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

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

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) solicits applications for PDXNet Data Commons and Coordinating Center (PDCCC) that will interact with and coordinate with the PDX (Patient-Derived Xenograft) Development and Trial Centers Research Network (PDXNet) which will be comprised of four PDX Development and Trial Centers (PDTCs; supported by a companion FOA, RFA-CA-17-003 ) and the PDCCC in a collaborative network. The PDXNet is an NCI program that will use advances in patient-derived models (PDMs), with a focus on patient derived xenografts (PDXs) in which advanced molecular characterization will be applied to identify active combinations of targeted agents, and the molecular characteristics of tumors most likely to respond to these combinations, for subsequent testing in early phase clinical trials.

Each PDTC will encompass a research program with PDX development and PDX drug response experience, and bioinformatics expertise. The PDCCC will help to organize these individual PDTCs into the coordinated PDXNet network, by facilitating network interactions and collaborations, establishing and maintaining bioinformatics and data analysis platforms, providing the mechanisms for sharing PDXNet data with the larger scientific community, and coordinating participation in cross-PDXNet pilot projects. In addition, PDXNet and the PDCCC will be expected to collaborate closely with the NCI Patient-Derived Models Repository (PDMR) at the Frederick National Laboratory for Cancer Research (FNLCR). Through these collaborative efforts, PDXNet can accelerate the integration and translation of important research findings generated from pre-clinical PDX models to benefit cancer patients.

Key Terms for this FOA:

Patient-derived xenografts. The term patient-derived xenograft or "PDX" refers to cancerous tissue from a patient's tumor that is implanted directly into an immunodeficient animal (usually mouse).

PDX trials. A "PDX trial" is a controlled experiment where drug and drug combinations are administered to mice bearing PDX s, and where the outcome is the response of the tumor to the therapy. In a large-scale PDX trial, the molecular characterization of the PDX models is used to identify potential biomarkers of response to the regimen.

PDX development. The development of PDX models can include steps from the tumor cell acquisition from the patient through the original implantation in the host through characterization of the tumor in successive passages. PDX development can also include using PDX material for in vitro assays to improve the efficiency of determining promising regimens for in vivo studies.

Clinical validation. PDX trials are expected to identify drug combinations that are active against molecularly-defined subsets of tumors. The clinical validation of PDX experimental results requires a human study where the patients tumor has the biomarker(s) that match those of the responsive PDX model(s), and where the drugs and schedule of administration closely match the PDX trial. The clinical study determines whether the PDX biomarkers actually help identify patients who will benefit from the PDX drug combination.

Use of PDX Models for Translational Cancer Research. PDX models represent an emerging platform for translational cancer research. When properly derived from original biospecimens and properly maintained, PDX models more accurately represent human cancers than established cancer cell lines. Therefore, testing anticancer agents in PDXs may be more accurate in predicting the response of patients' tumors to these agents in the clinic than traditional testing in established cell lines. In addition, advances in genomic sequencing technology and bioinformatics make it possible to extensively characterize each PDX model. By combining advances in the establishment of PDX models and in the depth of molecular characterization, PDXs could be used to identify the optimal combination therapy for increasingly smaller groups of more precisely defined cancers (i.e., addressing the emerging goals of the precision cancer medicine).

As both the number of experimental anticancer agents and the number of recognized tumor sub-types grow larger, the paradigm of conducting Phase 1 studies followed by Phase 2 studies of each promising drug combination on each tumor subset becomes prohibitive, both in terms of cost and practicalities of patient accrual. Cancer precision medicine requires new effective ways to match the sub-types of patients' tumors (that can be precisely characterized at molecular levels) to available cancer therapeutic agents (which increasingly often act on specific molecular targets). PDX models have the potential to facilitate this matching as they can be used in multiple tumor models against multiple therapeutic drug combinations.

By using PDX’s in multiple pre-clinical clinical trials that test numerous agent combinations against numerous extensively characterized human tumors, evidence-based guidance could be obtained on the most promising combinations to test in defined sub-populations of cancer patients. To realize this promise, research is needed on the optimal ways to integrate PDX drug response data with the vast molecular characterization data that are available for most PDX models. Such research, to optimally mimic human cancer heterogeneity, should use large-scale collections of PDX models to increase the likelihood that PDX-based predictions of clinical responses are reflective of the complexities of individual patients' cancers.

