Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Cancer Institute (NCI)
Funding Opportunity Title	Pediatric Phase 1/Pilot Consortium (Limited Competition UM1)
Activity Code	UM1 Multi-Component Research Project Cooperative Agreements
Announcement Type	Reissue of RFA-CA-07-502
Related Notices	June 09, 2017 - This RFA has been re-issued as RFA-CA-17-027.
Funding Opportunity Announcement (FOA) Number	RFA-CA-12-502
Companion FOA	None
Number of Applications	Only one application from eligible institution is allowed as defined in Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.395
FOA Purpose	The purpose of this Funding opportunity Announcement (FOA) is to continue the NCI’s program for Pediatric Phase 1/Pilot Consortium. The function of the Consortium is to conduct Phase 1 and pilot studies in children with cancer so that new agents can be introduced into the pediatric oncology setting in a timely manner. The Consortium's ability to quickly conduct first in children studies is critical to NCI’s overall clinical research program for children with cancer. To accomplish the objectives of the FOA, a strong multi-institutional, multi-disciplinary research team is needed that can rapidly and efficiently design and conduct Phase 1 and pilot clinical trials and that is experienced in doing so within the ethical constraints applicable to research involving children. The ultimate purpose for supporting the Pediatric Phase 1/Pilot Consortium is to improve therapy outcomes for children with cancer. The Consortium applicants must plan to serve this goal through the safe and efficient introduction of promising new agents and treatment regimens into the pediatric clinical setting through the conduct of well-designed Phase 1 and pilot studies. In addition, Consortium applicants must plan to incorporate pharmacokinetic and pharmacodynamic endpoints (to include imaging and translational laboratory studies) as appropriate into Phase 1 and pilot studies to facilitate future development of the new treatment approaches. The Consortium covered by this FOA is designed to be a complementary program to the Children Oncology Group (COG), another NCI-sponsored program that is mainly focused on Phase 2 and Phase 3 pediatric clinical trials. The Consortium is expected to collaborate with COG Disease Committees in the development of its pilot studies of new treatment approaches for children with specific types of cancer.

Posted Date	January 5, 2012
Letter of Intent Due Date	February 20, 2012
Application Due Date(s)	March 20, 2012
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	May-June, 2012
Advisory Council Review	August, 2012
Earliest Start Date(s)	September 1, 2012
Expiration Date	March 21, 2012
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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

The purpose of this Limited Competition Funding Opportunity Announcement (FOA) is to continue the NCI’s program for conducting Phase 1 and pilot studies in children with cancer. The goal of the program is to facilitate a quick conduct of first in children studies of new therapeutic agents so that new treatments can be introduced into the pediatric oncology setting in a timely manner.

The eligibility to apply in response to this FOA is limited to the current Consortium awardees. To accomplish the objectives of the FOA, applicants must have a strong multi-institutional, multi-disciplinary research team. The team must have appropriate experience and ability to rapidly design and efficiently conduct Phase 1 and pilot clinical trials, all within the ethical constraints applicable to research involving children. The Pediatric Phase 1/Pilot Consortium covered by this FOA is designed as a complementary program to the Children Oncology Group (COG), another NCI-sponsored program that is mainly focused on Phase 2 and Phase 3 pediatric clinical trials.

The specific objectives for the Consortium in the coming 5-year funding period will be:

• To safely and efficiently introduce novel anticancer agents into the pediatric setting through the conduct of Phase 1 clinical trials;
• To collaborate with COG Disease Committees to develop and conduct pilot studies of promising new treatment approaches for children with specific types of cancer; and
• To incorporate pharmacokinetic and pharmacodynamic endpoints (to include imaging and translational laboratory studies) as appropriate into Phase 1 and pilot studies to facilitate future development of the new treatment approaches.

The NCI is the primary source of support for early phase evaluations of new agents and new treatment approaches for children with cancer. The support that NCI has provided for early phase clinical trials has resulted in children with cancer having access to a broad range of new anti-cancer agents and has contributed to the identification of curative treatments for approximately 80% of children with cancer. Nonetheless, as many as 20% of children with cancer succumb to their disease, and a significant number of survivors experience significant short- and long-term toxicities. Additionally, the rate of decline in childhood cancer mortality rates slowed in the late 1990s, a trend most noticeable for pediatric solid tumors. There remains a critical need for safely introducing new agents and new treatment approaches for children with cancer so that children can benefit from advances in cancer biology and drug development. The reissuance of the Pediatric Phase 1/Pilot Consortium FOA represents a continuation of NCI’s historic commitment to childhood cancer research as well as a forward-looking program for extending targeted therapeutics into the pediatric population as validated targets are identified for specific childhood cancers.

This FOA builds upon experience gained during the two earlier funding periods of the Phase 1/Pilot Consortium. The continuation of the Consortium program is grounded in basic principles guiding the conduct of pediatric Phase 1 clinical trials, as listed below. Consortium applicants responding to this FOA are expected to follow these general principles in their plans for the new funding period.

