Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

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

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

Through this non-competitive single source cooperative agreement Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) solicits an application from the Public Health Institute with the intent of funding a single award to continue to support and enhance the Pediatric Early Phase Clinical Trials Network (PEP-CTN) for conducting early phase clinical trials in children with cancer, and to thereby facilitate the timely introduction of high priority novel agents into pediatric oncology clinical testing. NCI is supporting PEP-CTN for its ability to efficiently and expeditiously conduct first in children clinical trials is critical to NCI’s overall clinical research program for children with cancer. The PEP-CTN is involved in designing and conducting pediatric phase 1 trials that often include phase 2 expansion cohorts. Conduct of the phase 2 components of these studies within the PEP-CTN is efficient and is expected to expedite development of the agents for pediatric cancer patients. When pediatric phase 1 testing results are available for an agent, phase 2 studies will also be within the remit of the PEP-CTN. As well, the PEP-CTN will conduct pilot studies of novel regimens to determine their tolerability and feasibility so that the regimens can proceed to definitive testing in phase 3 clinical trials.

Rationale for Single Source

Extensive funds and resources have been expended by the Cancer Therapy Evaluation Program (CTEP) of the NCI to create and optimize the current PEP-CTN led by the Public Health Institute as a cohesive, efficient infrastructure for conducting early phase clinical trials for children with cancer. This includes integration with the CTEP-developed clinical trial resources, including the Cancer Trials Support Unit (CTSU) Enterprise System which is utilized for regulatory and roster data, the Oncology Patient Enrollment Network (OPEN) Portal that is used for web-based registration of patients, and the NCI Central IRB that provides patient protection oversight. It also includes development of the consortia itself, with its more than 40 institutions that are trained by the PEP-CTN to conduct complex early phase clinical trials that require extensive data collection as well as specimen collection (e.g., blood specimens for pharmacokinetic and pharmacodynamic studies). Any attempt to recreate the PEP-CTN anew would result in substantial delays in implementing new clinical trials because of the time and effort required to establish again the necessary clinical trials infrastructure within the new entity and to make the connections with the CTEP clinical trials resources that already exist for the PEP-CTN.
While the NCI recognizes and endorses the need for full and open competition, and by preference utilizes open competition in the vast majority of its initiatives, we believe that the investments made by the NIH and the proven effectiveness of the PEP-CTN in developing early phase clinical trials within the CTEP-developed clinical trials infrastructure warrants an exception. To recapitulate the time and resources needed to recreate this infrastructure de novo would be costly and would significantly reduce the pace with which innovative clinical trials could be initiated and completed. Consequently, the serious disruptions in clinical trial planning and conduct that would result from such an endeavor would have adverse effects on bringing new agents into clinical testing for children with cancer.
We request the opportunity to compete the Pediatric Early Phase Clinical Trials Network (PEP-CTN) as a Single Source NOFO, open only to the current PEP-CTN. The requested project would cover the same core elements of responsibility: specifically, the design, development, conduct, and reporting of early phase clinical trials for children with cancer. The anticipated budget would be $4.5M total costs per year for a five-year period of performance.

Background

NCI is a primary source of support for early phase clinical evaluations of novel 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 5-year survival rates increasing to more than 80% for children with cancer. Nonetheless, many children with cancer succumb to their disease, and a substantial number of survivors experience significant short- and long-term toxicities. Therefore, continuing to support the PEP-CTN fulfills 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.

The reissuance of the Pediatric Early Phase Clinical Trials Network (PEP-CTN) NOFO represents a continuation of NCI’s historic commitment to childhood cancer research. That said, the changing landscape of oncology drug development requires continuing adaptation so that NCI can best contribute to identifying more effective treatments for children with cancer. A challenge for the PEP-CTN is establishing ways to effectively work with pharmaceutical companies within the context of the changing regulatory landscape generated by the Food and Drug Administration (FDA) Reauthorization Act of 2017, section 504, which incorporates the Research to Accelerate Cures and Equity (RACE) for Children Act. To boost the ability of the PEP-CTN to successfully collaborate with industry partners, the Cancer Therapy Evaluation Program (CTEP) of NCI will work with the PEP-CTN to streamline its decision-making processes and to enhance its clinical trials infrastructure for collecting high quality data suitable for regulatory submissions.

