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.

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

The purpose of this Funding Opportunity Announcement (FOA) is to enhance NCI’s program for conducting early phase clinical trials in children with cancer, currently supported as the Children's Oncology Group (COG) Phase 1 & Pilot Consortium. The overall goal is to ensure that high priority novel agents can be tested in pediatric patients in a timely manner. Towards this end, the clinical research activities now supported through the COG Phase 1 & Pilot Consortium will be continued (and enhanced) by the Pediatric Early Phase Clinical Trials Network (PEP-CTN).

Investigators responding to this FOA and applying for PEP-CTN award are expected to provide the capabilities needed to implement and maintain a vigorous and scientifically strong pediatric cancer early phase clinical trials program, including:

• Strong scientific leadership in pediatric drug development, which should include expertise in the application of imaging, genomics and translational biology, and pharmacokinetics to early phase pediatric clinical trials;
• Ability to ensure timely development of clinical trial protocols;
• Effective data management, including appropriate Quality Assurance/Quality Control (QA/QC) methods as well as central study monitoring;
• Regulatory expertise for clinical trials involving investigational agents; and
• Appropriate expertise and capabilities for statistical design and analysis of early phase clinical trials.

To accommodate the changing landscape of oncology drug development, the key changes incorporated into this FOA in comparison to the current COG Phase 1 & Pilot Consortium include:

• An organizational structure to facilitate seamless transitions from Phase 1 to Phase 2 testing;
• A streamlined prioritization process for identifying novel agents for testing through the PEP-CTN that is intended to reduce the timeline for moving agents into pediatric testing;
• An enhanced program for study monitoring that builds upon a combination of existing annual on-site audits with the addition of central study monitoring of selected items for all patients; and
• Incorporation of genomic characterization as an essential component of the PEP-CTN, both for defining eligibility criteria for patients with specific characteristics and for facilitating understanding of observed antitumor activity.

Investigators proposed by the applicant institution will lead the PEP-CTN Operations and Data/Statistics Center (ODSC) and will interact with selected Core Member Institutions and Phase 2 Expansion Institutions on the conduct of early phase clinical trials. These clinical trials are expected to meaningfully advance pediatric oncology drug development during the award period.

NCI has historically been the primary source of support for evaluations of new agents and new treatment approaches for children with cancer in the United States. The support that NCI has provided for early phase clinical trials has resulted in children with cancer having access to a broad range of new anti-cancer agents and has contributed to the identification of curative treatments for approximately 80% of children with cancer. Nonetheless, as many as 20% of children with cancer succumb to their disease, and for selected cancer diagnoses this rate is much higher. Furthermore, a substantial number of childhood cancer survivors experience significant short- and long-term toxicities and other adverse health effects. Hence, there remains a critical need for safely introducing new agents and new treatment approaches for children with cancer so that children can benefit from advances in cancer biology and drug development. This ability to quickly and efficiently conduct first-in-children studies is critical to NCI’s overall clinical research program for children with cancer. This FOA represents a continuation of NCI s commitment to childhood cancer research but with updates to accommodate changes in the landscape of oncology drug development.

The scope of the PEP-CTN will be the design and conduct of pediatric Phase 1 trials that will often include Phase 2 expansion cohorts. As well, the Network will conduct pilot studies of novel regimens to determine their tolerability so that they can proceed to definitive testing in Phase 3 clinical trials. Through these activities, the PEP-CTN will allow high priority novel agents to be introduced into the pediatric oncology setting in a timely manner. Randomized Phase 2 trials will in most cases not be within the purview of the PEP-CTN, but rather will be conducted by the Children’s Oncology Group.

The Pediatric Early Phase (PEP) Agent Prioritization Committee will be established by NCI to prioritize agents for evaluation by the PEP-CTN. The goal for the Committee is to address a critical need within the childhood cancer research community by providing for the timely, rigorous, and transparent prioritization of agents under development for adult cancers for evaluation in the pediatric setting. The Committee will be led by the PEP-CTN Chairperson, and membership will include a range of pediatric drug development stakeholders (see Joint Responsibilities in Section VI.2 Cooperative Agreement Terms and Conditions). Requests for evaluation of agents for early phase clinical testing through the PEP-CTN will be accepted for review by the PEP Agent Prioritization Committee from PEP-CTN members, COG Disease Committees, pharmaceutical companies, and others.

Agents prioritized by the Committee will have protocols rapidly developed by the PEP-CTN that will then be reviewed by CTEP to ensure that all safety and regulatory issues have been addressed. The process will be expedited by the use of protocol templates developed by the PEP-CTN and approved by CTEP for Phase 1, Phase 1-2, and pilot studies. By providing a single pathway for agents to enter the PEP-CTN and by using pre-approved templates for protocol development, the time previously spent in multiple levels of review for Letter of Intent (LOI) submission and approval will be reduced. The process also provides greater transparency for the agent prioritization process for NCI-supported pediatric early phase clinical trials and provides a single portal by which pharmaceutical companies can propose agents for pediatric early phase clinical evaluation in collaboration with NCI and NCI-supported investigators.

The PEP-CTN will need to have the ability to identify patients with specific genomic alterations for its clinical trials. The PEP-CTN will also be expected to collect tumor tissue on all patients enrolled on its clinical trials and as well to collect specimens suitable for analyzing for circulating tumor DNA (ctDNA). Funds for genomic testing of selected specimens will be provided to the PEP-CTN for use for single gene or gene panel sequencing to determine eligibility and for more extensive sequencing (e.g., whole exome and RNAseq) to identify genomic characteristics associated with response (or lack thereof).