• Multi-institutional Studies. Single institution pediatric Phase 1 studies are generally not feasible due to limited patient numbers. Conversely, excessive numbers of institutions participating in Phase 1 trials is inefficient as well as sub-optimal in terms of monitoring and assuring patient safety. To conduct Phase 1 studies in children, it is essential to have a limited number of experienced institutions with proven experience and patient accrual capabilities.
• Timeliness of Study Development, Conduct, and Results Dissemination. Timely development and implementation of Phase 1 studies and pilot studies are essential to applying advances in cancer biology and drug development to the pediatric setting. These efforts require committed investigators as well as experienced clinical trial protocol development staff and efficient protocol development procedures, with clearly defined timelines for completion of each step in clinical trial protocol development and implementation as well as for publication of the results.
• Emphasis on Quality Data. Data from pediatric Phase 1 and pilot studies must be of the highest quality and must be submitted in a timely manner. This aspect requires committed, trained staff at local institutions, effective mechanisms for data collection and analysis, and mechanisms for onsite audits to verify reported data and to assure compliance with clinical trial protocol.
• Biological Data for Specifically-targeted Agents. Correlations between agent doses and biological effects are important for new agents with specific molecular targets, but ethical considerations limit the extent to which tumor sampling that is strictly for research purposes can be employed. Alternative methods must be employed to gain relevant information on the effects of specifically targeted agents (e.g., analyses of surrogate tissues, noninvasive imaging, etc.).
• Pharmacokinetic Data. Pharmacokinetic studies are central to pediatric Phase 1 trials, as they allow comparison to systemic exposures achieved in adult patients and in pediatric preclinical models. In both adults and in preclinical models, relationships between systemic exposure and target modulation can be demonstrated, thereby providing benchmarks for the drug levels and systemic exposures that should be targeted in children.
• Imaging Studies. Imaging methods have potential for determining the effect of agents on target tissues. The Consortium should apply state-of-the-art imaging methods to pediatric drug development. The implementation of this guideline will require appropriate scientific leadership as well as the staff and resources for central collection, analysis, and archiving of research images. It also requires the capability and commitment of participating institutions to perform imaging studies in adherence with the respective clinical trial protocol.
• Pilot Studies Exploring Promising Treatment Regimens. Pilot studies of promising multi-agent regimens (which may or may not involve a dose escalation) are a key step in the integration of new agents into the therapy of specific childhood cancers and require careful monitoring for toxicity and safety such as can be provided by the Consortium’s member institutions. Development and conduct of pilot studies will require close coordination with the relevant COG Disease Committees.
• Dynamic Selection of the Optimal Participating Institutions. Institutions that will conduct the Consortium clinical trials (referred to as "Member Institutions") should be selected and maintained as Consortium members based upon objective criteria and upon an impartial assessment of their ability to contribute both scientifically and through patient accrual to the Consortium. To ensure that the Consortium is dynamic and that its institutions are among the most capable in North America for conducting early phase pediatric clinical trials, competitive reapplications are needed on a regular basis for institutions in the lower tier of performance. This approach allows capable institutions that are not members of the Consortium to contend for one of the Consortium’s 20 membership slots and to replace institutions not maintaining the expected levels of performance and participation.
• Important Role of Public Funding Programs. Publicly-funded efforts have an important role in the development of new drugs for children with cancer, in addition to efforts supported by pharmaceutical/biopharmaceutical companies. Excessive reliance on pharmaceutical support increases the risk that new agents will be prioritized for evaluation in children based on their potential market size for adults with cancer rather than on the scientific rationale justifying their potential benefit to children. Research funding from pharmaceutical companies should enhance, rather than supplant, the NCI-supported infrastructure for safely and expeditiously evaluating the most promising new agents for the treatment of children with cancer.
• Coordination of NCI-supported Efforts. For NCI-supported efforts, the process of clinical trial development and study implementation is coordinated with the NCI Cancer Therapy Evaluation Program (CTEP, http://ctep.cancer.gov/). This coordination includes submitting to CTEP Letters of Intent (LOI) to develop a clinical trial protocol or pilot study and next submitting the developed protocol concept for NCI approval in accordance with the CTEP Investigator's handbook (http://ctep.cancer.gov/investigatorResources/investigators_handbook.htm).

The proposed COG Phase 1/Pilot Consortium must include the following components that meet the requirements specified below:

