Required Application Instructions

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

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

This Funding Opportunity Announcement (FOA) is for Research Programs for in vivo and in vitro testing of the activity of pediatric anticancer drug candidates. These Research Programs are the fundamental part of the Pediatric Preclinical Testing Consortium (PPTC) initiative, which also includes a PPTC Coordinating Center (supported under RFA-CA-14-019). The main goal for PPTC is to develop a rigorous preclinical testing system for pediatric antitumor drug candidates and to generate reliable data that can be used to inform new agent prioritization decisions and, thereby, accelerate the development of more effective treatments for children with cancer.

This FOA invites applications for drug testing Research Programs focused on specific tumor types that are particularly relevant to pediatric oncology. Each application must be for only one type of Research Program from the following four types (more than one type can be proposed but only through separate applications):

• Type A: Research Program for leukemia in vivo testing;
• Type B: Research Program for tumors of central nervous system (CNS) in vivo testing;
• Type C: Research Program for other (non-CNS) solid tumors in vivo testing; and
• Type D: Research Program for in vitro testing.

The PPTC research activities will complement other NCI-supported childhood cancer clinical research programs. The systematic preclinical efficacy and pharmacokinetic-pharmacodynamic testing of novel agents by the PPTC will facilitate the new agent prioritization process of pediatric oncology clinical research programs. The optimized prioritization process should increase the likelihood that agents selected for clinical trials will be efficacious, opening new therapeutic options for more effective treatments for children with cancer.

Effective prioritization of drug candidates is critical to successful childhood cancer drug development. Pediatric drug candidates are generally selected from among agents that are being developed for adult cancers. The latter agents are much more numerous than the small number that can be studied in pediatric clinical trials. Therefore, it is essential to identify through preclinical testing those investigational agents that are most likely to have clinical activity for selected childhood cancers. Such optimized selection can accelerate the pace at which treatments that are more effective than the current ones can be identified and incorporated into standard practice for children with cancer.

The challenges associated with developing new therapies for childhood cancers are distinctive compared to those encountered in developing therapies for the neoplastic diseases of adults. Childhood cancers are rare, the overall cure rate is greater than 80 percent, and event-free survival (EFS) is now 70% or higher for many cancer types. Reflecting these relatively high cure rates, the number of pediatric patients with progressive disease that are eligible for early phase clinical trials is low (compared to the situation for common cancers in adults). The low number of eligible patients is a major challenge to pediatric cancer drug development because it limits the number of new investigational agents that can be clinically evaluated in children with cancer. Furthermore, new anticancer agents are developed primarily for activity against adult neoplastic diseases (e.g., colon, lung, breast, etc.), so that agents with specific activity against childhood malignancies might not be readily identified without additional testing targeted at pediatric preclinical models.

NCI has supported pediatric preclinical testing through a contract mechanism via the Pediatric Preclinical Testing Program (PPTP). Since 2005, more than 80 anticancer agents have been tested under this program. The most promising agents from this testing have been prioritized for clinical evaluation through other NCI-supported clinical oncology programs, including Children Oncology Group (COG) Phase 1 Consortium, the COG Disease Committees, and the Pediatric Brain Tumor Consortium.

Given the significance of pediatric-specific preclinical research for pediatric drug development, the NCI decided to elevate the research aspect of these activities and change the form of support from the contract to cooperative agreement mechanism by creating the PPTC. The activities of individual PPTC Research Programs will be coordinated and integrated by the PPTC Coordinating Center. This reshaping is expected to take greater advantage of the creativity, expertise, and insights of childhood cancer researchers, to optimize the prioritization process, and to facilitate the entry of selected agents into pediatric clinical trials.

Application Types and General Capabilities. PPTC Research Programs may be proposed for either in vivo or in vitro testing but only for specific types of programs defined below. All programs proposed must be only a single type.

Type A: Research Program for leukemia in vivo testing that will be responsible for drug testing on acute lymphoblastic leukemia (ALL) (required) and testing on acute myeloid leukemia (AML)(optional);

Type B: Research Program for tumors of central nervous system in vivo testing that will be responsible for drug testing on CNS tumors, including medulloblastoma, high-grade glioma (including diffuse intrinsic pontine glioma), and ependymoma;

Type C: Research Program for other solid tumors in vivo testing that will be responsible for drug testing on one or more of the following tumors: Wilms tumor, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, neuroblastoma, and others (e.g., rhabdoid tumor, hepatoblastoma, etc.); and

Type D: Research Program for in vitro testing using cell lines representing common pediatric cancers.