To meet regulatory expectations, the PEP-CTN will have an enhanced program for study monitoring. This program will be built upon a combination of the existing annual on-site audits with the addition of central study monitoring of selected items for all patients. The on-site audits will continue to be supported by NCI through Theradex, and funding will be provided to the PEP-CTN to support central study monitoring.

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

Applicants will be required to have 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 ). PEP-CTN clinical trials will be conducted using these clinical trial research services and infrastructures. PEP-CTN clinical trials will be within the purview of the NCI Central IRB (https://ncicirb.org/cirb) , and PEP-CTN Member Institutions will be required to use the NCI Central IRB.

The governing body for the PEP-CTN will be its Steering Committee, which will set the overall research direction and research procedures of the Network. Details on the composition and functions of the Steering Committee are provided in Section VI.2 Cooperative Agreement Terms and Conditions.

Applicants will be expected to structure the activities of the proposed PEP-CTN across three main areas: Clinical and Translational Research Program; Operations and Data Management/Statistics; and Member Institutions. Major responsibilities for each of these areas include the following.

PEP-CTN Clinical and Translational Research Program:

• Pediatric drug development clinical research program;
• Genomics and translational biology for PEP CTN clinical trials;
• Pharmacokinetics program for PEP-CTN clinical trials; and
• Imaging for PEP-CTN clinical trials.

PEP-CTN Operations and Data/Statistics Center (ODSC) with responsibilities including:

• 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 PEP-CTN operations, including teleconferences, electronic communications, meetings, etc.
  
  

PEP-CTN Member institutions:

• "Core Member Institutions" for participation in all PEP-CTN clinical trials and for the support of PEP-CTN clinical research activities;
• Phase 2 expansion and pilot institutions for participation in selected clinical trials.

It is expected that the current members of the COG Phase 1/Pilot Consortium will become PEP-CTN Core Member Institutions. Accordingly, applicants should consider these sites and their capabilities. Applicants will be able to invite up to three additional institutions if a scientific leader(s) proposed by the applicant is not at one of these Core Member Institutions.

Importantly, the composition of the Core Member Institutions during the project period is meant NOT to be static but subject to adjustment based on performance evaluation. Therefore, applicants must be able and prepared to conduct rigorous performance evaluation and replace under-performing Core Member Institutions.

The current Core Member Institutions are listed below:

• Ann and Robert H Lurie Children's Hospital of Chicago
• Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
• C’s Mott Children's Hospital
• Children's Healthcare of Atlanta - Egleston
• Children's Hospital Colorado
• Children's Hospital of Alabama
• Children's Hospital of Los Angeles
• Children's Hospital of Orange County
• Children's Hospital of Philadelphia
• Children's Hospital of Pittsburgh of UPMC
• Children's National Medical Center
• Cincinnati Children's Hospital Medical Center
• Columbia University Medical Center/Herbert Irving Cancer Center
• Dana-Farber/Harvard Cancer Center
• National Institutes of Health Clinical Center
• Riley Hospital for Children
• Saint Jude Children's Research Hospital
• Seattle Children's Hospital
• UCSF Medical Center-Mission Bay
• University of Minnesota/Masonic Cancer Center
• Washington University School of Medicine

After the PEP-CTN award is made, up to an additional 20 institutions will be selected by the PEP-CTN Steering Committee to participate in PEP-CTN clinical trials when additional accrual potential is needed (e.g., for Phase 2 expansion cohorts).

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

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

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 but not as Core Member Institutions.

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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

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. Applicants may consider, for example, one PD/PI to be responsible primarily for the Clinical and Translational Research Program, who will be acting as Network Chairperson and another PD/PI to be responsible for the Operations and Data/Statistics Center (ODSC).

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

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).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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

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

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

The letter of intent should be sent to:

Malcolm A. Smith, MD, PhD
Telephone: 240-276-6087
Fax: 240-276-7892
Email: Malcolm.Smith@nih.gov

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 of the Proposed PEP-CTN - 12 pages

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

Sub-section C. Operations and Data/Statistics Center (ODSC) - 12 pages

Sub-section D. Member Institutions - 6 pages

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

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

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

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

Facilities & Other Resources: In addition to standard documentation for this attachment, applicants must document the extent of their expertise in using MediData Rave and describe their implementation of protocols and usage of MediData Rave capabilities. Applicants 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 incomplete.

Applicants must also document their capabilities for preparing and submitting Investigational New Drug Applications (INDs) in support of Network clinical trials and for meeting the regulatory responsibilities associated with being a study sponsor. Applications that fail to document these capabilities will be considered incomplete.

Other Attachments: Applicants 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). Brevity of the attached documentation is generally recommended.

Attachment 1: Sample Protocol Template for Phase 1 Clinical Trials with a Phase 2 Expansion (use filename "Protocol template").

Attachment 2: Procedures for Central Monitoring of Clinical Trials (use the filename "Central Monitoring"). Describe specific central monitoring procedure to include at a minimum 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.

Attachment 3: Procedures for Member Institutional Performance Monitoring (use filename "Institutional Performance Monitoring").