• Scientific Leadership. Strong scientific leadership is essential for prioritizing new agents for evaluation and for directing the development and implementation of scientifically and clinically sound phase 1 and pilot studies in children with cancer. Expertise in early phase clinical trials, pharmacology, translational research, and imaging is required for the leadership team. The scientific leadership includes the leaders of the Committees that the Consortium establishes to accomplish its research objectives.
• Clinical Research Program. The Clinical Research Program proposed must comprehensively address developing and managing clinical trial protocols (and managing related documentation), monitoring study conduct, assuring compliance with FDA and OHRP regulatory and patient protection requirements, coordinating manuscript development, and monitoring performance of institutional members. The activities of the Clinical Research Program must also include reporting on the performance of the Consortium in meeting pre-specified timelines for LOI/concept and protocol development, for study implementation, and for publication of studies.
• Member Institutions (Sites of Clinical Trials). The Consortium is expected to have approximately 20 Member Institutions that will conduct the Consortium clinical trials. Collectively, the participating member institutions should be capable of completing 5-6 Phase 1 trials per year (a total of 120-140 patients/year across all Phase 1 trials) and capable of completing a smaller number of pilot studies per year (a total of approximately 60 patients/year). Member institutions should have documented experience in participating in Phase 1 trials and should have the requisite highly qualified medical, nursing, and pharmacy staff. Member Institutions should have demonstrated ability to carefully monitor patients treated during Phase 1 trials and pilot studies, to report clinical data in a timely manner for central data collection repository, to contribute to the scientific leadership of the Consortium, and to employ state-of-the-art imaging studies in the Phase 1 setting. Member institutions of COG that are not Consortium members may have an opportunity to participate in selected Consortium trials if their investigators have unique capabilities needed to complete a particular trial or if they have contributed significant scientific leadership in the development of a new agent under investigation.
• The Statistics and Data Management Core. This Core will be responsible for data management and data analysis as well as for meeting the overall statistical needs of the Consortium.
• The Pharmacokinetic/Biology Component. A dedicated component is needed to integrate pharmacokinetic and biological studies into the Consortium’s clinical trials. This integration is expected to allow for the comparison of key pharmacokinetic parameters between adult and pediatric patients receiving analogous treatment to identify evidence of age effects and to determine how data from adult studies relating systemic exposure to target modulation can be applied in the pediatric setting. This component must have appropriate leadership, staff, and technical capabilities to design and conduct correlative studies to determine relationships between doses, pharmacokinetic parameters, and biological effects of the administered agents. One area of a particular focus is expected to be the identification of patients with tumors bearing specific genomic/pathway alterations for eligibility for clinical trials of agents targeting those alteration or their downstream effects. See Note below on initiating and funding Pharmacokinetics/Biology studies.
• The Imaging Core. This Core will be responsible for the incorporation of appropriate imaging studies into Consortium clinical trials and for the central collection, review, and archiving of the results of such studies. The anticipated research activities of the Core include both confirming that claims of agent activity (e.g., claims of objective responses) are accurate and reliable, as well as relating imaging findings to pharmacokinetic, pharmacodynamic, and clinical parameters as evidence of agent effect. See Note below on initiating and funding these studies.

Note on Process for Initiating and Funding of Patient Studies and the Biology/Pharmacokinetic Studies:

The Consortium is expected to establish procedures for initiating and funding auxiliary studies along with the main clinical Phase 1/Pilot studies. The Consortium applicants must provide plans to establish a process for soliciting and reviewing applications from researchers to perform pharmacokinetic and correlative studies.

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

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

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

PROGRAM EVALUATION. The program of Pediatric Phase 1/Pilot Studies will be subject to external evaluation near the end of the funding period (to be coordinated by the NCI Program Staff). Such evaluation is part of NIH efforts to optimize the efficiency of the funded research. The evaluation process will involve monitoring and assessing the progress of the Pediatric Phase 1/Pilot Studies program toward achieving its goals. This aspect includes evaluating the quality, value, and the quality and scientific impact of the research conducted by the Consortium. For the efficient evaluation of the Program, cooperation of the Consortium awardee will be important and expected.

CRN GOVERNANCE. The Pediatric Phase 1/Pilot Studies Consortium will be governed by the Steering Committee. Details on the composition and functions of the Consortium Steering Committee are provided in Section VI.2.A. Cooperative Agreement Terms and Conditions of Award.

Funding Instrument	Cooperative Agreement
Application Types Allowed	Renewal The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NCI intends to commit up to approximately $3.47 million in FY 2012 to fund one award.
Award Budget	Application budget (total costs) must not exceed $3.47 million.
Award Project Period	Five years.

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

The eligibility to apply in response to this FOA is limited to the current recipient of the Children's Oncology Group Phase 1/Pilot Consortium award.

Not Applicable.

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• eRA Commons

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

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

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

For institutions/organizations proposing multiple PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 Application Guide.

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

Eligible applicant institution may submit only one application.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

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

It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

The letter of intent should be sent to:

Malcolm A. Smith, MD, PhD
National Cancer Institute
Telephone: 301-496-2522
Email: Malcolm.Smith@nih.gov

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

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

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

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

All page limitations described in the PHS398 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

• Specific Aims (including Impact Statement) is limited to 1 page.
• Research Strategy, including tables, graphs, figures, diagrams, and charts is limited to: 12 pages for "Overview, Progress, and Scientific Leadership"; 12 pages for "Clinical Research Program"; 12 pages for "Member Institutions"; 6 pages for " Statistics and Data Management Core"; 6 pages for " Pharmacokinetic/Biology Component"; and 6 pages for "Imaging Core".

This FOA uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

Follow the current PHS 398 instructions to provide a detailed budget (direct costs) for the entire application for the first 12-month period (Form page 4) and the entire proposed project period (Form page 5).

Use additional Form Pages 4 and 5 to provide detailed separate budget information (first year and cumulative budgets for the entire project period) for the individual application components. This information must include:

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

Important Note on Budget:

