of data submission, timeliness of AdEERS reports submission, compliance with specimen submission, etc.).
• Procedures for establishing collaborations with other institutions with similar capabilities that might be willing to participate in PBTC clinical trials to accelerate the pace of PBTC clinical research.

Progress Report Publication List: Publications during the previous funding period (or during the past 4-5 years) should be listed as per PHS 398 instructions.

Multiple PD/PI Leadership Plan: If multiple PD(s)/PI(s) are proposed, the Multiple PD/PI Leadership Plan must also be completed as per PHS 398 instructions. The plan is expected to identify who of the proposed multiple PDs/PIs will serve as the Consortium chairperson (or whether such leadership will be shared by more individuals). The individual designated as Consortium chairperson is also expected to serve as a contact PD/PI.

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 modifications:

• 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.

In addition to standard items, include as Appendix material:

• Current protocol templates utilized by the Consortium; and
• The complete PBTC Data and Safety Monitoring Plan

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.

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

Upon receipt, 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 PBTC will be able to apply state-of-the-art methodologies for the design and conduct of clinical trials and translate multiple innovative therapies to early clinical testing.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the PBTC 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 research plans that the applicants have 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 PBTC address an important problem or a critical barrier to progress in the field? If the aims of the PBTC are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the lines of research proposed by the PBTC? 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?

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 for this FOA: Within the context of brain tumor clinical research involving children, to what extent do the research plans proposed by the PBTC reflect appropriate attempts to bring new research methods and new technologies into pediatric clinical trials?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the PBTC? 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 project 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 for this FOA:

Clinical Research Program: What is the likelihood that the proposed process for selecting new agents and treatment strategies (across all modalities) will adequately focus the PBTC efforts and priorities on agents/treatments that are most relevant to the pediatric brain tumor arena? To what extent will the methods proposed for protocol development and conduct ensure the successful and timely completion of PBTC clinical trials while meeting all regulatory requirements? How efficient is the PBTC Research Program infrastructure for communications across all PBTC components and appropriate training of PBTC staff/members for their respective roles?

Biostatistics and Data Management Core: To what extent do the proposed plans for statistical design of Phase 1 and Phase 2 studies reflect best practices for pediatric early phase clinical trials of special populations? How adequate are the plans for assuring data quality and data timeliness in PBTC clinical trials? How advanced are the plans for implementing the MediData Rave system? Are these plans sufficient for the compatibility and integration with other components of the NCI Clinical Trials Network?

Neuroimaging Core: How well do the plans for the Neuroimaging Core incorporate state-of-the-art approaches and to what extent are they feasible in multi-institutional studies for children with brain tumors? How optimal and likely are these plans to ensure that the Neuroimaging Core will add value in the context of PBTC Phase 1 and 2 clinical trials?

Pharmacokinetics/Biology/Genomics Core: How adequate are the procedures proposed for selecting appropriately validated high priority correlative and pharmacokinetic studies to be incorporated into PBTC clinical trials? To what extent are the plans for exome sequencing (or comparable methods supplying global genomic results) of the tumors and matching constitutional DNA of a subset of patients enrolled on PBTC studies (approximately 50 per year) consistent with state-of-the-art genomics methods for children enrolled on clinical trials? How well are the plans for the Core connected to the decision-making process for the use of Biology/Pharmacokinetics funds?

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

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?

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

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

For Renewals, the committee will consider the progress made in the last funding period.

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, an application submitted in response to this FOA: :

• Will receive a written critique.

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

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

Throughout these Terms and Conditions of Award, "Pediatric Brain Tumor Consortium" ("PBTC" or Consortium ) refers to the organizational structure which is composed of the Consortium PI(s) and other key personnel, the Clinical Research Program, the Statistics and Data Management component, the Pharmacokinetic/Biology/Genomics component, the Neuroimaging component, and the Member Institutions. All of the Consortium investigators and participating institutions agree to collaborate on research goals of the Consortium.

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).

Responsibilities of the Pediatric Brain Tumor Consortium:

The Clinical Research Program working with the Statistics and Data Management component will be responsible for coordinating clinical trial protocol development, protocol submission to the NCI for review and approval, study conduct (including central data collection and analysis), quality assurance including quality control and study monitoring, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations and protocol and performance reporting. Specific responsibilities are listed below.

1) Organization and Standard Operating Procedures (SOPs) for Clinical Trials: The Clinical Research Program, with the guidance of the PD(s)/PI(s) and Steering Committee, is responsible for development and maintenance of an appropriate organizational infrastructure and Standard Operating Procedures for the Consortium. It is responsible for establishing the appropriate scientific research committees, study committees and administrative committees necessary for developing and implementing the research plans of the Consortium and is responsible for developing a process for the selection of leadership for these committees.