• Include Standard Procedures for periodically evaluating the performance of Core Member Institutions, addressing for example, such aspects as:
• accrual of adequate number of eligible patients to the PEP-CTN clinical trials;
• timely submission of required data;
• observance of clinical trial protocol requirements;
• contributions to clinical trial protocol development and conduct;
• authorship of PEP-CTN publications; participation in PEP-CTN administrative and scientific committees; and
• Other aspects deemed relevant.
• Provide policies for handling unacceptable performance (for instance, use of warning letters, grace period to allow corrections);
• Provide a policy and mechanism for replacing institutions unresponsive to necessary correction action plans, including:
• Specific criteria (performance metrics) to identify the lower tertile of Core Member. Institutions (in terms of performance) and for competing these Network Core Member slots.
• Provide procedure to re-compete the slots of the lower quartile of Core Member institutions, including criteria to be used in reviewing applications for membership.

Attachment 4: Proposed Conflict of Interest Policy for the PEP-CTN (use the filename "COI Policy). This policy and associated procedures must be consistent with U.S. Public Health Service (PHS) requirements for ensuring that there is no reasonable expectation that the design, conduct, and/or reporting of research conducted by the proposed PEP-CTN will be biased by any conflicting financial conflict of interests of an investigator.

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

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

It is expected that the budget requested for the PEP-CTN will be apportioned in approximately the manner described below. With the exception of specific instructions for funds that must be included by the applicant (see italicized text below), these estimates are informational.

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

• Funded scientific leadership positions include the PD/PI (Chairperson of the PEP-CTN) and the PEP-CTN vice-Chair as well as the Genomics/Translational Biology, Pharmacokinetics, and Imaging scientific leaders. The effort level of the PEP-CTN 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 approximately $120,000 per year (based on $15,000 per chair for 8 active studies) but without providing specific individuals' names (i.e., use "To Be Determined").

B. PEP-CTN ODSC (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 PEP-CTN 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 ODSC 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 Core Member Institutions should be assumed with average capitation payment of $5,000 (i.e., $600,000 per year). Assume an additional $200,000 per year to support enrollment from Phase 2 Expansion Institutions. List a total for the Per Capita Reimbursement Fund of $800,000 per year under the "Other Expenses" category.
• Core Member Institutions Fund ($600,000 per year, independent of per capita reimbursement for patients enrolled in clinical trials) to support the non-accrual responsibilities associated with participating in the Consortium s clinical trials (e.g., site training, pharmacy set-up, and site administration) that must be met whether patients are ever enrolled on a study at an institution. Include $600,000 for Core Member Institutions Fund under "Other Expenses" category.
• Patient Studies Research Funds ($100,000 per year) to be allocated to support institutional costs of research that are not considered a cost of treatment by medical insurers, and therefore are not reimbursed by insurers (e.g., blood and urine collection and shipping for pharmacokinetic studies, tumor tissue handling and shipping to the tissue bank or Biopathology Center, and performance of research imaging studies). Include this fund in the "Other Expenses" category.

D. Genomics/Translational/Pharmacokinetics Research Fund ($180,000 per year) 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 $180,000 per year 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 Network's imaging objectives.

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

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

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

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

Research Strategy

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

Sub-Section A. Overview of the Proposed PEP-CTN.

Overview and Research Direction. Outline the overall goals for the PEP-CTN and an overarching research strategy for the conduct of pediatric early phase trials through the PEP-CTN.

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 Network in developing and implementing state-of-the-art clinical trials for children with cancer. Include plans for replacement of key leadership positions should leadership transitions be required. Specific key roles to be described include, for example, the Network Chairperson and Vice-Chair, Lead Biostatistician and Leader of ODSC (if different), Imaging leader, Pharmacokinetics leader, and Genomics/Translational Biology leader. Indicate when one person will be leading more than one activity.

Relevant Past Performance. Summarize the past performance of the applicant team in the past 5-6 years in leading and managing multi-institutional pediatric early phase clinical trials. In this context, adult early phase clinical trials may also be mentioned, provided those adult clinical trials were directly applicable to the development and conduct of pediatric early phase clinical trials that are the focus of this FOA. 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 the past 5-6 years in data management for multi-site 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;
• Other accomplishments in the past 5-6 years including, but not limited to, novel statistical designs for Phase 1 and 2 studies, imaging in early phase clinical trials, pharmacokinetic evaluations, and genomic and biology findings from early phase clinical trials.
• Record of reviewing the performance of member institutions in multi-institutional clinical trial consortia.
• 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 B. 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 cancer. Note that descriptions of specific clinical trials to be developed by the PEP-CTN are not part of the application.
• The general approach to recognizing agents with the greatest likelihood for benefiting children with cancer. Explain your vision for the identification of the most promising agents to bring to the PEP-CTN Prioritization Committee.
• Include your understanding of the opportunities and challenges for multi-site clinical trials in pediatric oncology drug 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 PEP-CTN 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 PEP-CTN.
• Strategies for incorporating promising new genomic biomarkers such as circulating tumor DNA (ctDNA) into PEP-CTN clinical trials. [Note: Collection of specimens for ctDNA analysis is encouraged, particularly from Phase 2 cohorts enrolled onto PEP-CTN clinical trials. As assays will often be disease-specific, applicants are encouraged to establish collaborations with research teams focusing on specific diseases.]
• The approach to incorporating pharmacokinetic analyses into PEP-CTN clinical trials and how these analyses will be used to inform the development of agents being studied by the PEP-CTN.

Imaging - Address the following areas:

• Describe the availability of adequate post-acquisition image storage, processing, and analysis capabilities to support the Network's imaging objectives.
• Describe how the PEP-CTN 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 Network to advance understanding of the effect (both positive and negative) of investigational agents and to advance the utility of imaging in early phase clinical trials.