Research Objectives, Focus, and Requirements

Through this NOFO, NCI seeks to renew the PEP-CTN so that it can continue to design and conduct pediatric phase 1 trials that will often include phase 2 expansion cohorts. Conduct of the phase 2 components of these studies within the PEP-CTN is efficient and is expected to expedite development of the agents for pediatric cancer patients. When pediatric phase 1 testing results are available for an agent, phase 2 studies will also be within the remit of the PEP-CTN. As well, the PEP-CTN will conduct pilot studies of novel regimens to determine their tolerability and feasibility so that the regimens can proceed to definitive testing in phase 3 clinical trials.

The PEP-CTN is encouraged to evaluate the wide range of agent classes being introduced into clinical testing for cancer patients. These include small molecular agents that inhibit or degrade critical proteins that control cancer cell growth and survival. Agents such as antibody-drug conjugates, T-cell engaging bispecific agents, and chimeric antigen receptor (CAR) T-cells products that target surface proteins relevant to one or more pediatric cancers are also a high priority.

To take advantage of advances in cancer biology, the PEP-CTN is encouraged to incorporate state-of-the-art methods to learn as much as possible from each patient's participation in a clinical trial. The PEP-CTN is highly experienced in incorporating pharmacokinetic evaluations into its studies, and these will continue to be foundational components of PEP-CTN clinical trials. Methods utilizing blood and plasma specimens for evaluating cancer responses to treatment is encouraged, as these allow insights into changes in tumor biology in response to treatment while avoiding the ethical issues associated with serial tumor biopsies in children.

The PEP-CTN requires scientific leadership and expertise in multiple clinical, laboratory, and administrative areas, as well as administrative and project management expertise to ensure timely conduct of studies while meeting all regulatory requirements. To address these requisite areas of proficiency, this NOFO specifies that the PEP-CTN have the following components.

• The Scientific Leadership of the PEP-CTN provides the requisite expertise in the design and conduct of early phase clinical trials, pharmacology, translational research, and imaging.
• The Operations Component responsibilities include protocol development, fulfilling the regulatory affairs and compliance requirements of the PEP-CTN, and providing logistical management for PEP-CTN operations (e.g., managing communications and meetings, etc.).
• The Biostatistics and Data Management Component is responsible for the statistical design and analysis of PEP-CTN clinical trials and for data collection and management, including supporting quality control/quality assurance measures.
• Member institutions. The PEP-CTN requires approximately 20 highly experienced institutions for participation in first in children early phase clinical trials and an additional set of institutions (n=20) to participate in phase 2 and pilot studies when additional accrual potential is needed.
• The Pharmacokinetic(PK)/Biology Component is responsible for integrating pharmacokinetic and biological studies into the Network’s clinical trials.
• The Imaging Component provides the leadership needed for incorporation of appropriate imaging studies into PEP-CTN trials and provides for the central collection, review, and archiving of research imaging studies.

The PEP-CTN functions within the clinical trials infrastructure developed and supported by the Cancer Therapy Evaluation Program (CTEP) of NCI. Clinical trials consortia and groups working within this infrastructure develop and implement clinical trials using Medidata Rave as their clinical trials data management system. The Cancer Trials Support Unit (CTSU) Enterprise System is utilized for regulatory and roster data, and the Oncology Patient Enrollment Network (OPEN) Portal, a web-based registration system, is used for patient enrollments onto PEP-CTN clinical trials. PEP-CTN clinical trials are within the purview of the NCI Central IRB, and PEP-CTN Member Institutions are required to use the NCI Central IRB.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Only the following applicant may apply for this single source funding: Public Health Institute. Please refer to Section I. Notice of Funding Opportunity Information for more details.

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.

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active 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.

Only the PI/PDs associated with the award issued under RFA-CA-17-027 to Public Health Institute is eligible to apply for this single source funding. Please refer to Section I. Notice of Funding Opportunity Information for more details.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

Only one application (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, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Letter of Intent

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

By the date listed in Part 1. Overview Information, 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, M.D., Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6087
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The Research Strategy must consist of the following subsections with the indicated page limits:

Sub-Section A. PEP-CTN Progress Report. - 6 pages

Subsection B. Clinical and Translational Research Program - 12 pages

Subsection C. PEP-CTN Operations and Statistics/Data Management Component (OSDMC) - 12 pages

Subsection D. PEP-CTN 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 NOFO.