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

• Funds for Per Capita Reimbusment. For the purposes of budget preparation for per capita reimbursement, an annual accrual rate of 180 patients should be assumed. Funds for per capita reimbursement should be included within the Clinical Research Program budget pages.
• Funds for Member Institutions (independent of per capita reimbursement for patients enrolled in clinical trials) to support the non-accrual responsibilities associated with participating in the Consortium’s clinical trials (e.g., IRB submission and continuing review, site training, pharmacy set-up, and site administration) that must be met whether patients are ever enrolled on a study at an institution.
• Patient Studies Research Funds (minimum $100,000 direct costs per year) to be allocated to support institutional costs of research that are not considered a cost of treatment by medical insurers, and therefore are not reimbursed by insurers (e.g., blood and urine collection and shipping for pharmacokinetic studies, tumor tissue handling and shipping to the tissue bank or Biopathology Center, and performance of research imaging studies). Include this within the Clinical Research Program budget pages.
• Biology/Pharmacokinetics Research Funds (minimum $100,000 direct costs per year) for laboratory studies (e.g., pharmacokinetic and pharmacodynamic studies) performed on specimens (e.g., blood, tumor tissue, buccal cells, etc.) obtained from children enrolled on Consortium clinical trials. Include this within the Pharmacokinetic/Biology Component budget pages.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:

For the Consortium application submitted in response to this FOA, the PHS398 Research Strategy Section must consist of the following sub-sections (modify Table of Content accordingly):

A. Overview, Progress, and Scientific Leadership: 12 pages

B. Clinical Research Program: 12 pages

C. Member Institutions: 12 pages

D. Statistics and Data Management Core: 6 pages

E. Pharmacokinetic/Biology Component: 6 pages

F. Imaging Core: 6 pages

Other sections of the PHS398 Research Plan (398 application instructions Part I, Section 5.5) remain unmodified and must be completed following standard instructions.

In this section address the following aspects:

1) Brief overview of Consortium formation and evolution

2) Progress accomplished during the current funding period, including:

• Clinical trial protocol development: A listing of clinical trial protocol development activities, including letters of intent (LOIs) submitted, clinical trial protocols submitted, and clinical trials activated, with timelines for specific steps in the clinical trial protocol development process;
• A brief summary of each clinical trial that has been initiated during the current funding period, addressing the important facets of the study (e.g., the rationale for evaluating the agent, schedule of administration, target patient population, etc.) and salient findings (e.g., dose levels evaluated and recommended dose for Phase 2 trials, important adverse events observed, and anti-tumor activity, if observed). Note that pharmacokinetic/biology accomplishments and imaging comments can be referred to in this section, but should be described in more detail in the sections that detail these activities.
• A table should be included (within the page limits for this Section) that enumerates accrual by year for each study; and
• Other significant accomplishments.

Note 1: Do not include in the Progress those elements that are required for the standard clinically-oriented sections of the Research Plan (Secions 4 and 6-9). Those Sections must be completed exactly as per PHS398 Inclusions.

Note 2: A list of publications, manuscripts accepted for publication, patents, and other printed materials should NOT be included under Progress but should be listed as per standard PHS398 instructions in Section 5 of Research Plan Bibliography and References Cited/Progress Report Publication List .

3. Scientific Leadership, including:

• Leadership structure for the Consortium in new funding period and a plan for replacement of key leadership positions should leadership transitions be required;
• Lines of authority and decision-making processes for the Consortium; and
• An overview of how the Consortium components will interact and work together to accomplish high quality Phase 1/pilot studies.

Note 3: If multiple PD(s)/PI(s) are proposed, the standard Section 12 of PHS 398 Research Plan Multiple PD(s)/PI(s) Leadership Plan must also be completed as per PHS 398 instructions.

Note 4: To fulfill the objectives of the FOA, individuals designated as PD(s)/PI(s) will need to engage meaningfully in Consortium activities. It is expected that an overall Consortium PD/PI will commit at least 2.4 person months effort and all other PD(s)/PI(s) (if designated) at least 1.8 person months effort to the Consortium. These commitments are expected to be maintained through the entire funding period.

In this section, identify the Program Leader(s) and Specific Aims. It is expected the overall consortium PD(s)/PI(s) will serve as Director(s) of the Clinical Research Program. In addition, address the following aspects:

• The strategy and research plans for Phase 1 clinical trials of systemically administered new agents and, particularly, investigational agents designed to affect specific molecular targets in children with cancer;
• The Consortium’s strategy for prioritizing new agents for Phase 1 evaluation and examples of agents (or classes of agents) that are planned for prioritization for the new funding period;
• The Consortium’s procedures and research plans for developing disease-specific pilot studies in collaboration with COG Disease Committees.
• Organizational structure and procedures for coordinating the development of clinical trial protocols in a timely manner, including timelines for key steps in this process and actions to be taken when these timelines are not met (include current protocol templates utilized by the Consortium in the Appendix materials);
• Procedures for study monitoring including establishing procedures for assigning drug dose level, assessment of patient eligibility and evaluability, timely medical review and assessment of clinical trial data, rapid reporting of treatment-related morbidity, and interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice for Phase 1 and pilot studies (summarize briefly relevant Consortium Standard Operating Procedures).
• Plans for training activities to maintain the proficiency of Member Institution personnel in the management of Phase 1 and pilot clinical trials;
• Plans for maintaining effective interaction and communication between Consortium Leadership, Study Committees and Member Institutions to facilitate clinical trial protocol development and safe and timely conduct of clinical trials;
• Procedures for timely reporting of all serious and/or unexpected adverse events via the AdEERS (Adverse Event Expedited Reporting System) system for investigational agents sponsored by the NCI and via sponsor-specified methods for other agents bearing the status of Investigational New Drug (IND); and
• Plans and procedures for assuring rapid publication of the results of clinical trials and laboratory studies conducted by the Consortium.