Sub-Section C. PEP-CTN Operations and Data/Statistics Center (ODSC)

Development of Clinical Trial Protocols.

• Describe the general strategies proposed by the applicant to ensure and support the timely development of pediatric Phase 1 and 2 clinical trials for agents that have been prioritized by the PEP-CTN Agent Prioritization Committee. Include timelines for the steps proposed for protocol development and subsequent clinical trial activation.

Note: See "Other Attachments" section for the required relevant documentation ("Sample Clinical Trial Protocol).

Data Management/Analysis and Quality Control/Quality Assurance. Describe the general approaches and strategies for all the following aspects (do not repeat details of specific procedures to be provided under corresponding Other Attachments):

• 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 PEP-CTN protocols.
• The approach to ensuring the technical integrity and security of the data management systems.
• The approach to study monitoring, including: 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 PEP-CTN clinical trials. (Detailed procedures for central monitoring are also required as Attachment 2, under "Other Attachments").
• On-site auditing including a description of how auditing will be coordinated with the CTEP Clinical Trials Monitoring Branch and the Clinical Trials Monitoring Service (http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_coop_ccop_ctsu.htm). Explain steps to be taken prevent or correct problems when problems are detected (e.g., preventative and corrective action plans, respectively).
• Approach to training and monitoring Member Site personnel to maintain proficiency and consistency in management of PEP-CTN trials.
• Plans for incorporating Pediatric and Proxy PRO-CTCAE into PEP-CTN clinical trials to evaluate how this approach can improve symptomatic adverse event reporting in early phase clinical trials involving children.
• Plans for electronic, web site, and web/teleconference communications to address the organizational and coordination needs of the PEP-CTN.

Statistical Design and Analysis of Early Phase Clinical Trials.

• Describe plans for the statistical support for the PEP-CTN clinical trials, and the statistical approach to the design and analysis of PEP-CTN 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 of 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 PEP-CTN 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 PEP-CTN 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 D. PEP-CTN Member Institutions

Plans/expectations for PEP-CTN Core Member Institutions. Include a description of the following aspects:

• The expected/required characteristics and capabilities of Core Member Institutions (e.g., leadership, experience in Phase 1-2 clinical trials, accrual potential, imaging capabilities, etc.). For the initial period, these characteristics/capabilities should be based on assumption that the current Core Member Institutions will continue serving this role for PEP-CTN.
• If desired, propose up to three additional Core Member Institutions (provided their key scientific leaders are not affiliated with any of the Core Member Institutions listed in Section I). For each additional institution proposed, describe how they meet the expected capabilities and characteristics of Core Member Institutions.

Strategy for performance evaluation and adjustments in participating Member Institutions. Without repeating details in respective Other Attachments, describe the following general aspects:

• The general approach for performance monitoring of institutions (.
• A general approach to handling with inadequate performance of institutions,.
• An approach to re-competition for selected slots for Core Member Institutions at least once during the project period.
• Plans for selecting approximately 20 institutions to participate in Phase 2 components of clinical trials when additional accrual is needed. Include the criteria you propose to use in selecting from among candidate institutions.
• Procedures for establishing subcontract agreements with member institutions for their participation in PEP-CTN 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, with the following modification:

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

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

Data Safety Monitoring Plan

A Data Safety Monitoring Plan attachment is required for all applicants.

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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.

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

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

For this particular announcement, note the following:

In assessing the merit of the application, reviewers will consider the leadership and the entire PEP-CTN applicant team in the context of their past performance, their overall capabilities, and proposed new directions. Reviewers will consider whether the PEP-CTN, as proposed, is highly likely to ensure that novel, promising agents can be introduced in a timely manner into rigorous clinical testing in pediatric cancer patients using state-of-the-art methodology.

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

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

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

Specific to this FOA: What is the likelihood that the PEP-CTN, as proposed, will be able to develop and implement important early phase pediatric clinical trials of high priority agents that meet strict regulatory requirements and that incorporate imaging and biology studies in ways that maximize the insights that are obtained?

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

Specific to this FOA: 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 pediatric early phase clinical trials? Are the team's expertise, capabilities, etc., sufficient for all types of activities needed, including imaging, pharmacokinetics, and genomics activities? Do the investigators demonstrate significant experience with coordinating multi-institutional collaborative clinical research, including relevant experience overseeing subcontracts with member institutions?

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?

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA:

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

How adequate are the approaches and activities of the Clinical Research Program in ensuring that PEP-CTN clinical trials investigate high priority investigational agents 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 imaging study objectives into pediatric early phase clinical trials maximize the insights that can be gained from these trials?

Are the critical PEP-CTN ODSC activities proposed based on appropriate work-flow, timeline, etc.? Are the approaches to study monitoring, including central monitoring, adequate 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 PEP-CTN? Do the plans of the applicants for preparing and submitting INDs in support of PEP-CTN 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 PEP-CTN?

How optimal are the plans for monitoring the performance of member institutions and replacing lower-performing institutions with regards to ensuring that PEP-CTN member institutions are performing at a high level?

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

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

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

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

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

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

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

Not Applicable

Not Applicable

Not Applicable

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

Not Applicable.