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.

Provide the following additional materials specified below. Each attachment should be uploaded as a separate PDF using the indicated filenames (which will serve as application bookmarks).

Attachment 1: Procedures for Central Monitoring of Clinical Trials (use the file name "Central Monitoring").

Attachment 2: Procedures for Member Institutional Performance Monitoring (use file name "Institutional Performance Monitoring").

Attachment 3: Table providing outcome decisions for all agents reviewed by the Agent Prioritization Committee and subsequent protocol development timelines for agents approved by the Agent Prioritization Committee (use the file name "Protocol Timelines").

Attachment 4: Tables listing PEP-CTN Core Member Institutions and non-Core Member Institutions (use the file name "Member Institutions").

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

R&R Budget

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

The following funding categories need to be included in the Budget:

• Per Capita Reimbursement Fund. For the purposes of budget preparation for per capita reimbursement, an annual accrual of 100 patients by Core Member Institutions should be assumed with average capitation payment of $5,000 (i.e., $500,000 per year). Assume an additional $150,000 per year to support enrollment from non-Core Member Institutions. List a total for the Per Capita Reimbursement Fund of $650,000 per year under the "Other Expenses" category.
• Additional Research Funds: Include a budget category designated as Additional Research Funds of $200,000. These funds may be used to support 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 PEP-CTN clinical trials, and additionally they may be used to support costs at institutions for clinical trial related activities that are not considered standard of care (e.g., special laboratory tests, research imaging studies, etc.), and therefore, are not reimbursed by third party payers.
• Imaging Activities. Include a budget category to provide funding for adequate post-acquisition image storage, processing, and analysis capabilities to support the Network's imaging objectives.
• Meetings and Travel: Include funds for at least one PEP-CTN meeting per year. Include funds to support travel for one representative from each core Member Site and appropriate Operations and Statistics/Data Management Component (OSDMC) staff for one meeting per year.

R&R Subaward Budget

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:

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

Subsection A. Progress Report.

Follow instructions in the SF424 (R&R) Application Guide.

Subsection B. Clinical and Translational Research Program

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 of the PEP-CTN. Include plans for replacement of key leadership positions should leadership transitions be required. Specific key roles to be described include, for example, the Chair and Vice-Chair, Lead Biostatistician and Leader of Operations Center, Imaging leader, Pharmacokinetics leader, and Genomics/Translational Biology leader.

Clinical and Translational Research Program - Address the following areas:

• 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 identifying agents with the greatest likelihood for benefiting children with cancer;
• Address how genomic and other biological evaluations will be incorporated into PEP-CTN clinical trials to both identify patient populations for enrollment and to inform understanding of clinical trial results (e.g., use of serial blood/plasma collections to evaluate changes in tumors during treatment);
• Describe 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; and
• Plans for incorporating Pediatric and Proxy PRO-CTCAE (Patient-Reported Outcome Common Terminology Criteria for Adverse Events) into PEP-CTN clinical trials to evaluate how this approach can improve symptomatic adverse event reporting in early phase clinical trials involving children.

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; and
• Describe how the PEP-CTN will centrally review imaging studies to verify that claims of treatment agent activity are accurate and reliable.

Subsection C. PEP-CTN Operations and Statistics/Data Management Component (OSDMC)

Development of Clinical Trial Protocols.

• Describe the procedures proposed to ensure the timely development of pediatric phase 1 and 2 clinical trials. Include timelines for the steps proposed for protocol development and subsequent clinical trial activation.

Data Management/Analysis and Quality Control/Quality Assurance. Describe the general approaches and strategies for all of 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 databases and care report forms for PEP-CTN protocols.
• The approach to ensuring the technical integrity and security of the data management systems, including plans for backing up PEP-CTN clinical trial data.
• 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 summary of the approach to central monitoring of PEP-CTN clinical trials. (Detailed procedures for central monitoring are also required as Attachment 1, 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 to 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.
• The Data and Safety Monitoring Plan for the PEP-CTN.
• 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 Cancer Therapy Evaluation Program Adverse Event Reporting System (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 and biological fluids to the COG Biopathology Center or to appropriate laboratories within the PEP-CTN and/or outside biospecimen repositories (as required by specific clinical trials protocols).