In this section, address the following aspects:

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

In this section, identify the Core Leader(s) and address the following aspects:

• Expertise of the leadership of the statistical and data management components. General organizational structure and workflow for data collection and management from multi-institutional Phase 1 and pilot clinical trials;
• Relevant facilities and data management resources and personnel;
• Procedures for ensuring the technical integrity and security of the data management systems;
• Procedures for development of data collection forms, and procedures for data transmittal, data editing, and quality control and verification of submitted data. Include a description for how the Consortium will utilize the clinical data management system (Medidata RAVE) that is being adopted for the NCI Clinical Trials Network;
• Procedures for on-site auditing (including a description of how auditing will be coordinated with the Clinical Trials Monitoring Branch and the Clinical Trials Monitoring Service) and a description of how the on-site auditing program will be integrated into the overall Quality Assurance/Quality Control (QA/QC) program for Consortium clinical trials data;
• The Consortium’s proposed statistical approach to the design and analysis of Phase 1 and pilot studies; and
• A description of the Consortium’s Data and Safety Monitoring Policy.

In this section, identify the Core Leader(s) and address the following aspects:

• Research expertise available for pharmacokinetic and biology studies associated with Consortium clinical trials in the new funding period;
• Highlights of pharmacokinetic and biology studies and accomplishments in current funding period;
• The general approach to the conduct of pharmacokinetic studies and biology/pharmacodynamic studies in Consortium clinical trials that is proposed for the new funding period;
• The decision-making process for use of the Biology/Pharmacokinetics Fund;
• The approach to identifying patient populations with specific biological characteristics (e.g., specific tumor gene mutations) when needed (e.g., to determine eligibility for enrollment in clinical trial); and
• Plans for the coordination of the acquisition and shipping of tumor specimens, biological fluids, and relevant clinical data to the appropriate laboratories within the Consortium and/or outside biospecimen repositories (as required by specific clinical trials protocols).

In this section, identify the Core Leader(s) and address the following aspects:

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

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS398 Application Guide:

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

Appendix

Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide, with the following modifications as described in the preceding Sections 1 7:

• Include sample clinical trial protocol template(s)

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS398 Application Guide.

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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

For this particular announcement, note the following:

The overarching goal of this FOA is to bring novel anticancer agents into pediatric oncology through Phase 1 and pilot clinical trials. In this context, the important aspects are whether the applicants have assembled a team of investigators capable of conducting state-of-the-art Phase 1 and pilot studies in children with cancer, and whether they will be able to work as a coherent research team to efficiently and expeditiously conduct early phase clinical trials. These aspects are expected to be assessed in part based on past performance/accomplishments and the extent to which the Consortium has set a standard for drug development efforts in global pediatric oncology. The assessment should also be based on the proposed research approach and direction for the coming funding period and on the documentation of its ability to accomplish the required specific objectives stated in this FOA.

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the COG Phase 1/Pilot Consortium to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the COG Phase 1/Pilot Consortium proposed).

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

Significance

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

Specific for this FOA: How likely is the prospect that the Consortium, as proposed, will introduce appropriate novel anticancer agents into pediatric oncology in a timely, safe, and efficient manner?

Investigator(s)

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

Specific for this FOA: How complete and comprehensive are the expertise of the PD(s)/PI(s) and the entire team of investigators assembled by the applicants in terms of their ability to conduct state-of-the-art Phase 1 and pilot studies in children with cancer? Will these investigators be able to work as a coherent research team to efficiently and expeditiously conduct early phase clinical trials? Are the proposed leadership structure and decision-making processes and interactions among the Consortium leadership and its various components optimal for the Consortium goals?

Innovation

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

Specific for this FOA: Within the confines of the ethical constraints applicable to Phase 1 trials in children, do the applicants propose novel or improved ways and/or methods to enhance or better serve the goals of the Consortium?

Approach

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

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

Specific for this FOA: How strong overall are the approaches proposed for individual components of the Consortium?

Environment

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

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

• Do the Consortium’s research plans for Phase 1 evaluations of systemically administered new agents in children with cancer demonstrate an appropriate understanding of research opportunities and challenges in pediatric drug development and of the methodologies available to exploit these opportunities? Does the Consortium’s strategy for prioritizing new agents for Phase 1 evaluation reflect an understanding of the current state-of-the-art for pediatric oncology drug development?
• Are the Consortium’s research plans for disease-specific pilot studies developed in collaboration with COG Disease Committees appropriate?
• Are procedures for coordinating protocol development adequate for the timely development of quality protocol documents and for timely activation of Consortium clinical trials?
• Are procedures for study monitoring appropriate for the safe, protocol-prescribed conduct of Consortium clinical trials?
• Does the Consortium provide appropriate training to maintain the proficiency of Member Institution personnel in the successful management of Phase 1 and pilot clinical trials?
• Are the Consortium’s procedures sufficient to ensure timely reporting of all serious and/or unexpected adverse events via the AdEERS (Adverse Event Expedited Reporting System) system for investigational agents sponsored by the NCI and via sponsor-specified methods for other agents bearing the status of Investigational New Drug (IND) ?
• Are Consortium procedures for publication sufficient to ensure that results from Consortium clinical trials are available to the research community in a timely manner?

