Department of Health and Human Services
Part 1. Overview Information
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 Clinical Trial Required)

Activity Code

UM1 Research Project with Complex Structure Cooperative Agreement

Announcement Type

Reissue of RFA-CA-13-502

Related Notices
  • August 23, 2019 - Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137
  • July 26, 2019 - Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-128
Funding Opportunity Announcement (FOA) Number

RFA-CA-19-059

Companion Funding Opportunity

None

Number of Applications

Only one application per institution is allowed, as defined in  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 tumors 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.

Key Dates
Posted Date

September 23, 2019

Open Date (Earliest Submission Date)

October 13, 2019

Letter of Intent Due Date(s)

October 13, 2019

Application Due Date(s)

November 13, 2019

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s). 

No late applications will be accepted for this Funding Opportunity Announcement.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

November-December 2019

Advisory Council Review

January 2020

Earliest Start Date

April 2010

Expiration Date

November 14, 2019

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.


There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
  4. Table of Contents

    Part 1. Overview Information
    Part 2. Full Text of the 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

    Part 2. Full Text of Announcement
    Section I. Funding Opportunity Description
    Purpose

    The purpose of this Funding Opportunity Announcement (FOA) is to continue support for the research activities of the PBTC with modifications aimed at developing a more robust pipeline of clinical trials and a more robust accrual base. This will be accomplished primarily by enhancing the accrual potential for the PBTC by incorporating additional member institutions, by enhancing support for the PBTC Operations, Biostatistics, and Data Management Center (OBDMC), by enhancing interactions between the PBTC and the Children's Oncology Group (COG) CNS Committee, and by promoting opportunities for collaboration with other NCI-supported consortia.

    Specific goals for the PBTC include:

    • The evaluation of novel treatment approaches based on research opportunities arising within PBTC institutions, within the COG CNS Committee, or within biopharmaceutical companies.
    • The conduct of pilot studies and phase 1 and 2 studies that require the specialized abilities of experienced neurosurgeons, neurooncologists, radiation oncologists and neuroimagers.
    • The implementation of laboratory studies (including pharmacokinetics and genomic characterization) related to PBTC clinical trials, to identify tumor-intrinsic factors associated with treatment response and to monitor or measure biological responses that may provide information relevant to the success or failure of therapy.
    • Exploration of treatment options for brain tumors with specific genomic and epigenomic features, including low-grade glioma with BRAF and other MAPK pathway mutations, medulloblastoma and ependymoma subtypes, and high-grade glioma with histone H3.3 mutations.
    • Exploration of scientific opportunities in immunotherapy interventions (e.g. tumor vaccines, checkpoint inhibitors, and oncolytic viruses).
    • Evaluation of approaches to the local therapy of pediatric brain tumors (e.g., convection-enhanced deliver, intrathecally-administered therapy, tumor-treating fields, and MRI-guided focused ultrasound).
    • The evaluation of novel treatment options for children with DIPG.
    Background

    The FOA will support the PBTC to take advantage of expanding scientific opportunities for advancing treatment options for childhood brain tumors. The molecular characteristics of childhood brain cancers are understood better today than when the PBTC was most recently renewed, and this intervening knowledge further highlights the distinctive biology of pediatric brain tumors and the need for a pediatric-focused clinical research program for these cancers. Examples include:

    • The role of BRAF genomic alterations and other genomic alterations affecting the MAPK pathway in pediatric low-grade gliomas.
    • The role of specific mutations in histone H3.3 genes (e.g., K27M and G34R in H3F3A), with K27M H3.3 mutations observed in most DIPG patients and midline high-grade glioma patients and with G34V H3.3 mutations occurring in high-grade gliomas arising in the cerebral cortex. 
    • Medulloblastoma, ependymoma, and atypical teratoid rhabdoid tumors that have been shown to have multiple biologically and genomically distinct subtypes, with distinctive opportunities for therapeutic targeting.  
    • Targeting elements of the tumor microenvironment that promote glioma progression.

    Immunotherapy is another area of scientific opportunity on which the PBTC will focus. While initial experience with checkpoint inhibitors has shown limited activity outside of the setting of patients with germline DNA repair mutations, approaches like oncolytic viruses and CAR T cells remain of high interest.   

    The FOA will support the PBTC to continue its role as a major mechanism by which NCI supports 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 novel agents using convection enhanced delivery for children with DIPG.  This capability may also apply to local therapeutic approaches to supratentorial high-grade gliomas, should such research opportunities arise.

    Overall Goals and Requirements of this FOA

    The applicant will be expected to structure the activities of the proposed PBTC across three main areas: Clinical and Translational Research Program; Operations, Biostatistics, and Data Management; and Member Institutions. Major responsibilities for each of these areas include the following.

    Clinical and Translational Research Program:

    • Clinical research program for prioritizing novel therapeutic strategies for children with brain tumors and for translating these strategies into clinical testing in appropriate patient populations;
    • Genomics and translational biology for PBTC clinical trials;
    • Pharmacokinetics program for PBTC clinical trials; and
    • Neuroimaging for PBTC clinical trials.

    Operations, Biostatistics, and Data Management:

    • Clinical trial protocol development;
    • Data Management/Analysis;
    • Quality Control/Quality Assurance including central data monitoring;
    • Statistical design and analysis of early phase clinical trials;
    • Regulatory affairs and compliance;
    • Managing tissue acquisition, tissue shipping, and tissue storage in a biorepository; and
    • Logistical management for PBTC operations, including teleconferences, electronic communications, meetings, etc.

    Member institutions:

    • Participation in all PBTC clinical trials and for the support of PBTC clinical research activities;
    • Contribution to the scientific and clinical research agenda of the PBTC;
    • The Consortium should have 16-18 member institutions, which represents an expansion beyond the current number of institutions. This number of institutions should allow the PBTC to complete approximately 4 trials per year and to enroll 120-150 patients onto clinical trials.