The programmatic intention is that all four types of programs will be covered by at least one, or in some situations more, awards.

Applicants proposing any type of in vivo testing programs must be capable of quantitative assessment of tumor regression and time to event for 6 to 10 new agents (or combinations of agents) annually across relevant, well-characterized preclinical models as outlined below. It is expected that all these capabilities and testing will be within a single applicant institution.

All applicants are expected to have substantial expertise regarding the biology and therapeutic opportunities for the tumor types that they propose to study.

Testing Models. Models proposed for in vivo and in vitro testing should be well characterized at the molecular levels to allow relating testing data to specific aspects of childhood cancer biology. For example, comprehensive data are generally expected to be available for gene expression, copy number alterations, and gene mutations (e.g., exome sequencing data).

Xenograft models to be proposed are generally expected to have been established by direct transplantation of human tumor specimens into immunocompromised mice without in vitro culture.

For in vivo leukemia models, the expectation is that the testing methods will mimic systemic disease conditions (e.g., initial tail vein inoculation will be used).

Agent Selection. Individual PPTC awardees will be expected to propose agents for the PPTC testing based on their expertise for the cancers for which they will be responsible. Based on this input, PPTC Steering Committee will determine the prioritized selection of specific agents to be tested by each of the PPTC Research Programs. It is expected that the agents to be tested will generally be obtained from pharmaceutical companies and will most often be agents that have entered or are anticipated to soon enter clinical testing. However, this does not preclude high priority agents developed by academic institutions from evaluation by the PPTC. Testing of agents by the PPTC will be performed under terms of the PPTC model Material Transfer Agreement (MTA). NCI staff members will assist PPTC investigators by negotiating MTAs with respective entities.

Collaboration of Research Programs with Coordinating Center. The PPTC Research Program Awardees will be required to collaborate closely with the PPTC Coordinating Center to be supported under the companion FOA RFA-CA-14-019. PPTC Coordinating Center will be responsible for integrating the activities of the individual PPTC Research Programs to create a functional consortium for pediatric preclinical testing. Specifically, the PPTP-CC will provide administrative coordination, data management and statistical support, as well as Consortium scientific coordination.

Pharmacodynamic (PD) and Pharmacokinetic (PK) Research Fund. PD and PK studies will be included in PPTC testing when considered appropriate by the PPTC Steering Committee. Such testing will be supported by a dedicated PD/PK Fund (to be managed by the PPTC-Coordinating Center).

Depending on the expertise needed for specific PD/PK assays, the PPTC Steering Committee will decide whether specific studies can be conducted by the PPTC investigators or outside collaborators. These outside collaborators may be from the pharmaceutical company supplying the agent when the company has relevant validated assays in place.

PPTC Governance. The PPTC will have a Steering Committee as a collective body responsible for setting general directions for PPTC, including prioritizing agents for evaluation, defining the scope and focus of research plans for agents selected for testing, and approving the general procedures under which the PPTC will operate (for details see Section VI.2. Cooperative Agreement Terms and Conditions).

Program Evaluation

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

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are 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 Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

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

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

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

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

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

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

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

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

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

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

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

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

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

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

The letter of intent should be sent to:

Malcolm A. Smith, MD, PhD
Phone: (240) 276-6087
Fax: (240) 276-7892
Email: [email protected]

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

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

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

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

All in vivo testing as well as all in vitro testing are expected to be conducted within a single institution per application.

All instructions in the SF424 (R&R) Application Guide must be followed. Additional instructions are defined below.

Project Summary/Abstract: Identify clearly the type of PPTC Research Program that is being proposed (from the list of Types A-D as defined in Section I of this FOA).

Other Attachments: Applicants should provide the additional supporting materials indicated below.

Upload these materials as pdf files using file names indicated in the list (these file names will become bookmarks in the application).

• Relevant standard operating procedures for maintaining and testing preclinical models (use file name "SOPs").
• Information on the clinical/demographic characteristics of the models proposed for testing (use file name "Models Demographic Characteristics").
• Information on the molecular characterization of the models proposed for testing, including relevant genomic alterations (SNVs/mutations, copy number gains and losses, etc.) for each of the models (use file name "Models Molecular Characteristics").

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.

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: Specific Sub-Sections A-D that must be included in the Research Strategy are described below. Note that for some sub-sections, instructions differ for Research Programs Types A-C (in vivo testing) versus Type D (in vitro testing).