2) Clinical Trial Protocol Development: The Clinical Research Program with input from the Statistics and Data Management component is responsible for all aspects of developing Phase 1, Phase 2, and pilot study clinical trials, including: defining study objectives and approaches (including details of experimental design), planning study implementation, data analyses and interpretations, and publication of study results. These responsibilities include 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.

The protocol development process for PBTC studies begins with proposals that are evaluated as either Letters of Intent (LOI) 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 (BMSC). 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 2 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 protocols should be developed, submitted, and implemented in accordance with the DCTD Investigator's Handbook" (http://ctep.cancer.gov/handbook/index.html).
• The Clinical Research Program is responsible for communicating the results of the CTEP Protocol Review Committee and Brain Malignancy Steering Committee (BMSC) 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) (see http://ctep.cancer.gov/protocolDevelopment/default.htm).
• The Consortium’s SOPs should include timelines for the steps involved in the development of LOIs, Concept Proposals, and clinical trial protocols, and should include mechanisms for monitoring the performance of the Clinical Research Program and Consortium members in meeting these time lines. These timelines must be consistent with the timelines established by the NCI Operational Efficiency Working Group (OEWG) as recorded at http://ctep.cancer.gov/SpotlightOn/OEWG.htm#oewg_timelines_sops. 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 should 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 at http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_coop_ccop_ctsu.htm. The Consortium is responsible for assuring accurate and timely monitoring of the progress of each study, and therefore must have standard procedures for timely data collection and data management consistent with the intensive data requirements and the need for rapid reporting necessary for Phase 1, Phase 2, and pilot studies. Procedures for study monitoring are expected to address at a minimum the following aspects:

• 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 must seek 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 evaluability;
• 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, including timeliness monitoring by study and by Member Institution (reports to be used for review of Member Institution performance and to address the Data and Safety Monitoring Plan);
• 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.cancer.gov/protocolDevelopment/electronic_applications/adeers.htm);
• 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 biannual 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 Management component for data management related to study monitoring include:

• Providing and maintaining central storage, security, processing, and retrieval of study results;
• Incorporating data 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.
• Using standard National Clinical Trials Network (NCTN) tools for all PBTC trials including, but not limited to: (a) the Common Data Management System for study design/build and data collection with case report reports (CRFs) that are compliant with the NCTN Program approved sections of the data dictionary for common data elements in the NCI Cancer Data Standards Registry and Repository (caDSR) (see https://cabig.nci.nih.gov/community/concepts/caDSR/); (b) NCTN information system for tracking biospecimen collection from NCTN trials (in development); (c) NCTN Oncology Patient Enrollment Network (OPEN) and Regulatory Support Services (RSS) via the Cancer Trials Support Unit (CTSU) for central registration and randomization of patients onto NCTN trials; (d) the NCI Common Terminology Criteria for Adverse Events (CTCAE); and (e) the Comprehensive Adverse Event and Potential Risks (CAEPR) for agents, if available.

5) CTRP/clinicaltrials.gov Registration and Outcomes Reporting: All PBTC 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/Quality Assurance (QC/QA) of Consortium Clinical Trials: 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 PBTC’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 PBTC 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 PBTC Member Institution failed to comply adequately with NCI guidelines for conduct of clinical trials, the accrual of new patients to PBTC protocols at the affected institution shall be suspended immediately upon notice of the NCI determination. The suspension will remain in effect until the PBTC 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 PBTC is responsible for the timely reporting of data from PBTC 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 3 studies; however, complete reporting of CDUS data on adverse events may be required for phase 3 trials by CTEP under certain circumstances.

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

a) The PBTC 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 PBTC’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 3 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 1 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 PBTC 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 PBTC’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 PBTC 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 3 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 PBTC Program Director. The PBTC is encouraged to send drafts of press releases on other topics to NCI for pre-review and/or pre-release notice.

f) The PBTC 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) PBTC Meetings: The Operations Center is responsible for the organization of semiannual meetings to review the PBTC’s progress, establish priorities, and plan future activities. Additional meetings between PBTC 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 Center and Statistics and Data Center are responsible for ensuring that copies of the Report (electronic and/or hard copy) are distributed to PBTC members and NCI program staff.