    Correlative studies and research imaging studies will be supported through the Genomics/Translational/Pharmacokinetics Research funds and through the Patient Study Research funds that the PBTC will distribute to laboratories and member institutions, respectively. The Patient Study Research funds will support the collection of blood and tissue specimens as appropriate for the conduct of pharmacokinetic and correlative studies, and they will also be used to reimburse institutions for the performance of imaging studies when these are necessary for research purposes to meet study endpoints. The Genomics/Translational/Pharmacokinetics funds will support the performance of the relevant laboratory testing using blood and tissue specimens from patients enrolled on PBTC protocols.

    To meet regulatory expectations, the PBTC will have a program for study monitoring. This program will be built upon a combination of the existing on-site audit program with central study monitoring for all patients.

    The applicant will be expected to have appropriate capabilities for preparing and submitting Investigational New Drug Applications (INDs) in support of Consortium clinical trials and for meeting the regulatory responsibilities associated with being a study sponsor. This is a critical capability so that the PBTC can encourage pharmaceutical and biotechnology companies to collaborate with the PBTC for agents for which NCI-CTEP does not have a CRADA with the corresponding company. 

    The PBTC will be required to demonstrate its experience developing and implementing clinical trials using MediData Rave, the Cancer Trials Support Unit (CTSU, https://www.ctsu.org/Public/Default.aspx), and the Oncology Patient Enrollment Network (OPEN) Portal system (https://open.ctsu.org/open/logonForm.open ). PBTC clinical trials will continue to be conducted using these clinical trial research services and infrastructures.  PBTC clinical trials will be within the purview of the NCI Central IRB (https://ncicirb.org/cirb), and PBTC Member Institutions will be required to use the NCI Central IRB.

    PROGRAM EVALUATION. 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.

    See Section VIII. Other Information for award authorities and regulations.

    Section II. Award Information
    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 scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

    Application Types Allowed

    Renewal

    The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

    Clinical Trial?

    Required: Only accepting applications that propose clinical trial(s)

    Need help determining whether you are doing a clinical trial?

    Funds Available and Anticipated Number of Awards

    NCI/DCTD intends to commit $4 million in FY 2020 to fund one award.

    Award Budget

    Application budget needs to reflect the actual needs of the proposed Consortium but must not exceed $3,300,000 in direct costs in the first year of the award.  

    Award Project Period

    A project period of 5 years must be requested.

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

    Section III. Eligibility Information
    1. Eligible Applicants
    Eligible Organizations

    Only the current PBTC awardee supported under RFA-CA-13-502 is eligible to apply.

    Foreign Institutions

    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 allowed. Member Sites as Foreign components are allowed only if they are Canadian institutions.

    Required Registrations

    Applicant Organizations

    Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

    • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
    • System for Award Management (SAM)– Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. 
    • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons.  Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
    • Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

    Program Directors/Principal Investigators (PD(s)/PI(s))

    All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

    Eligible Individuals (Program Director/Principal Investigator)

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

    For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

    If multiple PDs/PIs are proposed, these individuals may come from single or multiple institutions. The applicant may consider, for example, one PD/PI to be responsible primarily for the Clinical and Translational Research Program, who will be acting as Consortium Chairperson and another PD/PI to be responsible for the Operations, Biostatistics, and Data Management Center (OBDMC).

    2. Cost Sharing

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

    3. Additional Information on Eligibility
    Number of Applications

    Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed..

    The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

    • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
    • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
    • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).
    Section IV. Application and Submission Information
    1. Requesting an Application Package

    The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

    2. Content and Form of Application Submission

    It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) 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.

    Letter of Intent

    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, the applicant is 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, M.D., Ph.D.
    National Cancer Institute (NCI)
    Telephone: (240) 276-6087
    Fax: (240) 276-7892
    Email: Malcolm.Smith@nih.gov

    Page Limitations

    All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed. with the following modifications for this FOA.

    The Research Strategy must consist of the following sub-sections with the indicated page limits:

    Sub-section A. Overview and Organizational Structure - 6 pages

    Sub-section B. Relevant Past Performance - 12 pages

    Sub-section C. Clinical and Translational Research Program - 12 pages

    Sub-section D. Operations, Biostatistics, and Data Management Center (OBDMC) - 12 pages

    Sub-section E. Member Institutions: General Policies and Procedures - 6 pages

    Instructions for Application Submission

    The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

    SF424(R&R) Cover

    All instructions in the SF424 (R&R) Application Guide must be followed.  

    SF424(R&R) Project/Performance Site Locations

    All instructions in the SF424 (R&R) Application Guide must be followed.  

    SF424(R&R) Other Project Information

    All instructions in the SF424 (R&R) Application Guide must be followed. The following additional instructions apply.

    Facilities & Other Resources: Document available resources and facilities at the applicant institution that will be available to the awardee.

    The applicant must document the extent of their expertise in using MediData Rave and describe their implementation of protocols and usage of MediData Rave capabilities. The applicant must also document their experience in using the NCI CTSU and OPEN for conducting protocols that enroll patients across multiple institutions. Applications that fail to document this experience will be considered non-responsive.

    The applicant must also document their capabilities for preparing and submitting Investigational New Drug Applications (INDs) in support of Consortium clinical trials and for meeting the regulatory responsibilities associated with being a study sponsor.

    The applicant must describe the facilities and resources available to support the PBTC Neuroimaging Center, including the availability of adequate post-acquisition image storage, processing, and analysis capabilities.

    Other Attachments: The applicant must provide the following additional materials specified below in support of their application. Each attachment should be uploaded as a separate PDF using the indicated filenames (which will serve as application bookmarks. Each of these attachments is expected not to exceed 15-20 pages.