Sub-section A. Capabilities for Preclinical Testing

• Outline the major strengths and collective capabilities of the leadership and the team that will be responsible for preclinical testing. Explain the overall strategy for testing coordination and quality control, addressing the expectation that all testing is to occur at a single site. Note that if testing in multiple institutions per application is considered, it may be possible only in exceptional circumstances and strong justification must be provided.

Sub-section B. Preclinical Models Proposed

For Research Programs Types A-C (in vivo testing):

• Describe the preclinical models proposed for testing (e.g., xenografts, genetic models, etc.) These models are expected to have a high level of molecular characterization (e.g., gene expression, copy number alteration, and exome sequencing or equivalent), and the molecular characterization should confirm the relevance of the proposed models to clinical specimens for the cancer being studied. For xenograft models, the expectation is that models will generally have been established by direct transplantation into immunocompromised mice without in vitro culture.

For Research Programs Types D (in vitro testing):

• Describe the preclinical models proposed for testing. These are expected to have a high level of molecular characterization (e.g., gene expression, copy number alteration, and exome sequencing or equivalent), and the molecular characterization should confirm the relevance of the proposed models to clinical specimens for the cancers being studied.

Sub-section C. Approach to Preclinical Testing

For Research Programs Types A-C (in vivo testing):

• Describe the overall strategy, methodology, and analyses to be used to accomplish the in vivo testing research objectives.
• Describe the ability to quantitatively assess both tumor regression and time to event in models proposed for in vivo testing. Note that for leukemia models, the expectation is that the testing methods will mimic systemic disease conditions (e.g., through initial tail vein inoculation).
• Based on your experience and current capabilities, explain how the in vivo testing models and methods proposed will allow for the testing of 6 to 10 agents per year for the proposed disease panel(s).

For Research Programs Types D (in vitro testing):

• Describe the overall strategy, methodology, and analyses to be used to accomplish the in vitro testing research objectives.
• Describe the approach to assessing relevant in vitro testing parameters such as IC50 and Ymin (minimum T/C%), including the ratio of final cell number to starting cell number.
• Describe the approach to combination testing and the determination of whether synergy exists for combination.
• Based on your experience, provide the potential throughput of agents and combinations of agents for preclinical testing against the proposed cell line panel.

Sub-section D. Agents (Combinations of Agents) Proposed for Evaluation

For Research Programs Types A-C (in vivo testing):

• Applicants must list three agents (or combinations of agents) for in vivo testing against their proposed tumor panel(s), providing a succinct rationale for why these agents warrant prioritization for testing. The justification should be based on the biology of the models in the proposed panel(s) and on the mechanism of action of the agents. Briefly describe the experimental approach for testing these agents. Note that pharmacodynamic (PD) and pharmacokinetic (PK) studies may be proposed as part of the agent evaluations and that this FOA supports collection of relevant specimens to allow such studies to be conducted. However, the actual PK-PD studies may be performed by researchers within or outside of the PPTC as determined by the PPTC Steering Committee, and these studies may be done collaboratively with the pharmaceutical company supplying the agent when the company has relevant validated assays in place.

For Research Programs Types D (in vitro testing):

• Applicants must propose a screening experiment for a set of agents or combinations of agents using their proposed in vitro testing cell line panel, providing a succinct rationale for the proposed experiment. The rationale should be based on: the biology of the cell lines in the proposed panel; the mechanism of action of the agents to be tested; the potential for the experiments to generate hypotheses that the PPTC in vivo Research Programs can further evaluate; and the potential contribution of the screen results to childhood cancer drug development. Describe briefly the experimental approach for testing these agents. Note that in vitro studies of PD biomarkers may be proposed as part of the screening evaluations and that this FOA supports collection of relevant specimens to allow such studies to be conducted. However, the actual PD biomarker studies may be performed by researchers within or outside of the PPTC as determined by the PPTC Steering Committee, and these studies may be done collaboratively with the pharmaceutical company supplying the agent when the company has relevant validated assays in place.

Sub-section E. Capabilities for Preclinical Testing

For Research Programs Types A-C (in vivo testing):

• Describe team accomplishments relevant to the proposed research and to the in vivo testing panels proposed.
• Explain how this prior experience and existing capabilities support the capability for testing of 6 to 10 agents per year for the proposed disease panel(s).

For Research Programs Types D (in vitro testing):

• Describe team accomplishments relevant to the proposed research and to the in vitro cell line panel proposed.
• Estimate the potential throughput of agents and combinations of agents for preclinical testing against the proposed cell line panel. Justify this estimate by referring, as appropriate, to: previous collective experiences of the team (including skill level of individuals not covered by Biosketches); plans to hire additional personnel; available resources, instrumentation, established infrastructures and procedures, plans for upgrades in such areas, etc.