Challenges of PDX Models. Most PDX models are currently being developed in many isolated programs in institutions across the country, creating the situation where there is little standardization of procedures or the possibility of validating and replicating results. In addition, these isolated PDX collections are not large enough to sufficiently reflect the diversity of clinical tumors needed to provide the evidence basis for clinical trials of drug combinations in molecularly-defined cancers. Therefore, there is a need for a coordinated and collaborative research effort for large-scale development of PDXs using standardized procedures and rigorous model validation approaches to advance the clinical development of new anticancer agents.

The primary goal for the PDXNet will be to develop appropriate PDX models and methods for preclinical testing of single agents and drug combinations. These models should allow the determination of the optimal treatments (single drugs or combinations) that should be tested in clinical trials in increasingly smaller, molecularly-defined subsets of tumors. The proposed PDCCC must be able to contribute meaningfully to the overall goal for the entire PDXNet, and will be expected to directly address the challenge of precision cancer medicine how to prioritize the clinical testing of many targeted agents in many tumor subtypes.

It is also the goal of the PDXNet to develop drug combinations in defined tumor subsets in a context that can feasibly lead to clinical validation of the experimental results. Therefore, this FOA has an emphasis on NCI-IND agents that are primarily used by the Experimental Therapeutics Clinical Trials Network (ETCTN). By focusing PDXNet trials on these agents, there is a ready-made path to clinical development should the PDXNet experiments provide clinical leads that merit exploration. When NCI-IND agents are included in drug combinations in the PDTC research plans, NCI will be able to provide the ETCTN clinical platform for testing and clinical validation of the pre-clinical research results of the PDTC investigators to determine if the PDXNet research results can be translated into clinical benefit. Through the NCI Experimental Therapeutics (NExT) program, NCI s Division of Cancer Treatment and Diagnosis (NCI/DCTD) has formed collaborations with pharmaceutical companies and academic medical centers to develop over sixty anticancer agents. These agents are brought into clinical trials through the ETCTN, a network of early phase clinical trial sites supported by a centralized clinical trial infrastructure that is devoted to the conduct of early clinical studies of NCI-IND agents.

Research to be conducted by PDXNet may also include agents that are not under NCI-IND. However, since these agents will not have the ready-made path via the ETCTN to clinical development, they will require a clear and feasible strategy for the translation of PDX research results into novel clinical trials, so that the ultimate goals of the PDXNet can be fulfilled.

Role of Patient-Derived Models Repository at the FNLCR. Central to the creation of the PDXNet is the role of the NCI PDMR-FNLCR. This facility is developing PDX models from samples obtained from across the nation, with the goal of creating a large, genetically characterized PDX bank that will be shared with investigators to facilitate PDX research. PDTC investigators will be expected to deposit PDX models developed with PDMR-FNLCR so that these models can be shared with the wider research community. To facilitate collaborative interactions within the PDXNet, the PDMR-FNLCR staff will help to coordinate the development of Standard Operating Procedures (SOPs) both for PDX development and PDX drug response testing in the network, and will approve the SOPs to be used in PDXNet.

The proposed PDCCC must meet the following main attributes (for additional details on the requirements, please see Section IV. Application and Submission Information):

(A) Overall Role. The PDCCC will have an important role in integrating the effort of individual PDTCs. The Coordinating Center should provide administrative and logistic support for the PDXNet program and be able to connect available resources as well as serve as the network data management center. The PDCCC will be expected to interact with the PDTCs and coordinate various trans-Network activities, e.g., to standardize (as appropriate and needed) approaches, procedures, data formats, etc., and/or to minimize resources/effort duplication.

(B) Leadership and Administration. The Coordinating Center must be able to provide close coordination of trans-network and trans-disciplinary research conducted by the PDTCs. This role will require strong leadership, scientific oversight, and managerial capacity to bring diverse teams together.

(C) Bioinformatics. The Coordinating Center must be able to provide bioinformatics and biostatistics expertise suitable for the analyses and integration of complex biological data from multiple experimental platforms and other sources. The data to analyze will include: clinical data for cancer patients, whose tumors were used to derive individual PDX models, various molecular characterizations of PDX models, and PDX treatment response data collected at the PDTCs. It is expected that the PDCCC will serve the key role in PDXNet by integrating the findings of individual PDTCs and distilling them into actionable recommendations for the design of specific clinical trial (which will ultimately be developed and conducted by other NCI-supporting programs interacting with PDXNet).