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

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

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

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

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

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

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

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

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

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

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

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

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

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

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

The PEP-CTN awardee will be responsible for developing the PEP-CTN clinical and laboratory research program, including definition of objectives and approaches, planning, implementation, analysis, interpretations and conclusions of results. The awardee will develop Phase 1, Phase 2, and pilot clinical trial protocols in accord with the research interests, abilities and goals of the PEP-CTN and in accordance with the decisions of the Pediatric Early Phase (PEP) Agent Prioritization Committee, and will submit these protocols to CTEP for review prior to their implementation.

The leadership structure of the PEP-CTN will include the Network Chairperson, who will also be a PD/PI. If multiple PDs/PIs are proposed [e.g., one PD/PI to be responsible primarily for the clinical program acting as Network Chairperson and another PD/PI to be responsible for the Operations and Data/Statistics Center (ODSC)], then responsibilities will be delineated by the Network's standard procedures in a manner consistent with the Terms and Conditions of Award. The PEP-CTN Chairperson will also be the Chairperson of the Steering Committee and the Executive Committee as described below. The PD(s)/PI(s) will have overall responsibility for providing the leadership necessary to accomplish the goals and objectives of the PEP-CTN.

The following documents (and subsequent modification to them) are hereby incorporated by reference as terms of award. These documents describe the programmatic responsibilities of the conduct of the research supported by this cooperative agreement.

• INVESTIGATOR’s HANDBOOK, a Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm).
• Intellectual Property Option to Collaborator (https://ctep.cancer.gov/industryCollaborations2/default.htm).
• The awardee must comply with the NCI Clinical Terms of Award as required by the NCI policy http://deainfo.nci.nih.gov/grantspolicies/index.htm) for clinical studies and trials when they are a component of any research being funded by the NCI. The PD(s)/PI(s) must ensure that clinical studies and trials conducted under PEP-CTN award are monitored commensurate with the degree of potential risk to study subjects and the complexity of the studies. The PD(s)/PI(s) must also ensure compliance with reporting of all clinical trials to ClinicalTrials.gov per NIH policy on Dissemination of NIH-funded Clinical Trials Information (see NOT-OD-16-149).

Responsibilities of the Operations and Data/Statistics Center:

The PEP-CTN Operations and Data/Statistics Center (ODSC) 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 ODSC, with the guidance of the PEP-CTN Chairperson, the Director of the ODSC (if different) and the Steering Committee, are responsible for development and maintenance of an organizational structure and SOPs from the PEP-CTN.

2) Clinical Trials Protocol Development: It is the responsibility of the PEP-CTN to develop the details of the research design, including definition of objectives and approaches, planning, implementation, analysis, interpretation and conclusions of studies, and publication of results, using NCI-approved PEP-CTN protocol templates and standardized language for trial logistics and administrative issues. The ODSC is responsible, in accordance with the PEP-CTN SOPs, for the preparation and implementation of procedures for development and submission of PEP-CTN agent prioritization proposals to the PEP Prioritization Committee and for development and submission of protocols to the CTEP Protocol and Information Office (PIO) in a timely fashion for review and approval by NCI. [NOTE: If the PEP-CTN feels that it is unable to develop a clinical trial of an agent prioritized by the PEP Agent Prioritization Committee, then it may appeal to the NCI through the Project Scientist(s). If there is agreement that resources are so limited as to prevent the trial from going forward, then the PEP Agent Prioritization Committee will be notified. If there is lack of agreement, then procedures for Dispute Resolution (see below) will be followed.]

Specific issues are:

• 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 PEP-CTN will submit a protocol template(s) for pediatric early phase clinical trials to NCI for review and approval, and this NCI-approved template(s) will be used by the ODSC for PEP-CTN protocols.
• Submission of PEP-CTN clinical trial protocols for review and approval by NCI will be preceded by submission of an Agent Prioritization Request to the PEP Prioritization Committee. These submissions can come from the PEP-CTN or from other sources (e.g., pharmaceutical companies).
• The ODSC is responsible for communicating the results of the PEP Prioritization Committee to relevant PEP-CTN committees and members and for establishing study committees to quickly develop protocols for prioritized agents.
• The PEP-CTN SOPs should include timelines for the steps involved in the development of Agent Prioritization Requests and clinical trial protocols, and should include mechanisms for monitoring the performance of the ODSC and Member Sites in meeting these time lines. The PEP-CTN’s SOPs should also include corrective action plans outlining the steps to be taken when these times are not met. Data concerning the PEP-CTN’s performance in meeting timelines for protocol development should be provided in the Annual Progress Report.
• The PEP-CTN 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).

3) Study Monitoring: The PEP-CTN is responsible for assuring accurate and timely monitoring of each PEP-CTN 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 trials. Patients shall be enrolled through the CTSU’s Oncology Patient Enrollment Network (OPEN). 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 PEP-CTN wishes to continue accrual to a study beyond the accrual goal for eligible and ineligible patients specified in the clinical trial protocol, the PEP-CTN 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 PEP-CTN meeting agendas, and reports as required to comply with the PEP-CTN’s Data and Safety Monitoring Plan;
• Adequate policies and procedures for closure of studies; if the PEP-CTN wishes to close accrual to a study prior to meeting the initially established accrual goal, the interim results and other documentation should be made available to NCI staff for review and concurrence prior to implementation of that decision. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the clinical trial protocol in order to facilitate these decisions. In the event that the study is recommended for early closure for safety reasons, procedures in the Data Safety Monitoring Plan regarding notification of CTEP must be followed.