Subsection D. PEP-CTN Member Institutions

Refer to Attachment 4 for a listing of PEP-CTN Member Institutions and include a description of the following items:

• Required characteristics and capabilities of Core Member Institutions (e.g., leadership, experience in phase 1-2 clinical trials, accrual potential, imaging capabilities, etc.) and of non-Core Member institutions;
• The general approach proposed for monitoring the performance of institutions;
• The general approach to handling inadequate performance of institutions;
• The approach to re-competing at least once during the project period Core Member Institutions whose performance is in a low percentile compared to other Core Member Institutions; and
• 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.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

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

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

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

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier 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, NIH. Applications that are incomplete, and/or non-compliant will not be reviewed.

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

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

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

Overall Impact

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

Scored Review Criteria

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

Significance

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

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

Specific to this NOFO:

What is the likelihood that the PEP-CTN, as proposed, will be able to develop and implement important high priority early phase clinical trials for children with cancer that meet strict regulatory requirements and that incorporate imaging, pharmacokinetic, and biology/genomic studies in ways that maximize the insights that are obtained?

Investigator(s)

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

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

Innovation

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

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

Approach

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

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

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA:

To what extent are the governance rules and organizational structure well-designed to support the PEP-CTN in meeting its stated objectives of efficiently and expeditiously developing and implementing early phase clinical trials for children with cancer?

How well do the plans for incorporating translational (e.g., genomic and biological), pharmacokinetic, and imaging study objectives maximize the insights that can be gained from PEP-CTN clinical trials?

Are the critical PEP-CTN operational activities proposed based on appropriate work-flows, timelines, etc.?

How well are the approaches to study monitoring, including central monitoring, aligned to ensure rigor and high quality of data from clinical trials?

Environment

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

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

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

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

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

Additional Review Criteria

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

Study Timeline

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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

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

Revisions

Not Applicable

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

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications will receive a written critique.

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.

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Cancer Advisory Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

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

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

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

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

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

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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 NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 (HHS) grant administration regulations at 2 CFR Part 200, 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 recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility 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 consideration of the feedback provided by 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 Statistics/Data Management Component (OSDMC)], 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 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.

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

1. 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).
2. Intellectual Property Option to Collaborator (https://ctep.cancer.gov/industryCollaborations2/default.htm).
3. The awardee must comply with the NCI Clinical Trial 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.

Responsibilities of the PEP-CTN Operations and Statistics/Data Management Component (OSDMC):

The PEP-CTN OSDMC 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) Required Systems Use: The PEP-CTN will be required to use systems developed and maintained by NCI/CTEP to support its clinical trials infrastructure. These systems are the Cancer Trials Support Unit (CTSU), Identity and Access Management (IAM), Cancer Therapy Evaluation Program Enterprise (CTEP Enterprise), Medidata Rave, Oncology Patient Enrollment Network (OPEN), the NCI Pediatric Central Institutional Review Board (CIRB), the CTEP Adverse Event Expedited Reporting System (CTEP AERs). See: https://ctep.cancer.gov/initiativesPrograms/etctn_infrastructure.htm.

2) Clinical Trials Protocol Development: The protocol development process for PEP-CTN studies includes Letters of Intent (LOI) followed by submission of protocols. Specific issues include:

• Clinical trial protocols should be developed, submitted, and implemented in accordance with the DCTD Investigator’s Handbook (https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm).
• The PEP-CTN will submit a protocol template(s) for NCI for review and approval, and this NCI-approved template(s) will be used by the OSDMC for PEP-CTN protocols.
• The OSDMC is responsible for communicating the results of the CTEP Protocol Review Committee to relevant Network Committees and Network members.
• Submission of PEP-CTN LOIs and clinical trial protocols for review and approval by NCI will generally be preceded by review of the agent by the PEP-CTN Agent Prioritization Committee.
• The Network's SOPs should include timelines for the steps involved in the development of LOIs and clinical trial protocols, and should include mechanisms for monitoring the performance of the Network in meeting these time lines. These timelines must be consistent with the timelines established by the NCI Operational Efficiency Working Group (OEWG) as recorded at http://ctep.cancer.gov/SpotlightOn/OEWG.htm#oewg_timelines_sops. Data concerning the Network'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).