Governance of the PDXNet

The PDXNet (i.e., PDTCs and PDCCC) will be governed by the PDXNet Steering Committee. Details on the composition and functions of PDXNet Steering Committee are provided in Section VI.2, Administrative and National Policy Requirements, Cooperative Agreement Terms and Conditions.

Evaluation of the PDXNet Program

PDXNet awardees will be expected to participate in an external evaluation process that will be coordinated by the NCI Scientific staff. This evaluation will largely be based on the overall progress towards achieving the scientific goals of the entire PDXNet Program.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not 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.

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

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

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

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

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

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

The letter of intent should be sent to:

Jeffrey A. Moscow, M.D.
National Cancer Institute (NCI)
Telephone: 240-276-6101
Email: jeffrey.moscow@nih.gov

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.

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

Facilities and Resources: Describe infrastructure to support the PDCCC, including specifically information technology systems, data storage systems, and capacities, etc..

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

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

The budget should include:

• PD/PI Effort Commitment. Any PD/PI (whether designated as contact or not) must commit a minimum of 1.2 person-months effort per year to the award. This commitment cannot be reduced in later years of the award. Note that this is a minimum effort level that should be increased as appropriate to meet the needs of the work.
• The budget request should account for the efforts of statistician, computer scientist and data collection in the PDCCC. There are no restrictions on these effort levels but they should be well justified in the context of the PDCCC needs.
• The budget request may include the costs of additional computational hardware, software and data storage upgrade costs if necessary to meet the needs of PDXNet. However, such upgrade items must be well justified and their combined costs must not exceed $35,000 in any year of project period. Capital equipment (i.e., with unit cost over $5,000) is not allowed.
• The budget should also include travel funds for PD/PI and other senior investigators (up to three people) to attend the annual Network meetings and participate in other network-related activities

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: Instead of standard sub-sections, Research Strategy must consist of the following sub-sections A, B, and C.

Sub-section A. Overall Vision of the Proposed Data Commons and Coordinating Center

In this sub-section, address the following strategic goals:

• The scientific vision of the proposed PDXNet Data Commons and Coordinating Center;
• Major strengths and critical experience of the research team particularly in coordinating multi-disciplinary and multi-institutional programs (explain collective strengths without repeating information in individual biosketches);
• Innovative aspects of the Center and its potential for coordinating the trans-disciplinary research conducted through the entire PDXNet program;
• The proposed organization and staffing of the PDCCC, how the key personnel will interact and ensure efficient cooperation, communication and coordination across the PDCCC, PDTCs, and with NCI and PDMR-FNLCR; and how the proposed organization will create an integrated entity capable of effectively providing scientific, infrastructure and administrative support for the PDXNet and facilitating the Network s objectives.
  
  

Sub-section B. Leadership and Administration Unit

In this sub-section, address the following aspects:

• The structure and organization of the Administrative Unit;
• Plans for administrative support for the trans-network collaborative pilot projects, including proposed procedures for solicitation, review, selection, and oversight of such pilot projects;
• Plans for providing logistical support for the Steering Committee and its sub-committees, working groups (the plan should include co-organizing with the NCI the annual Steering Committee meeting and logistical support for other meetings, teleconferences, etc., as needed); and
• Plans for other logistical/administrative support that may be needed for the activities of PDXNet.

Sub-section C. PDXNet Data Commons

In this sub-section, address the following strategic goals:

• Establishing and operating a centralized data collection, management, analysis, and dissemination unit for the entire network to support the PDXNet. This includes the capacity for setting-up a database that collects PDX demographic data, molecular characterization data and drug response data across the network. The data must also include information about the regulatory approvals of specimen collections and the level of informed consent;
• Establishing plans for the analysis of complex data from multiple sources, including molecular characterization of PDX models used in consortium trials and response data collected at the PDTC s. The plan should include a description of how generated data will be distilled into recommendations for clinical trial designs
• Establishing procedures that would allow for efficient sharing of PDX models and/or associated data for collaborative research studies across PDXNet as well as with outside investigators as appropriate and consistent with achieving the goals of the program. The procedures should address the process for review and approval of requests for access to the specimens and/or data. The procedures should also describe the tracking and distribution of available specimens to investigators, consistent with achieving the goals of the program.