4) Quality Control of PEP-CTN Clinical Trials: Quality Control and Quality Assurance (QC/QA) Programs are inherently linked. The Clinical Trials Monitoring Branch (CTMB) of CTEP provides direct oversight of NCI-sponsored Consortia and National Clinical Trials Network (NCTN) QC/QA programs. The PEP-CTN is responsible for establishing and implementing mechanisms to assure the accuracy and reliability of its clinical trials data. Quality control is a complex topic spanning the entire range of diagnostic and therapeutic modalities employed by the PEP-CTN. 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 PEP-CTN 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; and
• Participation in PEP-CTN administrative and scientific committees and/or other PEP-CTN activities.

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

c) The PEP-CTN 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 PEP-CTN’s data submission policies and ongoing training for all CRAs concerning changes to PEP-CTN 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 PEP-CTN 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 ODSC will document Good Clinical Practice (GCP) training for relevant ODSC 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 PEP-CTN clinical trials. Central monitoring is to include source data verification for patients at each enrolling site [e.g., informed consent, eligibility, first two courses of treatment (drug administration and AEs), and any other key data items] with tracking of source data verification (preferably through 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: PEP-CTN is expected to work closely with NCI and a Clinical Monitoring Service (CTMS, currently through a contract with Theradex) to ensure proper completion of all actions and steps associated with on-site auditing, including review of corrective and preventative action plans when problems are detected.

• In the event that the NCI determines that a PEP-CTN Member site failed to comply adequately with NCI guidelines for the conduct of clinical trials, the accrual of new patients to PEP-CTN protocols at the affected institution shall be immediately suspended upon notice of the NCI determination. The suspension will remain in effect until the NCI conducts the required audit and the audit report or remedial action is accepted by the NCI.
• The ODSC 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: Report to CTEP will use the Clinical Data Update System (CDUS) or any systems that replace it, and will include:

• For most PEP-CTN studies using NCI-sponsored investigational agents, CDUS Complete reporting procedures (or a replacement alternative) will be used, which capture demographic, adverse event information (by course, and response data;
• For clinical studies that do not use NCI-sponsored investigational agents, reporting to CTEP will generally use the CDUS Abbreviated Procedures (demographic data only); and
• Reporting of serious and unknown adverse events requirements shall be reported using NCI reporting mechanisms (currently CTEP-AERS).

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

• The PEP-CTN 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 PEP-CTN’s components in meeting these timelines. Corrective action plans will be implemented when these timelines are not met.
• Publication or oral presentation of work conducted under the PEP-CTN’s Cooperative Agreement requires appropriate acknowledgement of NCI support.
• For investigations using an agent supplied under a CRADA or Clinical Trials Agreement (CTA), the NCI pharmaceutical collaborator will have an opportunity to review manuscript drafts prior to their submission for publication as per the NCI Standard Language for CRADAs and CTAs.
• The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies.

7) PEP-CTN meetings: The ODSC 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 PEP-CTN meetings per year. Regular teleconferences with member institutions will be scheduled to update sites on ongoing and new clinical trials. Additional meetings between PEP-CTN members and meetings with NCI staff will be organized as needed. Relevant responsibilities of the ODSC related to these meetings include:

• Developing meeting priorities and agendas;
• Providing the report of ongoing studies to include information detailing patient accrual and demographics, data timeliness, toxicities experienced by study participants, and other items (e.g., outcome data) as appropriate;
• Preparing summaries as appropriate after each meeting to be sent to PEP-CTN members and NCI program staff members; and
• Addressing logistical issues for teleconferences and face-to-face meetings.

8) PEP-CTN communications: The ODSC must establish routine electronic communication with Member Sites to facilitate clinical trial development and study monitoring and to facilitate the work of the PEP-CTN’s committees. Relevant communication methods include web site postings, email, teleconferences and web/video conferences. The ODSC must also establish communications with NCI’s CTSU for data transfer (see role of CTSU, section 2.A.2., and Fiscal management, section 2.A.1.12).

9) Compliance with Federal Regulations Concerning Clinical Research: The PEP-CTN Chairperson and the Director of the ODSC (if different) will be responsible for ensuring that the PEP-CTN is in compliance with all applicable federal regulations concerning the conduct of human subjects research. Policies and guidelines to be addressed include:

• OHRP assurances: The ODSC must assure that each participant site has a current, approved assurance of file with OHRP.
• Assuring appropriate Informed Consent: The ODSC must assure that each patient (or legal representative) gives written informed consent prior to entry on study.
• IRB Review of PEP-CTN protocols: The NCI/CTEP-managed Pediatric Central IRB (CIRB) will provide centralized review of all protocols, and thus timely submission of protocols to the Pediatric CIRB is mandatory.
• Adverse Event Reporting: The ODSC is responsible for assuring timely reporting of all serious and/or unexpected adverse events. Adverse events should be reported using the Common Terminology Criteria for Adverse Events (CTCAE), which is the NCI’s standard language for reporting adverse events in clinical trials (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). For investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP, via the CTEP Adverse Event Reporting System (CTEP-AERS), or its successor application, according to CTEP guidelines specified in each clinical trial protocol (https://ctep.cancer.gov/branches/pio/reporting_guidelines.htm)
• Assuring that the PEP-CTN is in compliance with CTEP requirements described in the DCTD Investigators Handbook for storage and accounting for investigational agents (including NCI/DHHS Drug Accountability Records [DAR] procedures), and is in compliance with FDA requirements for investigational agents.