    Attachment 1: Procedures for Member Institution Selection and Performance Monitoring (use filename "Institution Selection Performance Monitoring"). Include clinical and research capabilities required (or highly desired) for PBTC Member Institutions. Describe performance expectations for Member Institutions and the Standard Procedures for monitoring Member Institution performance and for identifying the lower tertile of Member Institutions (in terms of performance). Describe the process for selecting new Member Institutions that is to be completed during Year 1 of the award and the process for competing the lower tertile Member Institution slots during Year 3 of the funding period.  

    Attachment 2: Procedures for Central Monitoring of Clinical Trials (use the filename "Central Monitoring").

    Attachment 3: Data and Safety Monitoring Plan for the PBTC (use the filename "DSM Plan").

    Attachment 4: Member Institutions (use the filename "Member Institutions").

    Include a table(s) that summarizes key aspects of the performance of Member Institutions (e.g., accrual to Consortium trials by year, enrollment of eligible and evaluable patients, timeliness of data submission, timeliness of AdEERS reports submission, compliance with specimen submission, etc.). For each member institution include a one-page summary of the capabilities of the institution addressing the number of brain tumor patients available for PBTC clinical trials, neuro-oncology staffing, neurosurgical expertise, access to neuroimaging, and clinical research infrastructure to support PBTC clinical trials.  

    SF424(R&R) Senior/Key Person Profile

    All instructions in the SF424 (R&R) Application Guide must be followed. 

    R&R Budget

    All instructions in the SF424 (R&R) Application Guide must be followed. It is expected that the budget requested for the PBTC will be apportioned in approximately the manner described below. Except for specific instructions for funds that must be included by the applicant (see italicized text below), these estimates are for applicants' guidance only.

    A. Scientific Leadership (approximately 5-10% of direct costs requested):

    • Funded scientific leadership positions may include the PD/PI (Chairperson of the PBTC) and the PBTC vice-Chair as well as the Genomics/Translational Biology, Pharmacokinetics, and Imaging scientific leaders.  The effort level of the PBTC Chairperson should be budgeted at a minimum of 1.8 person-months. This effort level cannot be reduced during the award period.
    • Support for study chairs totaling up to $120,000 per year in direct costs may be included (e.g., $15,000 per chair in direct costs for 8 active studies), but without providing specific individuals' names (i.e., use "To Be Determined").

    B. PBTC OBDMC (approximately 40-45% of direct costs requested):

    • Include support required for protocol development activities, data management activities, central monitoring and quality control/quality assurance activities, regulatory and human subjects' protections, communication with member institutions, and biostatistical support for data analysis and clinical trials development.
    • Include support for PBTC meetings (two in-person network-wide meetings per year).
    • Travel: expenses to support travel for one representative from each Member Site (up to 20 sites) and appropriate OBDMC staff to travel to up to two in-person meetings per year.

    C. Funds for Member Institutions (approximately 35-40% of direct costs requested)

    Per Capita Reimbursement Fund. For the purposes of budget preparation for per capita reimbursement, an annual accrual rate of 120 patients by Member Institutions should be assumed with suggested average capitation payment of $5,000 in direct costs. List a total for the Per Capita Reimbursement amount under the "Other Expenses" category.

    • Member Institutions Baseline Funding. This funding is independent of per capita reimbursement for patients enrolled in clinical trials and is 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 ($100,000 per year in direct costs) 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 fund in the "Other Expenses" category.

    D. Genomics/Translational/Pharmacokinetics Research Fund ($150,000 per year in direct costs) to be used 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 $150,000 per year in direct costs for this Genomics/Translational/Pharmacokinetics Research Fund under "Other Expenses" category.

    E. Imaging Activities (approximately 5% of direct costs requested). Use standard budget categories, as needed, for support of adequate post-acquisition image storage, processing, and analysis capabilities to support the Consortium's imaging objectives.

    R&R Subaward Budget

    All instructions in the SF424 (R&R) Application Guide must be followed.

    PHS 398 Cover Page Supplement

    All instructions in the SF424 (R&R) Application Guide must be followed.  

    PHS 398 Research Plan

    All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: 

    Specific Aims: Outline succinctly the overall strategic goals and overarching research strategy for the proposed PBTC and the general organizational structure and plan to achieve these goals.

    Research Strategy

    Research Strategy must consist of Sub-Sections A-E as defined below.

    Sub-Section A. Overview and Organizational Structure.

    Overview and Research Direction. Outline the overall goals for the PBTC and an overarching research strategy for the conduct of early phase trials and pilot studies for children with brain tumors through the PBTC.

    Leadership Structure and Key Roles: Define the general organizational and governing structure, lines of authority and decision-making processes that you propose. Explain how this organization and structure are designed to meet the needs of the Consortium in developing and implementing state-of-the-art clinical trials for children with brain tumors. Include plans for replacement of key leadership positions should leadership transitions be required. Specific key roles to be described include, for example, the Consortium Chairperson and Vice-Chair, Lead Biostatistician and Leader of OBDMC (if different), Imaging leader, Pharmacokinetics leader, and Genomics/Translational Biology leader. Indicate when one person will be leading more than one activity.

    Sub-Section B. Relevant Past Performance

    Relevant Past Performance. Summarize the performance of the PBTC in the past 5-6 years in leading and managing multi-institutional pediatric early phase clinical trials for children with brain tumors. The description should deal with the team capabilities and cumulative accomplishments without repeating the information from individual researchers' biosketches. In particular, address the following areas:

    • ·    Accomplishments with regards to clinical trials completed and key findings from these clinical trials and their contributions to the overall development of the agents evaluated for children with cancer.
    • ·    Timeliness of the development of clinical trials protocol documents and of the implementation of multi-site clinical trials through the Cancer Trials Support Unit (CTSU), including site initiation and training and study monitoring. Specific information/data about the number of clinical trials implemented and timelines met in developing these trials should be presented.
    • ·    Accomplishments in data management for PBTC clinical trials using Medidata Rave, including timely development of study databases and case report forms as well as ensuring timely submission of data and ensuring the quality and accuracy of data. 
    • ·    Accomplishments related to pharmacokinetic evaluations, and genomic and biology findings from PBTC clinical trials. 
    • ·    Accomplishments related to neuroimaging, including highlights of imaging studies incorporated into PBTC clinical trials in the current funding period.
    • ·    Record of reviewing the performance of PBTC Member Institutions.
    • ·    Record of negotiating contracts with pharmaceutical and biotechnology companies to provide agents and/or support for clinical trials, and experience submitting and preparing INDs and serving as a study sponsor as part of these collaborations.