4) 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 clinical trials. Standard procedures for monitoring should include (but are not limited to):

• Precise tracking of patient accrual and adherence to accrual goals, with development of corrective action plans if accrual goals are not achieved (Note: 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. If the study is recommended for early closure for safety reasons, procedures in the Data Safety Monitoring Plan regarding notification of CTEP must be followed.

4) Quality Control of PEP-CTN Clinical Trials: The PEP-CTN is responsible for establishing and implementing mechanisms to assure the accuracy and reliability of its clinical trials data, including, but not limited to the following:

a) Institutional performance evaluations to ensure that PEP-CTN institutions are submitting high quality data in a timely manner.

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

1. 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;
2. Instruction for appropriate Member Site participants and study chairs on their responsibilities for study monitoring;
3. 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
4. Training of Clinical Sites on protocol-specific requirements for trial implementation, procedures, and monitoring.
5. Note: The OSDMC will document Good Clinical Practice (GCP) training for relevant OSDMC 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 with tracking of source data verification (preferably through Medidata Rave), and with SOPs for the timeliness of data submissions and query resolutions, and with guidelines describing factors that may trigger more frequent monitoring or on-site audits. Central review of claimed objective responses will also be performed.

e) On-site auditing: The PEP-CTN 's on-site monitoring program will be coordinated with the Clinical Trials Monitoring Branch (CTMB) of CTEP. The PEP-CTN is responsible for maintaining its on-site auditing program in compliance with the Clinical Trials Monitoring Branch (CTMB, CTEP) guidelines (http://ctep.cancer.gov/branches/ctmb/clinicalTrials/monitoring_coop_ccop_ctsu.htm) and for submitting the results of audits to the NCI in accordance with the guidelines.

5) Timely reporting of data to CTEP:

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

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

1. 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.
2. 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.
3. All press releases issued by the Network on primary study findings and results require review by NCI, NIH, and DHHS. Pre-review timing for press releases on study finding and results must be discussed with and approved by the PEP-CTN Program Director. The PEP-CTN is encouraged to send drafts of press releases on other topics to NCI for pre-review and/or pre-release notice.

7) PEP-CTN meetings: The OSDMC 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.

8) PEP-CTN communications: The OSDMC 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.

9) 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 patients enrolled on its clinical trials and transmit them to the appropriate laboratories for testing and to the COG Biopathology Center for storage of specimens that are to be used for correlative studies.

10) Conflict of Interest Policy: The OSDMC 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.

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) Participation of Site investigators in the design and development of PEP-CTN clinical trials, including:

• Serving as clinical trial protocol Chairs or as members of protocol study teams;
• Participating in the Scientific and Administrative Committees as requested (such as Steering Committee and Institutional Performance Committee) needed to support the 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) Implementation of 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 OSDMC.

5) Compliance 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) Participation in the NCI Central IRB for review of all PEP-CTN clinical trial protocols.

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

9) Investigational agent responsibilities:

• Implementation of 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).
• Compliance with CTEP requirements described in the DCTD Investigators Handbook for storage and accounting for investigational agents (including NCI/DHHS Drug Accountability Records [DAR] procedures), and compliance with FDA requirements for investigational agents.

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

11) Participation in PEP-CTN procedures for the timely publication of major findings.

12) Conflict of Interest: Compliance with the Conflict of Interest Policy of the PEP-CTN.

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

NCI program staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The substantially involved NCI program staff member(s), acting as Project Scientist(s), will coordinate in a centralized fashion the various activities of the recipients. Specific responsibilities of the NCI Project Scientist(s) will include, but will not be limited to