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

10) PBTC Communications: The Operations Center must establish routine electronic communication with Member Institutions to facilitate clinical trial protocol development and study monitoring and to facilitate the work of the PBTC’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 PBTC PD(s)/PI(s) will be responsible for ensuring that the PBTC 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 PBTC must assure that each member has a current, approved Federalwide 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 PBTC Protocols: The Operations Center must assure that each PBTC 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 PBTC must assure that each protocol for a PBTC 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 PBTC 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 PBTC trials.

c) Assuring Appropriate Informed Consent: The PBTC 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 PBTC 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 DSMB/DMC must be used to monitor all phase 3 trials and randomized Phase 2 trials led by the PBTC. The PBTC'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 PBTC Program Director.

Data and Safety Monitoring plans developed for other PBTC studies (e.g., Phase 1 and Phase 2 studies, pilot studies, etc.) 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 PBTC 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 PBTC 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 PBTC'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 PBTC-related activities at each Member Institution;

b) Administration of the Pharmacokinetic/Biology/Genomics Fund, including the process for selecting laboratories to perform specific studies (a competitive process is encouraged when feasible); and

c) Distribution of funds from the Patient Studies Research Fund to member institutions to support special clinical research costs for patients accrued onto PBTC 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 PBTC 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 PBTC. The report will use the PHS 2590 and include:

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

b) Summary data on performance of each PBTC 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 PBTC 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 PBTC 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 PBTC protocols.

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

e) See the Quality Control/Quality Assurance section for requirements for the evaluation of the performance of Member Institutions.

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

19) Re-competition for Institutions: The PBTC will be responsible for conducting a competition in year 3 of the project period in which those institutions rated in the lower tertile of performance in the first two years of the award must compete with non-PBTC institutions to maintain their position in the PBTC.

20) Correlative Science Studies: Correlative science studies embedded in PBTC 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 DHHS, 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:

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 pediatric brain tumors, this follows from input from experts in the PBTC, the Children's Oncology Group and its Brain Tumor Committee, 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 PBTC studies begins with proposals that are evaluated as either Letters of Intent (LOI) 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 (BMSC). 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 2 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).

Trials 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 4 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 pediatric 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 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 PBTC will have a Steering Committee as a governing body. The Steering Committee will include as voting members: the Consortium chairperson (expected to serve also as the PD/PI and Director responsible for Clinical Research Program), representatives from Member Institutions (e.g., site PD/PI or another designated investigator), the PDs/PIs/Core Directors responsible for the Biostatistics and Data Management Core, Neuroimaging Core, and Pharmacokinetics/Biology/Genomics Core, and a patient/family representative. Each voting member will have one vote.

The NCI Project Scientist will serve as an advisory (non-voting) member to the Steering Committee. Additional NIH representatives may participate as advisors and observers in the Steering Committee meetings as needed and will also not have voting rights.

The Steering Committee may form any subcommittees that are deemed necessary. One specific sub-committee that is expected to be formed is an Advisory Panel. The Advisory Panel should include as members pediatric oncologists and brain tumor experts, who are unaffiliated with the PBTC (e.g., from other relevant NIH programs).

The NCI Project Scientist and other NCI representatives may participate in any subcommittee as non-voting members.

The Steering Committee will be primarily responsible for:

• The approval of any changes to the PBTC organizational structure and PBTC Standard Operating Procedures
• Establishing priorities for clinical trials;
• Developing and providing preliminary approval of clinical trial protocols (prior to submission to NCI and final NCI approval);
• Reviewing progress in the development and conduct of Consortium clinical trials;
• Reviewing on a regular basis the performance of the Clinical Research Program and Biostatistics and Data Management Core;
• Establishing a process for the selection of the laboratories to perform laboratory studies associated with individual clinical trial protocols
• Approving the ancillary scientific activities (imaging, pharmacology, and biologic studies) and authorizing the spending of funds from the Biology/Pharmacokinetics/Genomics Fund and the Patient Studies Research Fund.
• Evaluating the performance of PBTC components responsible for conduct of auxiliary studies.
• Assuring that deficiencies identified during the reviews of PBTC activities are adequately addressed in a timely manner.
• Reviewing Member Institutions for adequate performance with the authority to place on probation underperforming Member Sites, to suspend Members, and to add new Members to replace any suspended Members.

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 Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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: GrantsInfo@nih.gov

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

Malcolm A. Smith, MD, PhD
National Cancer Institute
Telephone: (240) 276-6087
Fax: (240) 276-7892
Email: Malcolm.Smith@nih.gov

Referral Officer
Division of Extramural Activities
National Cancer Institute
Telephone: (240) 276-6390
Fax: (240) 276-7682
Email: ncirefof@dea.nci.nih.gov

Shane Woodward
Office of Grants Administration
National Cancer Institute
Telephone: (240) 276-6303
Email: woodwars@mail.nih.gov

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

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