10) Managing and coordinating the acquisition and shipping of protocol-specified tumor specimens and biological fluids (with relevant clinical data): The PEP-CTN will collect protocol-specified specimens from it 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 ODSC will be responsible for establishing a Conflict of Interest policy for the PEP-CTN. This policy should ensure that there is no reasonable expectation that the design, conduct, or reporting of research conducted by the Group will be biased by any conflicting financial interest of an investigator. The policy should be in compliance with the general policies with the NCI and the NIH.

12) Fiscal management of the PEP-CTN: Responsibilities for PEP-CTN fiscal management include:

• Establishment of consortium arrangements with Member Sites to support PEP-CTN-related activities at each member institution;
• Distribution of funds to Member Sites to support costs of patients accrued onto PEP-CTN clinical trials.

13) Submission of annual progress reports to the NCI: These reports will describe activities and accomplishments during the previous year of the PEP-CTN.

14) Reporting and accounting for Program Income: Reporting policy is described in the NIH Grants Policy Statement (https://grants.nih.gov/grants/policy/nihgps/HTML5/section_8/8.3_management_systems_and_procedures.htm). The method to be used will be included in the NOA.

Responsibilities of Member Sites:

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

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

3) Participating in research design and clinical trial protocol development, 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 PEP-CTN’s research objectives;
• Participation in meetings: appropriately participating in the regular meetings and teleconferences as deemed necessary for institutions performing PEP-CTN activities;
• Following the PEP-CTN’s SOPs for the conduct of clinical research.

4) Implementing the core data collection method and strategy of the PEP-CTN: It is the responsibility of each Member Site to ensure that the procedures for data submission for each PEP-CTN 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 ODSC.

5) Complying with mechanisms for quality assurance and quality control of therapeutic and diagnostic modalities employed in PEP-CTN 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 PEP-CTN to meet OHRP and Federal requirements for the protection of human subjects.

7) Participating in the NCI Central IRB for review of all PEP-CTN clinical trial protocols.

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

9) Investigational agent responsibilities:

• Implementing the procedures established by the PEP-CTN for assuring that PEP-CTN investigators performing clinical trials involving DCTD Investigational Agents are NCI registered investigators (Form 1572).
• Ensuring 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) Participating in PEP-CTN procedures for the timely publication of major findings.

12) Conflict of Interest: Complying with the Conflict of Interest Policy of the PEP-CTN to ensure that there is no reasonable expectation that the design, conduct, or reporting of research conducted by the PEP-CTN will be biased by any conflicting financial interest of an investigator. PEP-CTN awardee institution and Members Sites institutions will be required to accept and implement policies approved by the Steering Committee to the extent consistent with grant regulations.

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

The NCI will coordinate and facilitate various activities of the PEP-CTN. The NCI staff members will have substantial programmatic involvement that is above and beyond the normal stewardship role in cooperative agreement awards. An NCI Program staff member, acting as Project Scientist will provide oversight, advice to the awardee on scientific and/or analytic and programmatic issues as outlined below. The NCI Program Official may also have a role of a Project Scientist. In that case, the individual involved will not attend peer review meetings of renewal or revision applications or will seek NCI waiver as stated above.

Specific responsibilities of NCI will include the following:

1) Monitoring PEP-CTN progress: Performance of the PEP-CTN will be reviewed at least annually by the NCI Project Officer on the basis of the information provided at the semi-annual and other meetings, in the annual progress reports and in the CDUS reports submitted to CTEP for each of the PEP-CTN’s clinical trials. Insufficient patient accrual or progress or progress, or non-compliance with the terms of the award, including these Terms and Conditions of Award, may result in a reduction of budget, withholding of support, suspension, or termination of the award. The NCI retains, as an option, the right to conduct periodic external review of progress.

2) Scientific liaison: Serving as a resource with respect to other ongoing NCI and other NIH activities that may be relevant to the PEP-CTN research efforts to identify promising new leads, to facilitate compatibility with other NCI research projects and to avoid unnecessary duplication of effort.

3) CTEP review of proposed clinical trials protocols: Protocols developed by the PEP-CTN for agents prioritized by the PEP Agent Prioritization Committee will be reviewed by the PRC, which meets weekly and is chaired by the DCTD Associate Director, CTEP. Following the review of the clinical trial protocol by the PRC, the NCI Project Scientist will provide the PEP-CTN with a consensus review that describes recommended modifications and other suggestions, as appropriate (see DCTD Investigator’s Handbook, for further information regarding protocol review at CTEP). As all protocols will be for agents prioritized by the PEP-CTN Agent Prioritization Committee, the CTEP review will focus on patient safety issues, compliance with federal regulatory requirements, methods of monitoring and reporting to NCI, and any issues that the PEP-CTN Agent Prioritization Committee highlighted as needing scrutiny at the time of protocol review.

In the unlikely event that a proposed clinical trial is disapproved, the specific measures for lack of approval will be communicated in writing by the NCI Project Scientist to the PEP-CTN as a consensus review within 30 days of protocol receipt by the NCI. NCI will not provide investigational agents or permit expenditure of NCI funds for a clinical trial that is not approved. The NCI Project Scientist will be available to assist the PEP-CTN in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the PEP-CTN and the NCI.

4) CTEP protocol amendment review: Any change in the protocol document subsequent to its approval by CTEP must be submitted in writing and approval prior to implementation (see Section 8.6 The Investigator’s Handbook for further discussion of these procedures).

5) CTEP involvement in auditing member sites: The Clinical Trials Monitoring Branch (CTMB) of CTEP will coordinate with the PEP-CTN the performance of on-site audits at PEP-CTN Member Sites, which are to occur at approximately 1 year intervals by a clinical trial monitoring service (currently Theradex). The CTMB will review audit results and the corrective plans developed by the PEP-CTN in response to the audits.