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 SF424 (R&R) Application Guide, with the following modification:

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

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

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

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

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

See more tips for avoiding common errors.

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

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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.

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

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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?

In addition, specific to this FOA: Are the preclinical models and methodology proposed adequate to meet the requirement for developing robust preclinical data using molecularly defined, clinically relevant models?

Investigator(s)

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

In addition, specific to this FOA: How well does the PD(s)/PI(s) demonstrate an understanding of and ability to apply the principles of preclinical in vivo drug testing (or in vitro drug testing) to childhood cancer drug development as illustrated by their experience and by their application? How well do the PD(s)/PI(s) demonstrate an understanding of the biology and therapeutic opportunities of the specific cancers for which they are proposing to serve as a Research Program? How well does the team assembled by the PD(s)/PI(s) appear suited to implementing a systematic testing program to meet the research objectives of the PPTC?

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?

In addition, specific to this FOA: Given the specific agents proposed for testing by the applicant, what is the potential of the proposed Program for identifying novel agents highly warranting preclinical testing?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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?

In addition, specific to this FOA: Does the proposed approach correspond well to the biology of the cancers on which applicants are focused? Do the preclinical models proposed for testing (e.g., xenografts, genetic models, cell lines) have the requisite level of molecular characterization (e.g., gene expression, copy number alteration, and exome sequencing or equivalent) and does this molecular characterization confirm the likely relevance of the models to the clinical setting? For in vivo xenograft models, have these primarily been established by direct transplantation into immunocompromised mice without prior in vitro culture (or subsequent use of in vitro culture for passaging)? Does the approach follow sound principles of oncology drug development? For in vivo Research Programs, does the applicant provide an appropriate approach to preclinical testing that allows quantitative assessment of both tumor regression and time to event (for in vivo Research Programs)? For in vitro testing Research Programs, does the applicant describe an appropriate approach to preclinical testing that allows determination of all relevant in vitro testing parameters? For in vivo Research Programs for leukemia, do the in vivo testing procedures mimic systemic disease conditions? To what extent does the approach proposed by the applicant support the ability to complete testing of 6 to 10 agents per year against their in vivo testing panels? Based on the information provided, how likely are the applicants to successfully implement their proposed testing strategy as part of the PPTC?

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

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?

In addition, specific to this FOA: For in vivo Research Program applications, are the applicant's facilities to house and maintain a rodent colony sufficient for the type and quantity of rodents proposed? For in vitro testing Research Program applicants, are the tissue culture facilities/equipment suitable for the scope of in vitro testing proposed?

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

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

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

Not Applicable

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

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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.

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

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

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

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

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

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR 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.

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

Defining the scientific objectives and approaches and providing oversight of all scientific activities of individual Research Programs. Specific responsibilities are listed below.

Responsibilities of the PPTC Research Program PD(s)/PI(s) will include:

• Membership on the PPTC Steering Committee: The PD(s)/PI(s) of each Research Program will serve on the PPTC Steering Committee. Research Program PD(s)/PI(s) will contribute to the identification of agents for testing and the development of research plans based on their disease expertise for the tumor panel for which they are responsible.
• Participation in the interpretation of testing results, in preparing study reports, in proposing additional testing based on results from initial testing, and in co-authoring manuscripts under the direction of the PPTC-Coordinating Center and as per the PPTC SOPs.
• Compliance with the PPTC Standard Operating Procedures (SOP), as developed by the PPTC Steering Committee.
• Performance of toxicity testing of agents as needed to identify the appropriate dose of the test agent for efficacy evaluations. Such testing typically involves 3 to 5 animals per dose level.
• Performance of the testing of agents prioritized by the PPTC Steering Committee with submission of results to the PPTC-Coordinating Center (anticipate 6 to 10 agents per year for in vivo testing for each disease panel). Testing results must be electronically submitted to the PPTC-Coordinating Center for analysis and archiving.
• Performance of dose-response testing as appropriate for agents with activity in initial fixed dose testing that are prioritized by the Steering Committee for further evaluation.
• Collection of timed blood and tissue specimens for PK and PD studies.
• Performance of pharmacodynamic testing for selected agents prioritized by the Steering Committee for such evaluations.
• Performance of regular identity testing of cell lines and xenografts.
• Ensuring that molecular characterization data for PPTC preclinical models are available to the investigator community.
• Annual Progress Reports: Submission of annual progress reports to the NCI that describe activities and accomplishments during the previous year of the PPTC-Coordinating Center.
• Cooperation with NCI for the conduct of periodic external evaluation of the PPTC program.