    Sub-section C. Clinical and Translational Research Program

    Clinical Research Program - Address the following areas:

    • ·    The overarching research strategy for the conduct of early phase clinical trials for children with brain cancers. Note that descriptions of specific clinical trials to be developed by the PBTC are not part of the application.
    • ·    The general approach to recognizing agents and therapeutic approaches with the greatest likelihood for benefiting children with brain cancers.
    • ·    Include your understanding of the opportunities and challenges for multi-site clinical trials in pediatric neuro-oncology therapeutics development and your specific strategy to overcome these challenges, taking into account the current status of the field.
    • ·    Describe the general approach to the design of early phase clinical trials, with details of plans for statistical analysis provided in Sub-Section D.

    Genomics and Translational Biology and Pharmacokinetics - Address the following areas:

    • ·    The approach to identifying patient populations with specific biological characteristics (e.g., specific tumor gene mutations) when needed for PBTC clinical trials (e.g., to determine eligibility for enrollment in clinical trial).
    • ·    Plans for genomic analysis of patient tumors and matching constitutional DNA when this contributes to understand the antitumor activity of agents studied by the PBTC.
    • ·    Strategies for incorporating promising new genomic biomarkers such as circulating tumor DNA (ctDNA) into PBTC clinical trials.
    • ·    The approach to incorporating pharmacokinetic analyses into PBTC clinical trials and how these analyses will be used to inform the development of agents being studied by the PBTC.

    Neuroimaging - Address the following areas:

    • ·    Describe how the PBTC will centrally review imaging studies to verify that claims of treatment agent activity are accurate and reliable.
    • ·    Describe potential research uses of the imaging capabilities of the Consortium to advance understanding of the effect (both positive and negative) of investigational therapeutic approaches and to advance the utility of imaging in clinical trials for children with brain cancers. 

    Sub-Section D.  PBTC Operations, Biostatistics, and Data Management Center (OBDMC)

    Standard Procedure for the Development of Clinical Trial Protocols.

    • ·    Describe the standard procedures proposed by the applicant to support the timely development of pediatric phase 1 and 2 clinical trials for agents that have been prioritized by the PBTC Steering Committee and the CTEP Protocol Review Committee. Include timelines for the steps proposed for protocol development and subsequent clinical trial activation.

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

    • ·    General organizational structure and workflow for data collection and management from multi-institutional phase 1, phase 2, and pilot clinical trials.
    • ·    Process for timely development of Medidata Rave data collection forms for PBTC protocols.
    • ·    The approach to ensuring the technical integrity and security of the data management systems.
    • ·    The approach to study monitoring, including establishing procedures for: a) assessment of patient eligibility and evaluability; b) timely medical review and assessment of clinical trials data; c) rapid reporting of treatment-related morbidity; d) interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice for early phase clinical trials.
    • ·    The approach to central monitoring of PBTC clinical trials. Address various aspects relating to central monitoring of data such as source data verification of patients at each enrolling site [e.g., for informed consent, eligibility, first two courses of treatment (drug administration and AEs), and any other key data items] and tracking of source data verification (preferably through Medidata Rave), timeliness of data submissions and query resolutions, and factors that may trigger more frequent monitoring or on-site audits. Details of the procedures for central monitoring should be included in the "Other Attachments" section.
    • ·    Procedures for on-site auditing including a description of how auditing will be coordinated with the CTEP Clinical Trials Monitoring Branch (http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_coop_ccop_ctsu.htm).  Include procedures for review of corrective and preventative action plans when problems are detected.
    • ·    Approach to training and monitoring Member Site personnel to maintain proficiency and consistency in management of PBTC trials.
    • ·    The Data and Safety Monitoring Plan for the PBTC (to be included in the "Other Attachments" section of the application) which should be consistent with the NIH and NCI guidelines for data and safety monitoring in early phase clinical trials (https://rrp.cancer.gov/clinicalTrials/data_safety_monitoring_plan.htm).
    • ·    Plans for electronic, web site, and web/teleconference communications to address the organizational and coordination needs of the PBTC.

    Statistical Design and Analysis of Early Phase Clinical Trials.

    • ·    Describe plans for the statistical support for the PBTC clinical trials, and the statistical approach to the design and analysis of PBTC phase 1, phase 2, and pilot clinical trials.

    Regulatory Affairs and Compliance. Describe the following elements:

    • ·    Procedures for timely reporting of all serious and/or unexpected adverse events via CTEP-AERS.
    • ·    Approach to meeting Office for Human Research Protections (OHRP) requirements for the protection of human subjects, including informed consent, institutional review board (IRB) review of protocols using the NCI Pediatric Central IRB, and institutional assurances.
    • ·    Procedures for assuring that PBTC investigators performing clinical trials involving investigational agents sponsored by the NCI Division of Cancer Treatment and Diagnosis (DCTD) have current Good Clinical Practice (GCP) training as per NIH Policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html).
    • ·    Plans for collaborating with pharmaceutical and biotechnology companies by preparing and submitting Investigational New Drug Applications (INDs) in support of PBTC clinical trials and for meeting the regulatory responsibilities associated with being a study sponsor for these clinical trials when agents are not in the CTEP portfolio and the collaborating company does not want to hold the IND itself.