The description must include the following specific aspects:

• Plans to develop a secure internet-accessible interface for the PDXNet where each participating PDTC can deposit molecular profiling data and PDX preclinical trial data in a standardized format with the required data elements provided for trans-network collaborative projects;
• Plans to integrate or adapt existing bioinformatics datasets and data platforms (e.g., genomics, proteomics) for application in the participating site efforts with sharing of tools with individual sites, as appropriate;
• Plans to integrate network data for PDX model characterization with the PDMR-FNLCR database (SQL, that is currently under construction)--describe, for example, how PDX data and associated clinical data will be transferred to the PDMR-FNLCR database;
• Plan to work with the PDMR-FNLCR and the PDTCs to ensure there are uniform approaches to molecular profiling data standardization to enable data sharing among PDXNet participants
• Plans to create new approaches for connections across data types, including various Omics data (e.g., genomics, proteomics);
• Plans to develop strategies to provide access to all curated data from the participating sites for sharing with the larger research community.

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

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

Appendix:

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

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

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

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 proposed Center address the needs of the PDXNet research network that it will coordinate? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the PDXNet research network]?

Specific to this FOA: Will the Center, as proposed, play an important role in integrating the effort of individual PDTCs?

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing similar research? Do the investigators demonstrate significant experience with coordinating collaborative translational research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach and organizational structure appropriate for the Center? Does the applicant have experience overseeing selection and management of subawards, if needed?

Specific to this FOA: Have the PD(s)/PI(s) demonstrated experience and an ongoing record of accomplishments in managing multi-institutional cancer research? Do the investigators demonstrate significant experience with multi-disciplinary and/or multi-institutional programs related to preclinical cancer models and/or anticancer drug testing/development?

Innovation

Does the application propose novel, effective organizational concepts or management strategies, in coordinating the research of PDTCs that the Center will serve? Are the concepts, strategies, or instrumentation novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts or management strategies proposed?

Specific to this FOA: Does the application propose effective and innovative concepts or strategies for managing data flows and data analytics in coordinating the PDXNet research? How creative are the proposed approaches in terms of ability to efficiently engage Network participants, efficiently implement centralization and standardization of data collection components, etc.? Do the applicants propose novel and effective ways of coordinating, acquiring, curating, and packaging PDXNet data for research use, as well as allowing access for research?

Approach

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the PDXNet research that the Center will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the PDXNet, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the resource is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the resource? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects?

Specific to this FOA: Have the investigators presented adequate plans to address relevant biological and technical variables inherent in early-passage patient derived xenograft models across multiple sites?

Environment

Will the institutional environment in which the Center will operate contribute to the probability of success in facilitating the PDXNet research network/consortium it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

Specific to this FOA: How sufficient are resources available to support bioinformatic needs for data storage and data analysis activities expected for the PDXNet?

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.

Leadership and Administration Unit

Are the research infrastructure, programs, and collaborations adequate to support the PDTCs? Is there adequate evidence for the managerial and collaborative capabilities of the proposed Coordinating Center leadership? How appropriate is the leadership structure of the proposed Coordinating Center in terms of (a) the overall goals of PDXNet program; (b) the coordination of multiple institutions participating in the PDXNet; and (c) understanding and familiarity with the state of the science in this field of research? Given the administration infrastructure proposed, what is the likelihood that PDCCC will have sufficient capabilities to efficiently collaborate and interact with the PDTCs, FNLCR and NCI program staff on scientific progress, peer-reviewed publications, web sites, evidence-based dissemination, or new collaborations and partnerships?

Bioinformatics Unit

How appropriate and balanced are the proposed plans to create the PDX Data Commons? Does the Coordinating Center have the capacity and expertise for establishing and managing a database that collects PDX characterization (including clinical annotation and molecular characterization) and treatment response data of all PDX models used in the PDXNet program at all participating sites? Are the plans well justified and include appropriate safeguards for privacy and confidentiality protections of identifiable data? Does the plan describe a program that will efficiently support the sharing of specimens and information across the PDXNet as well as access by extramural collaborating investigators as appropriate and consistent with achieving the goals of the program? Does the plan enable the tracking and distribution of available specimens to investigators, consistent with achieving the goals of the program? Does the plan include strategies to integrate or adapt existing bioinformatics tools and data platforms (e.g., genomics, proteomics) for application in the participating site efforts with sharing of tools with individual sites?