• Serving as a member of the PEP-CTN Steering Committee and participating in its activities;
• Monitoring PEP-CTN progress and working collaboratively with PEP-CTN investigators if corrective actions are needed;
• Serving as a scientific liaison and a resource to PEP-CTN investigators with respect to other ongoing NCI and other NIH activities that may be relevant to the PEP-CTN research efforts (e.g., to identify promising new leads, to facilitate compatibility with other NCI research projects and to avoid unnecessary duplication of effort);
• Coordinating the NCI review of proposed clinical trials protocols, which will involve the following steps (for further details, see the DCTD Investigator's Handbook at https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm):
  • Review of Letters of Intent (LOI) for PEP-CTN studies;
  • CTEP review of protocol documents prepared by the PEP-CTN in follow-up to approved LOIs or Concepts.
• Other CTEP Roles (see DCTD Investigator's Handbook at https://ctep.cancer.gov/investigatorResources/investigators_handbook.htm):
  • Reviewing any protocol amendment; Any change in a PEP-CTN protocol must be reviewed and approved by CTEP prior to implementation (see Section 8.6 The Investigator’s Handbook for further discussion of these procedures).
  • Auditing of member sites; The Clinical Trials Monitoring Branch (CTMB) of CTEP will coordinate with the PEP-CTN the performance of on-site audits at Member Institutions. CTMB will review audit results and the corrective plans developed by the Network in response to the audits.
  • Option to initiate clinical trial closure: Protocol closure is primarily the responsibility of the PEP-CTN and the specific protocol committee. The NCI Project Scientist 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).
  • One or more CTEP staff will serve as non-voting members on the PEP-CTN's Data and Safety Monitoring Committee (DSMC).

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

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

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.

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

Areas of Joint Responsibility include:

The PEP-CTN will have a Steering Committee as the governing body of the Network. The Steering Committee will include as voting members: the PEP-CTN Chair and Vice-Chair, the PEP-CTN OSDMC Director, Member Institution representatives (site PD/PI or another designated investigator), Discipline representatives (e.g., imaging, pharmacology, biology/genomics), and a patient/family representative. Each voting member will have one vote. Other members may be added as needed. The NCI Program Director and/or Project Scientist will serve as an advisory (non-voting) member(s) to the Steering Committee. Additional NIH representatives may participate as advisors and observers in the Steering Committee meetings as needed and will also not have voting rights. The Steering Committee may form any subcommittees that are deemed necessary. The NCI Program Director and/or Project Scientist and other NCI representatives may participate in any subcommittee as non-voting members.

The Steering Committee responsibilities may include the following:

• The approval of any changes to the PEP-CTN organizational structure and PEP-CTN Standard Operating Procedures;
• Establishing priorities for clinical trials;
• Reviewing progress in the development and conduct of Network clinical trials;
• Reviewing on a regular basis the performance of the OSDMC;
• Overseeing selection of the laboratories to perform laboratory studies associated with individual clinical trial protocols;
• Evaluating the performance of PEP-CTN components responsible for conduct of auxiliary studies;
• Selection of sites for phase 2 and pilot study participation;
• Reviewing and approving proposals for use of the Biology/Genomics/Pharmacokinetics Research Funds;
• Assuring that deficiencies identified during the reviews of PEP-CTN activities are adequately addressed in a timely manner;
• Developing guidelines and overseeing re-competition of the lower performing Member Sites at least once during the award period; and
• Reviewing Member Institutions for adequate performance with the authority to place on probation under-performing Member Sites, to suspend Members, and to add new Members to replace any suspended Members.

PEP-CTN leadership and the NCI Program Officers will meet regularly (e.g., monthly) to review progress and plans for the PEP-CTN. PEP-CTN leadership and NCI Program Officers 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.

Agent Prioritization Committee: PEP-CTN leadership and the NCI Program Director and/or Project Scientist will together be responsible for overseeing the PEP-CTN Agent Prioritization Committee to obtain additional feedback from experts on the priority of new agents for testing through the PEP-CTN. The Agent Prioritization Committee members will be jointly selected by PEP-CTN leadership and the NCI Program Director and/or Project Scientist and will include PEP-CTN members, NCI clinical researchers, non-PEP-CTN drug development experts, and patient advocates. PEP-CTN leadership and the NCI Program Director and/or Project Scientist will work together to develop agendas for Agent Prioritization Committee meetings and to encourage pharmaceutical companies to submit agents for consideration by the Committee.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: 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 recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

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

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Malcolm A. Smith, M.D., Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6087
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Shane Woodward
National Cancer Institute (NCI)
Telephone: 240-276-6303
Email: [email protected]

Section VIII. Other Information

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

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 and 2 CFR Part 200.