• Do the investigators of the Consortium's Member Institutions possess the requisite expertise and experience to successfully participate in Consortium clinical trials?
• How adequate are the proposed procedures and criteria for monitoring the performance of the Member Institution in an ongoing manner?
• How appropriate/optimal are the procedures proposed for competing for membership slots to replace the lowest performing Member Institutions in Year 3? Will these procedures ensure selecting highly qualified institutions to join the Consortium?

• Does the Consortium have appropriate statistical leadership and support?
• Has the Consortium utilized appropriate study designs for pediatric Phase 1 and pilot studies, and does it propose appropriate statistical designs for Phase 1 and pilot clinical trials for the coming funding period?
• Does the application adequately demonstrate the capabilities of the applicant in the collection, management, and analysis of data from multi-institutional clinical trials, including use of appropriate QA/QC procedures to ensure the accuracy of the data and use of procedures that maintain and protect the technical integrity and security of the data?

• Does the Consortium have appropriate scientific leadership in the areas of pharmacology and translational science?
• Do the Consortium’s past performance and proposed plans for incorporating pharmacokinetic endpoints into its clinical trials indicate an understanding of how these studies can optimally inform pediatric oncology drug development?
• Do the Consortium’s past performance and proposed plans for incorporating biology endpoints into its clinical trials indicate an understanding of how these studies can optimally inform pediatric oncology drug development? Assessments of the research plans for biology endpoints need to consider the ethical constraints applicable to Phase 1 trials in children that limit (and in most cases prevent) obtaining tumor biopsies strictly for research purposes.
• Does the Consortium’s plan for determining tumor biological characteristics when these define protocol eligibility reflect appropriate, state-of-the-art technology?
• Are the Consortium’s plans for collecting relevant specimens from patients sufficient to support a robust pharmacokinetic and biology research program?

• Does the Consortium have sufficient radiologic expertise to guide innovative use of imaging in the Consortium's clinical trials?
• Has the Consortium appropriately addressed issues related to the acquisition, storage, and analysis of imaging studies?
• Are the research plans for incorporating imaging endpoints into the Consortium’s overall research program reasonable, and do they demonstrate an understanding of the contributions that imaging studies can make to pediatric oncology drug development?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

The committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

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

In particular: Has the Consortium shown appropriate progress in developing productive and highly successful early phase clinical trials program for children with cancer?

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/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

• Application will be evaluated for scientific and technical merit by an appropriate Scientific Review Group(s) convened by the NCI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.
  
  As part of the scientific peer review, applicants will receive a written critique.

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

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

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

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

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

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

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

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

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

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

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

Throughout these Terms and Conditions of Award, "Pediatric Phase 1/Pilot Consortium" (or Consortium ) refers to the organizational structure which is composed of the Consortium PD(s)/PI(s) and other key personnel, the Clinical Research Program, Member Institutions, the Pharmacokinetic/Biology Component, the Statistics and Data Management Core, and Imaging Core. All of Consortium investigators and participating institutions agree to collaborate on research goals of the Consortium.

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

• Defining the overall research goals and strategies for the Consortium and its components;
• Overseeing the development of Phase 1 and pilot clinical trial protocols in accord with the research interests, abilities and goals of the Consortium;
• Ensuring that these protocols are properly submitted to CTEP for review prior to their implementation;
• Participating as voting member(s) in the activities of the Consortium Steering Committee and implementing recommendations of the Steering Committee to the extent consistent with relevant grant regulations; and
• Overseeing the planning and conducting of all other scientific, organizational, and administrative activities of the Consortium indicated below;

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

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

Responsibilities of Clinical Research Program:

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

1) Organization and Standard Operating Procedures (SOPs) for Clinical Trials: The Clinical Research Program, with the guidance of the PD(s)/PI(s) and Steering Committee, is responsible for development and maintenance of an appropriate organizational infrastructure and Standard Operating Procedures for the Consortium.

2) Clinical Trial Protocol Development: Clinical Research Program is responsible for all aspects of developing Phase 11 clinical trials and Pilot studies, including: defining study objectives and approaches (including details of experimental design), planning study implementation, data analyses and interpretations, and publication of study results. These responsibilities include preparation and implementation of procedures for development and submission of Consortium clinical trial protocols to the CTEP Protocol and Information Office (PIO) in a timely fashion for review and approval by NCI.

• Clinical trial protocols should be developed, submitted, and implemented in accordance with the DCTD Investigator's Handbook" (http://ctep.cancer.gov/handbook/index.html).
• Submission of Consortium clinical trial protocols for review and approval by NCI should be preceded by a written Letter of Intent (LOI) to the CTEP LOI Coordinator declaring interest in conducting a particular study. LOIs should be submitted using the LOI template (http://ctep.info.nih.gov/guidelines/index.html).
• The Clinical Research Program is responsible for communicating the results of the CTEP Protocol Review Committee to relevant Consortium Committees and Consortium members.
• The Consortium will not expend NCI funds to conduct any study disapproved by CTEP unless CTEP's disapproval has been modified by the arbitration process (see Section VI.2.A.4 Arbitration Process).
• All clinical trials utilizing NCI-sponsored investigational agents shall be conducted in accordance with the terms of the Intellectual Property Option to Collaborators (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) and the NCI Standard Protocol Language for Cooperative Research and Development Agreements (CRADAs) and Clinical Trial Agreements (CTAs) (see http://ctep.cancer.gov/protocolDevelopment/default.htm).
• The Consortium’s SOPs should include timelines for the steps involved in the development of LOIs, Concept Proposals, and clinical trial protocols, and should include mechanisms for monitoring the performance of the Clinical Research Program and Consortium members in meeting these time lines. The Consortium’s SOPs should also include corrective action plans outlining the steps to be taken when these time lines are not met. Data concerning the Consortium’s performance in meeting timelines for protocol development should be provided in the Annual Progress Report.