    Tissue Acquisition, Shipping, and Storage:

    • ·    Describe 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). Also describe plans for the tissue repository that will store specimens until they are used for protocol-specified studies.

    Sub-Section E. PBTC Member Institutions: General Policies and Procedures.

    Include a description of the following aspects (reference may be made to Attachments 1 and 4 for details):

    • ·    A list of the Consortium Member Institutions and the lead investigator at each site who will be responsible for PBTC activities.
    • ·    The expected/required characteristics and capabilities of Member Institutions (e.g., leadership, experience in phase 1-2 clinical trials, accrual potential, neuroimaging and neurosurgical capabilities, etc.).
    • ·    The process for selecting 6-8 new Member Institutions that is to be completed during Year 1 of the award.
    • ·    The general process to be employed for performance monitoring of institutions (addressing for example, accrual of adequate number of eligible patients to the PBTC clinical trials, timely submission of required data, observance of clinical trial protocol requirements, contributions to clinical trial protocol development and conduct, authorship of PBTC publications, participation in PBTC administrative and scientific committees, etc.).
    • ·    The general approach to responding to inadequate performance of institutions, with policies for removing institutions with unacceptable performance (for instance, use of warning letters, grace period to allow corrections, and a policy and mechanism for replacing institutions unresponsive to necessary correction action plans).
    • ·    A plan to compete the lower quartile of Member Institutions (based on performance metrics) at least one time during the funding period, including criteria to be used in reviewing applications for membership.
    • ·    Procedures for establishing subcontract agreements with member institutions for their participation in PBTC research activities.

    Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide

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

    Appendix:

    Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

    PHS Human Subjects and Clinical Trials Information

    When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

    All instructions in the SF424 (R&R) Application Guide must be followed.

    Delayed Onset Study

    Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

    All instructions in the SF424 (R&R) Application Guide must be followed with the following additional guidance:

    Applicants must add and complete the Delayed Onset Study record and must check the box "Anticipated Clinical Trial?".

    Enter "Multiple Delayed Onset Studies" as the title of the delayed onset record.

    Justification Attachment: Indicate that multiple clinical trials will be designed and conducted by the PBTC during the project period. Each clinical trial protocol developed will be subject to a standardized NCI CTEP approval procedure that begins with development of a concept or Letter of Intent. If the concept or Letter of Intent receive approval, the next step is to develop a full clinical protocol, which will be subject to review and approval by NCI/CTEP and the NCI Central Institutional Review Board (CIRB) prior to activation in the PBTC.

    PHS Assignment Request Form

    All instructions in the SF424 (R&R) Application Guide must be followed. 

    3. Unique Entity Identifier and System for Award Management (SAM)

    See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

    4. Submission Dates and Times

    Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

    Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

    Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

    Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

    5. Intergovernmental Review (E.O. 12372)

    This initiative is not subject to intergovernmental review.

    6. Funding Restrictions

    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.

    7. Other Submission Requirements and Information

    Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

    Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

    For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

    Important reminders:

    All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

    The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

    See more tips for avoiding common errors.

    Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by the NCI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

    Post Submission Materials

    Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

    Section V. Application Review Information
    1. Criteria

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

    Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

    A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

    For this particular announcement, note the following: In assessing the merit of the application, reviewers will consider the leadership and the entire PBTC applicant team in the context of their past performance, their overall capabilities, and proposed new directions. The evaluation will focus on the likelihood of whether the PBTC, as proposed, can ensure that novel, promising therapeutic approaches are introduced in a timely manner into rigorous clinical testing in children with brain tumors using state-of-the-art methods.

    Overall Impact

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

    Scored Review Criteria

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

    Significance

    Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

    Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy?  For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

    Specific to this FOA: What is the likelihood that the PBTC, as proposed, will be able to develop and implement important early phase clinical trials for children with brain cancers of high priority therapeutic approaches that meet strict regulatory requirements and that incorporate neuroimaging and biology/genomic studies in ways that maximize the insights that are obtained? 

    Investigator(s)

    Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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? 

    With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

    Specific to this FOA: Based on past performance, how strong are the qualities of the PD(s)/PI(s) and the entire team in terms of appropriate expertise, training, demonstrated experience, and an ongoing record of accomplishments in managing and leading essential components of early phase clinical trials for children with brain cancers? Are the team's expertise, capabilities, etc., sufficient for all types of activities needed, including neuroimaging, pharmacokinetics, and genomics activities? Do the investigators demonstrate sufficient experience with coordinating multi-institutional collaborative clinical research? 

    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?  

    Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

    Approach

    Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? 

    Does the application adequately address the following, if applicable:

    Study Design

    Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

    Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

    Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

    Data Management and Statistical Analysis

    Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

    Specific to this FOA:

    To what extent are the governance rules and organizational structure well designed to support the PBTC in meeting its stated objectives?

    How adequate are the approaches and activities of the Clinical Research Program in ensuring that PBTC clinical trials investigate high priority therapeutic strategies using efficient study designs that obtain reliable and clinically meaningful answers to the posed questions of therapy?

    How well do the plans for incorporating genomic, pharmacokinetic, and neuroimaging study objectives maximize the insights that can be gained from PBTC trials?

    Are the critical PBTC OBDMC activities proposed based on appropriate work-flow, timeline, etc.? How well are the approaches to study monitoring, including central monitoring, aligned to ensure rigor and high quality of data from clinical trials? 

    To what extent do the plans for regulatory affairs and compliance demonstrate an understanding of the regulatory responsibilities of the PBTC? Do the plans of the applicant for preparing and submitting INDs in support of PBTC clinical trials and for meeting the regulatory responsibilities associated with being a study sponsor for these clinical trials provide confidence that such studies can be conducted as needed by the PBTC?