6) CTEP involvement in clinical trial closure: Protocol closure is primarily the responsibility of the PEP-CTN 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).

7) CTEP involvement in data management and logistical support activities: The Cancer Trials Support Unit (CTSU) will provide:

• a system to operate, and maintain a comprehensive, fully electronic system for management of all clinical trials data (OPEN), including logistical support for and templates for data submission;
• a Regulatory Support System, to include an IRB database to track approval, an investigator and site credentials database, and a document management system;
• posting of PEP-CTN trials on the CTSU website menu; and
• training of clinical sites on clinical trial procedures related to the interface with the CTSU.

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

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

10) PEP-CTN meetings: The NCI Program Officers will attend PEP-CTN Steering Committee, Executive Committee and other PEP-CTN meetings to participate in the discussion of relevant scientific information, progress in the clinical trials, and the status of newly available investigational agents and other research opportunities in order to plan future activities. Other NCI staff members from CTEP (e.g., from the Investigational Drug Branch) as well as Program Directors from other programs in the Division of Cancer Treatment and Diagnosis (DCTD, e.g., from the Cancer Diagnosis Program) will attend as needed.

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

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

13) 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 PEP-CTN 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.

14) Access to agents for pre-clinical testing: For NCI-sponsored IND agents, NCI will facilitate transfer of material to investigators with a Materials Transfer Agreement (MTA).

Areas of Joint Responsibility include:

1) PEP-CTN Steering Committee: The Steering Committee will serve as a governing body for the PEP-CTN and will include the following voting members the PEP-CTN:

• Chairperson and Vice-Chair;
• The Lead Statistician at the ODSC and the Director of the ODSC (if different);
• Other PEP-CTN leaders, as appropriate (e.g., Member Institution representatives and the Chairperson of the Institutional Performance Committee);
• Discipline leaders (e.g., Imaging, Pharmacology, Biology/Genomics);
• A patient advocate; and
• NCI Project Scientist.

Each Member will have one vote except for NCI representatives, who will collectively have one vote for NCI.

Other NCI representatives such as NCI-designated biostatistician may participate as advisors and observers in the Steering Committee meetings as needed but will not have voting rights.

The Steering Committee will be responsible for the overall research program of the PEP-CTN, including:

• Establishing PEP-CTN priorities;
• Overseeing the development and review of Agent Prioritization Requests by PEP-CTN members;
• Overseeing and reviewing changes to the PEP-CTN organizational structure and PEP-CTN Standard Operating Procedures;
• Reviewing on a regular basis the performance of the ODSC and other aspects of the PEP-CTN;
• Reviewing Member Sites for adequate performance, approving plans for review of corrective action plans, and reviewing these plans when submitted by the site, and then placing on probation or suspending Members;
• Developing guidelines and overseeing re-competition of the lower performing Member Sites at least once during the award period;
• Reviewing and approving proposals for use of the Biology/Genomics/Pharmacokinetics Research Funds; and
• Selection of sites for Phase 2 and pilot study participation.

The Steering Committee will include Subcommittees, as needed.

2) PEP-CTN Executive Committee: The PEP-CTN will also establish an Executive Committee to manage the activities of the Steering Committee. This may include the PEP-CTN Chairperson and Vice-Chair, the Lead Statistician at the ODSC and the Director of the ODSC (if different), and the NCI Program Officers (Program Director and Project Scientist). The Executive Committee will set agendas for Steering Committee meetings and will coordinate interactions of the PEP-CTN with pharmaceutical companies. The Executive Committee will have access to all response data from PEP-CTN clinical trials (non-randomized) and will be responsible for determining when these data can be confidentially disclosed to selected parties or can be publicly disclosed.

3) Pediatric Early Phase (PEP) Agent Prioritization Committee: NCI will establish and administer the PEP Agent Prioritization Committee to prioritize agents for evaluation by the PEP-CTN. Membership in the Committee will include: PEP-CTN leadership, COG leadership and COG Disease Committee representatives, NCI staff, FDA representatives, independent researchers and patient advocates. The PEP-CTN Chairperson will serve as Chairperson of the PEP Agent Prioritization Committee. The NCI Project Scientist and the PEP-CTN Chairperson will establish agendas for Committee meetings based on agent proposals received. Proposals will be accepted from PEP-CTN members, COG Disease Committees, and pharmaceutical- biotechnology companies. The NCI Project Scientist will be responsible for preparing summaries of the PEP Prioritization Committee Meetings, and following review by Committee members, these summaries will be provided to the submitter. Summaries for agents recommended for prioritization will be provided to the PEP-CTEN, which will then rapidly develop a protocol using NCI-approved protocol templates.

4) PEP-CTN PHRMA/BIO Advisory Board. NCI and PEP-CTN leadership will establish a PEP-CTN PHRMA/BIO Advisory Board by selecting and inviting persons from relevant companies to join the Board. The Board will provide feedback to the PEP-CTN on expectations of pharmaceutical companies and biotechnology companies for pediatric early phase clinical trials and will provide advice to the PEP-CTN on steps that it can take to collaborate more effectively with Industry partners. The PEP-CTN ODSC will organize meetings of the PEP-CTN PHRMA/BIO Advisory Board.

Dispute Resolution:

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

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

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

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

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.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

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

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

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

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

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

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