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

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

A designated NCI Program staff member serving as Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members may also become substantially involved as needed.

All the substantially involved NCI staff members (i.e., Project Scientists) will not attend peer review meetings of renewal or supplemental applications. If such participation is essential, these individuals will seek a waiver according to the NCI procedures for management of conflict of interest

Main responsibilities of substantially involved NCI staff members include the following:

• Negotiating Material Transfer Agreements (MTAs) with pharmaceutical companies: The Regulatory Affairs Branch (CTEP, NCI) will negotiate MTAs with pharmaceutical companies to allow testing of agents by the PPTC. MTAs will be based on the PPTC Model MTA template (see below).
• Serving as a scientific resource with respect to other ongoing NCI activities that may be relevant to the Consortium research efforts to identify promising new research avenues, to facilitate compatibility with other NCI research projects, and to avoid unnecessary duplication of effort.
• Assisting awardees by reviewing their research plans prior to submission to pharmaceutical companies and reviewing PPTC manuscripts prior to submission for publication.
• Advising awardees regarding mechanisms for ensuring appropriate quality control of preclinical testing.
• Meeting at least once per year with the Consortium (in addition to regular conference calls and electronic communications) to address issues related to Consortium research.
• Participating in the Activities of the Consortium Steering Committee and its Scientific Meetings: The NCI Program Director and other selected NCI staff (e.g., from the Investigational Drug Branch, the Clinical Investigations Branch, and the Developmental Therapeutics Program) will be members of the Consortium Steering Committee (see below) and will attend the Consortium meetings to discuss relevant scientific information, to discuss progress in preclinical testing, and to discuss the status of newly available investigational agents and other research opportunities in order to plan future activities.
• Reviewing compliance with Federally mandated regulatory requirements.
• Monitoring Consortium progress: Actions necessary for monitoring may include, but are not limited to, the following: regular communications with the PPTC PD(s)/PI(s) and staff, periodic site visits for discussions with awardee research teams, fiscal review, review of study 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.
• Integrating the efforts of the PPTC with other NCI-supported programs for children with cancer (e.g., COG, the COG Phase 1 Consortium, and the Pediatric Brain Tumor Consortium). NCI staff will organize regular meetings with leaders of these groups (at least two times a year) to confidentially review PPTC results so that clinical application of these results can proceed in a timely manner.

NCI will have access to all data generated under this cooperative agreement and may review the data as necessary. 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 MTAs, and when these agreements are in place the Industry Sponsor will have complete access to the data for any and all regulatory filings.

Agents tested will be provided by pharmaceutical collaborators and academic investigators under MTAs based on the provisions of a standard Model MTA ( http://ctep.cancer.gov/MajorInitiatives/Pediatric_Preclinical_Testing_Program.htm).

The NCI reserves the right to adjust funding, withhold, suspend, or terminate the support to the PPTC awardee institution if it is unable to meet the performance requirements set forth in these Terms and Conditions of Award, or significantly change the level of performance.

An NCI Program staff member, 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 PPTC 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 PPTC Steering Committee will serve as the body for prioritizing agents for evaluation by the PPTC, for defining the scope of research plans for agents selected for testing, and for approving the general SOPs under which the PPTC operates. The Steering Committee will include: the PD(s)/PI(s) of the PPTC-Coordinating Center and the PD(s)/PI(s) of each of the Research Programs, the NCI Program Director, and representatives from the CTEP Investigational Drug Branch, the CTEP Clinical investigations Branch, and the NCI Developmental Therapeutics Program.
• The Steering Committee may establish sub-committees for specific purposes. The NCI Project Scientists will serve on such sub-committees, as they deem appropriate.
• The Steering Committee is expected to form an Advisory Panel as a sub-committee. The Advisory Panel should include as members pediatric oncologists and preclinical testing experts, who are unaffiliated with the PPTC. The Advisory Panel should meet at least in Year 2 and Year 4 to formally review the progress of the PPTC.
• On-site Auditing of Research Programs: The PPTC’s Research Program awardees will be visited at least one time during the 5-year award period, with a site visit occurring during the first 18 months of funding. Testing procedures, data management, records maintenance, and animal care facilities will be reviewed. The site visits will be coordinated by the PPTC-Coordinating Center with NCI input.

Dispute Resolution:

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

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

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

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

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

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Contact CenterTelephone: 800-518-4726
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GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: [email protected]

Malcolm A. Smith, MD, PhD
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]

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.