    How capable are the PBTC Member Institutions for conducting the multi-institutional clinical trials for children with brain tumors envisioned for the PBTC? How optimal are the plans for monitoring the performance of member institutions and for replacing lower-performing institutions with regards to ensuring that PBTC member institutions are performing at a high level?

    If the project involves human subjects and/or NIH-defined clinical research, are the plans to address

    1) the protection of human subjects from research risks, and

    2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?  

    Environment

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

    If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

    Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

    If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

    If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?  

    Additional Review Criteria

    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.

    Study Timeline

    Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

    Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

    Protections for Human Subjects

    For research that involves human subjects but does not involve one of the 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  categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

    Inclusion of Women, Minorities, and Individuals Across the Lifespan 

    When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

    Vertebrate Animals

    The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

    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.

    Additional Review Considerations

    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)  Genomic Data Sharing Plan (GDS).

    Authentication of Key Biological and/or Chemical Resources:

    For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

    Budget and Period of Support

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

    2. Review and Selection Process

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

    As part of the scientific peer review, all applications:

    • Will receive a written critique.

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

    Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the 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.
    3. Anticipated Announcement and Award Dates

    After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

    Section VI. Award Administration Information
    1. Award Notices

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

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

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

    Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

    Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. 

    ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

    Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. 

    Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

    Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE). 

    2. Administrative and National Policy Requirements

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

    Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

    For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html.  Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

    In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements.  FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award.  An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS.  The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

    Cooperative Agreement Terms and Conditions of Award

    The following special terms of award are in addition to, and not in lieu of, otherwise applicable 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 Part 75, 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.

    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. The NCI will have access to all data generated under this cooperative agreement and may periodically review the data.


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

    The PBTC will be responsible for the following overarching activities:

    • 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 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:

    Responsibilities of the Operations, Biostatistics and Data Management Center (OBDMC):

    The PBTC OBDMC is responsible for coordinating the development of clinical trial protocols, submission of these protocols for review and approval, study conduct (including data analysis), quality assurance/quality control and study monitoring, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations and protocol and performance reporting. Specific responsibilities include:

    1) Organizational Structure and Standard Operating Procedures (SOPs): The OBDMC, with the guidance of the PBTC Chairperson, the Director of the OBDMC, and the PBTC Steering Committee are responsible for development and maintenance of an organizational structure and SOPs from the PBTC.

    2) Required Systems Use: The PBTC will be required to use systems developed and maintained by

    NCI/CTEP. These systems are the Cancer Trials Support Unit (CTSU), Identity and Access Management (IAM), Cancer Therapy Evaluation Program Enterprise (CTEP Enterprise), Medidata Rave, Oncology Patient Enrollment Network (OPEN), the NCI Pediatric Central Institutional Review Board (CIRB), the CTEP Adverse Event Expedited Reporting System (CTEP AERs). See: https://ctep.cancer.gov/initiativesPrograms/etctn_infrastructure.htm.

    3) Clinical Trials 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). 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.

    Specific issues include:

    • Clinical trial protocols should be developed, submitted, and implemented in accordance with the DCTD “Investigator’s Handbook” (https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm).
    • The PBTC will submit a protocol template(s) for NCI for review and approval, and this NCI-approved template(s) will be used by the OBDMC for PBTC protocols.
    • The OBDMC 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’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.
    • The PBTC will not expend funds to conduct any study disapproved by CTEP unless CTEP’s disapproval has been modified by the arbitration process (see Section VI. 2. Dispute Resolution)
    • All clinical trials utilizing NCI-sponsored investigational agents shall be conducted in accordance with the terms of the “Intellectual Property Option to Collaborators” (https://ctep.cancer.gov/industryCollaborations2/default.htm) and the NCI Standard Protocol Language for Cooperative Research and Development Agreements (CRADAs) and Clinical Trial Agreements (CTAs).

    4) Study Monitoring: The PBTC is responsible for assuring accurate and timely monitoring of each PBTC clinical trial in accordance with guidelines for CTEP-sponsored trials, and therefore must have standard procedures for timely data collection and data management consistent with the data requirements for phase 1 and phase 2 clinical trials. Standard procedures for monitoring should include (but are not limited to):

    • Precise tracking of patient accrual and adherence to accrual goals, with development of corrective action plans if accrual goals are not achieved; if the PBTC wishes to continue accrual to a study beyond the accrual goal for eligible and ineligible patients specified in the clinical trial protocol, the PBTC 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 the timely medical review and assessment of individual patient data;
    • Adequate measures to ensure timely submission of clinical trials data (e.g., adverse events, anticancer responses) from Member Sites;
    • Rapid reporting of treatment related morbidity information and measures to ensure communication of this information to all relevant parties; for investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP, according to CTEP guidelines specified in each protocol (https://ctep.cancer.gov/branches/pio/reporting_guidelines.htm);
    • Preparation of study monitoring reports describing patient accrual and demographics, data timeliness, toxicity, and other items as appropriate; examples of study monitoring reports include reports prepared for study chairs, the reports needed for PBTC meeting agendas, and reports as required to comply with the PBTC’s Data and Safety Monitoring Plan;
    • Adequate policies and procedures for closure of studies; if the PBTC wishes to close accrual to a study prior to meeting the initially established accrual goal, the interim results and other documentation should be made available to NCI staff for review and concurrence prior to implementation of that decision. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the clinical trial protocol in order to facilitate these decisions. If the study is recommended for early closure for safety reasons, procedures in the Data Safety Monitoring Plan regarding notification of CTEP must be followed.