3) Study Monitoring: The Consortium must follow the general guidelines for study monitoring for CTEP-sponsored trials as described at http://ctep.info.nih.gov/monitoring/section2.html#2.2.2. The Consortium is responsible for assuring accurate and timely monitoring of the progress of each study, and therefore must have standard procedures for timely data collection and data management consistent with the intensive data requirements and the need for rapid reporting necessary for Phase 1 and pilot studies. Procedures for study monitoring are expected to address at a minimum the following aspects:

• Precise tracking of patient accrual and adherence to accrual goals defined by clinical trial protocol-defined accrual goals - if the Consortium wishes to continue accrual to a study beyond the total accrual goal for eligible and ineligible patients specified in the clinical trial protocol, the Consortium must seek approval from CTEP prior to continuing patient accrual;
• Procedures for assigning dose level (for Phase 1/dose escalation studies) at the time a new patient is enrolled in a study, and assuring that the required observation period has elapsed before beginning a higher dose level;
• Ongoing assessment of patient eligibility and "evaluability";
• Adequate measures to ensure timely medical review and assessment of individual patient data;
• Adequate measures to ensure timely submission of clinical trials data (e.g., adverse events, anticancer response, etc.) from Member Institutions, including timeliness monitoring by study and by Member Institution (reports to be used for review of Member Institution performance and to address the Data and Safety Monitoring Plan);
• Rapid reporting of treatment-related morbidity information and measures to ensure communication of this information to all relevant parties. For investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP, via the Adverse Event Expedited Reporting System (AdEERS) according to CTEP guidelines specified in each protocol (http://ctep.info.nih.gov/reporting/adeers.html);
• Preparation of study monitoring reports describing patient accrual and demographics, data timeliness, toxicity, and other items as appropriate. Examples of study monitoring reports include reports prepared for study chairs, the biannual reports for Consortium meeting agendas, and reports as required to comply with the Consortium’s Data and Safety Monitoring Plan; and
• Adequate policies and procedures for closure of studies. If the Consortium wishes to close accrual to a study prior to meeting the initially established accrual goal, the interim results and other documentation should be made available to NCI staff for review and concurrence prior to implementation of the decision. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the clinical trial protocol in order to facilitate these decisions. In the event that the study is recommended for early closure for safety reasons, procedures in the Data and Safety Monitoring Plan regarding notification of CTEP must be followed.

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

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

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

a) Evaluation of the performance of Member Institutions in terms of:

• Accrual of adequate number of eligible patients onto Consortium trials;
• Timely and accurate submission of required data;
• Rigorous adherence to clinical trial protocol requirements;
• Participation in study development and in timely publication of study findings; and
• Participation in Consortium administrative and scientific committees and/or other Consortium activities.

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

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

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

d) Procedures for central review of the reliability of the key elements defining the outcome of clinical trials, including such aspects as: claims of therapeutic responses; adequacy of imaging studies, sufficiency of the submitted data to verify protocol compliance in terms of dose administration and dosage modification, etc.

e) On-site Auditing of Consortium Member Institutions: The Consortium’s on-site monitoring program is expected to be coordinated with the CTEP Clinical Trials Monitoring Branch (CTMB) and the Clinical Trials Monitoring Service (CTMS). On-site auditing of Consortium Member Institutions will occur approximately annually, with the timing of audits to be based in part on Member Institution accrual. The on-site audit will address issues of data verification, protocol compliance, compliance with regulatory requirements for the protection of human subjects and investigational agent accountability. The Clinical Research Program, together with Statistics and Data Management Core, will be responsible for providing the CTMS with the accrual and the protocol-specified data needed to conduct institutional audits. Any serious problems with data verification or compliance with Federal regulations must be reported to CTMB immediately. In the event that the NCI determines that a Consortium Member Institution failed to adequately comply with NCI guidelines for conduct of clinical trials, the accrual of new patients to Consortium protocols at the affected institution shall be suspended immediately upon notice of the NCI determination. The suspension will remain in effect until the Consortium conducts the required audit and the audit report or remedial action is accepted by the NCI. The Clinical Research Program will be responsible for notifying any affected participating institution of the suspension. During the suspension period, no funds from this award may be provided to the participating institution for new accruals, and no charges to the award for new accruals will be permitted.

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

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

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

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

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

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

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

3) CTEP Assistance in Clinical Trial Protocol Development: The clinical trial protocol must be a detailed written plan of a clinical experiment mutually acceptable to the Consortium and to the CTEP Protocol Review Committee (PRC). The PRC meets weekly and is chaired by the CTEP Associate Director. Communication at the various stages of protocol development is encouraged as necessary to promote protocol development and implementation.

Submission of clinical trial protocols should be preceded by a written Letter of Intent (LOI) from the Consortium declaring interest in conducting a particular study. The PRC will formally review the LOI. Following review, the NCI Project Scientist will provide the Consortium with a summary evaluation. This evaluation will address such issues as: (a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort; (b) information including relevant pharmacokinetic and pharmacodynamic data concerning investigational agents; (c) availability of investigational agents; (d) the PRC's assessment of the scientific rationale and value of the proposed study, its design, and statistical requirements; (e) appropriate inclusion of NCI Standard Protocol Language for CRADAs and CTAs in the protocol; and (f) the implementation of the study, if indicated. The LOI mechanism is designed to allow for the rapid preliminary review of study concept, facilitate agreement on study priority and design, and expedite the development and implementation of optimized clinical trial protocol (for further details of these mechanisms, see the DCTD Investigator's Handbook at http://ctep.cancer.gov/handbook/).

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

• The strength of the scientific rationale supporting the study;
• The clinical importance of the question being posed;
• The avoidance of unnecessary duplication with other ongoing studies;
• The appropriateness of study design;
• Consistency with development plans for particular IND agents;
• A satisfactory projected accrual rate and follow up period;
• Patient safety;
• Compliance with Federal regulatory requirements;
• Adequacy of data management;
• Appropriateness of patient selection, evaluation, assessment of adverse events, response to therapy and follow up; and
• Methods of monitoring and reporting to NCI to be used.

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

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

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

7) CTEP Involvement in Imaging Research: The NCI Imaging Research Coordinator will advise the Consortium Steering Committee and the NCI Project Scientist with respect to ongoing NCI activities and research opportunities related to the application of imaging in drug development. He/she will participate in CTEP review of Consortium protocols with imaging components and will assist the NCI Project Scientist in the overall review of Consortium imaging research activities and accomplishments.

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

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

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

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

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

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

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

15) Access to Data: The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. Data must also be available for external monitoring as required by NCI's Drug Master File Agreement with the FDA relative to the responsibility of the NCI as an IND agent sponsor. Data from studies of non-NCI sponsored agents must be available for external monitoring as described in the policies and procedures established by the Consortium for onsite auditing of clinical trials data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS and NIH policies. The awardee will comply with the data access provisions of applicable CTAs and CRADAs, and when these agreements are in place the Industry Sponsor will have complete access to the data for any and all regulatory filings.

16) Access to Agents for Pre-Clinical Testing: For NCI-sponsored IND agents, NCI will facilitate transfer of material to investigators with a Materials Transfer Agreement (MTA).

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

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

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

Areas of Joint Responsibility include the following:

The Consortium Steering Committee. The Consortium Steering Committee will consist of the following voting members:

• The overall Consortium PD/PI (who is expected to chair the Steering Committee);
• One representative of from the leadership of each of the Consortium components: Clinical Research Program, Pharmacokinetic/Biology Component, Statistics and Data Management Core, and Imaging Core;
• One representative from each Member Institution;
• One patient/family representative; and

NOTE: Each voting member representing the Consortium will have one vote (including those individuals who may have multiple responsibilities).

The NCI Project Scientist will serve as an advisory member. Other NCI staff may serve as advisory members as appropriate.

The Steering Committee will be responsible for the following tasks:

• Approval of any changes to the Consortium organizational structure and Consortium Standard Operating Procedures
• Establishing priorities for the Consortium clinical trials;
• Providing preliminary approval of clinical trial protocols (prior to submission to NCI and final NCI approval);
• Review progress of clinical trial execution;
• Reviewing on a regular basis the performance of the Clinical Research Program and Statistics and Data Management Core and the performance of the Imaging Core,
• Assuring that deficiencies identified during these reviews are adequately addressed in a timely manner
• Reviewing the performance of Member Institutions;
• Placing on probation and suspending Member Institutions that underperform and/or do not adhere to the requirements defined in the Terms of Award;
• Selecting new Members to replace any members suspended or otherwise eliminated from the Consortium;
• Establishing a process for the selection of the laboratories to perform laboratory studies associated with specific clinical trial protocols; and
• Approving such selections (including the authorization to allocate the Biology/Pharmacokinetics Funds and the Patient Studies Research Funds).

The Steering Committee may form subcommittees as needed.

The Consortium Steering Committee will meet twice per year in person and monthly via phone conference. Some of these face-to-face meetings are expected to be scheduled during the Consortium Scientific Meetings.

Biannual Consortium Scientific Meetings. The Consortium Steering Committee (with logistic assistance of the Clinical Research Program) will co-organize with NCI the twice-yearly Consortium Scientific Meetings. These meetings will generally be scheduled to coincide with COG Group meetings or with a CTEP Early Drug Development Meeting.

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

The annual reports are expected to include:

• A summary of the overall performance of the Consortium and its components in terms of clinical trial protocol development, study monitoring, and complying with Federal regulations;
• Summary data on performance of each Consortium Member Institution, including clinical trial accrual, quality and timeliness of submitted data, and involvement in clinical trial protocol development activities; and
• Research plans, changes in procedures and/or staff, and the proposed budget for the coming year.

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

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

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

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

Malcolm A. Smith, MD, PhD
National Cancer Institute
Telephone: 301-496-2522
Email: Malcolm.Smith@nih.gov

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

Leslie Hickman
Grants Management Specialist
National Cancer Institute
8490 Progress Drive
Suite 400, Room 4085
Frederick, MD 21701
Phone: (301) 631-3009
Fax: (301) 451-5391
E-mail: HickmanL@mail.nih.gov

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

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