    4) Quality Control of PBTC Clinical Trials: The PBTC is responsible for establishing and implementing mechanisms to assure the accuracy and reliability of its clinical trials data. Key items that should be addressed concerning quality control procedures include:

    a) Institutional performance evaluations. Performance factors to be considered include (but are not limited to):

    • Accrual of adequate number of patients onto PBTC trials;
    • Timely and accurate submission of required data, including expedited reporting of serious adverse events;
    • Rigorous adherence to clinical trial protocol requirements;
    • Participation in study development and in timely publication of study findings;
    • Submission of all required specimens for protocol-specified correlative studies; and
    • Participation in PBTC administrative and scientific committees and/or other PBTC activities.

    b) Procedures for placing Member Sites on probation for inadequate performance and for removing such institutions from the PBTC if performance is not adequate during the probationary period or at any time that the institution does not meet PBTC standards for institutional performance.

    c) The PBTC will implement educational functions that address data collection, data management and overall data quality. These aspects include, but are not limited to, the following elements:

    • Training for new Clinical Research Associates (CRAs) in the PBTC’s data submission policies and ongoing training for all CRAs concerning changes to PBTC procedures and instructions for data submission in new protocols;
    • Instruction for appropriate Member Site participants and study chairs on their responsibilities for study monitoring;
    • Instruction for Member Site Leaders and all members at participating sites on their responsibilities in complying with the PBTC’s SOPs and Federal regulations at their institution; and
    • Training of Clinical Sites on protocol-specific requirements for trial implementation, procedures, and monitoring.
    • Note: The OBDMC will document Good Clinical Practice (GCP) training for relevant OBDMC staff and for member institution staff as per NIH Policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html).

    d) Procedures for central monitoring of key elements that impact on eligibility and conclusions of PBTC clinical trials. Central monitoring is to include source data verification for patients at each enrolling site with tracking of source data verification (preferably through Medidata Rave), and with SOPs for the timeliness of data submissions and query resolutions, and with guidelines describing factors that may trigger more frequent monitoring or on-site audits. Central review of claimed objective responses will also be performed.

    e) On-site auditing: The PBTC’s on-site monitoring program will be coordinated with the Clinical Trials Monitoring Branch (CTMB) of CTEP. 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.  If 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.

    5) Timely reporting of data to CTEP:

    • Reporting to CTEP will use the Data Mapping Utility (DMU).
    • Reporting of serious and unknown adverse events requirements shall be reported using NCI reporting mechanisms (currently CTEP-AERS).

    6) Publications and Presentations: 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.

    • 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 it will 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.
    • For investigations using an agent supplied under a CRADA or Clinical Trials Agreement (CTA), the NCI pharmaceutical collaborator will have an opportunity to review manuscript drafts prior to their submission for publication as per the NCI Standard Language for CRADAs and CTAs.
    • All press releases issued by 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.

    7) PBTC meetings: The OBDMC is responsible for the organization and conduct of meetings of the Executive Committee and Steering Committee as well as up to two face-to-face PBTC meetings per year. Regular teleconferences with member institutions will be scheduled to update sites on ongoing and new clinical trials.

    8) PBTC communications: The OBDMC must establish routine electronic communication with Member Sites to facilitate clinical trial development and study monitoring and to facilitate the work of the PBTC’s committees.

    9) Compliance with Federal Regulations Concerning Clinical Research: The PBTC Chairperson and the Director of the OBDMC will be responsible for ensuring that the PBTC is in compliance with all applicable federal regulations concerning the conduct of human subject research.

    10) Managing and coordinating the acquisition and shipping of protocol-specified tumor specimens and biological fluids (with relevant clinical data): The PBTC will collect protocol-specified specimens from patients enrolled on its clinical trials and transmit them to the appropriate laboratories for testing and to a tumor/specimen repository for storage of specimens that are to be used for correlative studies.

    11) Conflict of Interest Policy: The OBDMC will be responsible for establishing a Conflict of Interest policy for the PBTC. This policy should ensure that there is no reasonable expectation that research conducted by the Group will be biased by any conflicting interest of an investigator.

    Responsibilities of Member Sites:

    1) Documentation of appropriate education, training and experience of staff associated with PBTC clinical trials.

    2) Offering participation in PBTC studies to eligible patients and entering a sufficient number of patients to meet accrual targets.

    3) Participation of Site investigators in the design and development of PBTC clinical trials, including:

    • Serving as clinical trial protocol Chairs or as members of protocol study teams;
    • Participating in the Scientific and Administrative Committees as requested (such as Steering Committee and Institutional Performance Committee) needed to support the PBTC’s research objectives;
    • Participation in meetings: appropriately participating in the regular meetings and teleconferences as deemed necessary for institutions performing PBTC activities;
    • Following the PBTC’s SOPs for the conduct of clinical research.

    4) Implementation of the core data collection method and strategy of the PBTC: It is the responsibility of each Member Site to ensure that the procedures for data submission for each PBTC clinical trial protocol are understood by investigators at the site and that protocol-specific data are submitted accurately and in a timely manner to the OBDMC.

    5) Compliance with mechanisms for quality assurance and quality control of therapeutic and diagnostic modalities employed in PBTC trials, including central monitoring and participation in the on-site monitoring program established by the appropriate NCI-associated CTMS (currently through a contract with Theradex).

    6) Human Subjects Protections: Each institution must comply with OHRP and FDA regulations concerning protection of human subjects. Member institutions must implement the procedures established by the PBTC to meet OHRP and Federal requirements for the protection of human subjects.

    7) Participation in the NCI Central IRB for review of all PBTC clinical trial protocols.

    8) Adverse Event Reporting: Implementation of the procedures established by the PBTC for assuring timely reporting of all serious and/or unexpected adverse events.

    9) Investigational agent responsibilities:

    • Implementation of the procedures established by the PBTC for assuring that PBTC investigators performing clinical trials involving DCTD Investigational Agents are NCI registered investigators (Form 1572).
    • Compliance with CTEP requirements described in the DCTD Investigators’ Handbook for storage and accounting for investigational agents (including NCI/DHHS Drug Accountability Records [DAR] procedures), and compliance with FDA requirements for investigational agents.

    10) Submission of Specimens: Acquisition and submission of protocol-specified tumor specimens, biological fluids, and relevant clinical data to the appropriate laboratories where these specimens will be tested and/or stored for future studies.

    11) Participation in PBTC procedures for the timely publication of major findings.

    12) Conflict of Interest: Compliance with the Conflict of Interest Policy of the PBTC.

    13) Non-US (Canadian) Member Sites: Providing appropriate regulatory oversight for PBTC trials conducted in Canada and addressing all human subjects protections requirements (NOTE: participation in the NCI Central IRB is not required).

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

    An NCI Program staff member(s) acting as a Project Scientist(s) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members may be designated to have substantial involvement (as Project Scientists).

    Additionally, an NCI program director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

    The main responsibilities of substantially involved NCI staff members include, but are not limited to, the following activities:

    • Serving as a member of the PBTC Steering Committee and participating in its activities;
    • Attending PBTC Steering Committee, Executive Committee and other PBTC meetings to participate in the discussion of relevant scientific information, progress in the clinical trials, and the status of newly available investigational agents and other research opportunities in order to plan future activities;
    • Monitoring PBTC progress and working collaboratively with PBTC investigators if corrective actions are needed;
    • Serving as a scientific liaison and a resource to PBTC investigators with respect to other ongoing NCI and other NIH activities that may be relevant to the PBTC research efforts (e.g., to identify promising new leads, to facilitate compatibility with other NCI research projects and to avoid unnecessary duplication of effort);
    • For NCI-sponsored agents, facilitate transfer of these agents to investigators for preclinical testing under a Materials Transfer Agreement (MTA);
    • Coordinating the NCI review of proposed clinical trials protocols, which will involve the following steps (for further details, see the DCTD Investigator's Handbook at https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm):
    • Review of either Letters of Intent (LOI) or Concepts for PBTC studies;
    • Review and prioritization of Concept Proposals for phase 2 clinical trials by the Brain Malignancy Steering Committee (BMSC) following procedures outlined in the NCTN Guidelines (https://ctep.cancer.gov/initiativesPrograms/nctn.htm);
    • NCI/DCTD staff (approximately 4 representatives including biostatistical staff and medical staff) are full members on the Brain Malignancy Steering Committee and Clinical Imaging Scientific Steering Committee. 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.
    • Expedited review by CTEP of clinical trials concepts prioritized by BMSC 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.
    • CTEP review of protocol documents prepared by the PBTC in follow-up to approved LOIs or Concepts.
    • Other CTEP Roles (see DCTD Investigator's Handbook at https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm):
    • Reviewing any protocol amendment; Any change in a PBTC protocol must be reviewed and approved by CTEP prior to implementation (see Section 8.6 – The Investigator’s Handbook for further discussion of these procedures).
    • Auditing of member sites; 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.
    • Option to initiate clinical trial closure: Protocol closure is primarily the responsibility of the PBTC and the specific protocol committee. The NCI Project Scientist and Program Director will also monitor clinical trial progress and may request protocol closure to further patient accrual for the following reasons: (a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol performance; (d) patient safety or regulatory concerns; (e) study results are already conclusive, and (f) emergence of new information that diminishes the scientific importance of the study question. NCI will not provide investigational agents or permit expenditures of NCI funds for a study after requesting closure (except for patients already on study).

    The Cancer Trials Support Unit (CTSU). Data management and logistical support activities for the PBTC will be provided by CTSU as a service that is separately supported by the NCI.

    Data Management and Analysis Review: NCI Biometrics Research Staff will review mechanisms established by the PBTC for data management and analysis. When deemed appropriate, staff will make recommendations to ensure that data collection and management procedures are adequate for quality control and analysis, and as simple as appropriate to encourage maximum participation of physicians entering patients and to avoid unnecessary expense. Data must also be available for external monitoring as required by NCI’s agreement with the FDA relative to the NCI’s responsibility as drug sponsor.

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

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

    Access to data: The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. For trials using NCI IND agents, 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 PBTC for on-site auditing of clinical trials data. The awardee will comply with the data access provisions of applicable CTAs and CRADAs, and when these agreements are in place the Industry Sponsor will have complete access to the data for any and all regulatory findings.

    Note: The NCI reserves the right to reduce the budget or withhold an award in the event of substantial awardee underperformance (vastly insufficient patient accrual or progress) or other substantial failure to comply with the terms of award. The NCI retains, as an option, the right to conduct periodic external review of progress.

    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 PBTC Chair and Vice-Chair, the PBTC OBDMC Director, Member Institution representatives (site PD/PI or another designated investigator), Discipline representatives (e.g., neuroimaging, pharmacology, biology/genomics), and a patient/family representative. Each voting member will have one vote. Other members may be added as needed. 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 responsibilities may include:

    • 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 (CTEP) and final NCI approval);
    • Reviewing progress in the development and conduct of Consortium clinical trials;
    • Reviewing on a regular basis the performance of the OBDMC;
    • 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 Genomics/Translational/Pharmacokinetics 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.

    3. Reporting

    When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

    In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

    Section VII. Agency Contacts

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

    Application Submission Contacts

    eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)
    Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
    Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

    General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
    Email: GrantsInfo@nih.gov (preferred method of contact)
    Telephone: 301-945-7573

    Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
    Contact Center Telephone: 800-518-4726
    Email: support@grants.gov

    Scientific/Research Contact(s)

    Malcolm A. Smith, M.D., Ph.D.
    National Cancer Institute (NCI)
    Telephone: 240-276-6087
    Email: Malcolm.Smith@nih.gov

    Peer Review Contact(s)

    Referral Officer
    National Cancer Institute (NCI)
    Telephone: 240-276-6390
    Email: ncirefof@dea.nci.nih.gov

    Financial/Grants Management Contact(s)

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

    Section VIII. Other Information

    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.

    Authority and Regulations

    Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.

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