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

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

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

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

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

Not Applicable

Not Applicable

Not Applicable

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

Not Applicable

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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

• Determine the PDCCC’s directions, coordinate research approaches and procedures, and oversee the analyses and interpretation of research data;
• Oversee the timely release and sharing of specimens and data according to the approved plans;
• Participate in the development and evaluation of pilot projects, cross-PDXNet Projects, and cross-PDXNet activities that will cross-test novel projects;
• Serving as a voting member on the PDXNet Steering Committee, including participation in annual meetings, and periodic conference calls, etc.;
• Cooperate with NCI Project Scientists in the program evaluation process;
• Accept and implement all scientific and practical decisions approved by the PDXNet Steering Committee to the extent consistent with applicable grant regulations;
• Provide information to the NCI Program Directors concerning progress by submitting annual progress reports in a standard format;
• Prepare for administrative site visits by NCI staff members;
• Take advantage of collaboration with other NCI and NIH initiatives and programs, as appropriate for advancing the Center research and the PDXNet program;
• The PDCCC and the entire PDXNet program will be subject to periodic performance evaluation (coordinated by the PDXNet Steering Committee Chair) and external evaluation (coordinated by the NCI)--PDXNet Awardees will be expected to participate in these evaluations;
• 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 HHS, PHS, and NIH policies;
• The PDCCC will be expected to share with the PDXNet program knowledge, specimens, data, research materials, and any other resources necessary and relevant to the PDCCC award.
• Participate in the evaluation of applications from outside investigators for access to resources in PDXNet centers, and collaborate with funded investigators when appropriate;
• The PDCCC is expected to operate under SOPs developed by the consortium in collaboration with PDMR-FNLCR to ensure reproducibility and comparability of data between consortium centers--SOPs will include methods for the development of PDX models and for testing anticancer agents in these models; and
• PDs/PIs are expected to conform with all human subjects research guidelines, including ensuring that consent forms allow for PDX model development and sharing of data or indicate willingness to add language into existing protocols for research specimen collection.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
The designated NCI Program staff members will have substantial involvement as Project Scientists in the awards under this FOA. The specific roles of the substantially involved NCI staff members include the following activities:

• Serve as the NCI lead Project Scientists and voting members of the PDXNet Steering Committee;
• Assist in avoiding unwarranted duplications of effort across the PDXNet program;
• Help coordinate collaborative research efforts that involve the PDCCC and the multiple PDTCs;
• Monitor the operations of the PDXNet PDCCC and make recommendations on overall project directions and allocations of funds;
• Review the progress of PDCCC and specific activities shared among the Research Centers and Coordinating Center;
• Participate in the development and evaluation of cross-PDXNet Projects;
• Co-organize and participate in the annual PDXNet Steering Committee meeting;
• Participate as Collaborators of the PDXNet investigators in some shared activities, if appropriate;
• Assist the PDXNet awardees as a liaison in stimulating their broader interactions with other NCI and NIH programs to disseminate results and outcomes and effectively leverage existing NIH/NCI resources and infrastructures;
• Provide clinical background on agent clinical development to guide the development of PDX trials;
• Provide a liaison between PDXNet investigators and investigators in the ETCTN to facilitate translation of PDXNet research results into clinical trials
• NCI staff at FNLCR will receive, analyze and characterize PDX models received from PDX Network investigators;
• NCI staff at FNLCR will coordinate the development of SOPs to be used by PDX Network investigators; and
• Evaluate the adherence of PDXNet awardees to approved resource sharing plans.
• A 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.

Areas of Joint Responsibilities include:

The PDXNet Steering Committee will serve as the main governing board of the PDXNet program.

The committee will consist of the following voting members:

• The PD(s)PI(s) of each awarded PDTC who will collectively have one vote;
• The PD/PI of the PDCCC and a designated senior investigator who will collectively have one vote;
• The NCI/CTEP Project Science Officer(s) who will collectively have one vote representing CTEP/NCI; and
• The NCI/PDMR/FNLCR liaison who will have one vote.

The PDXNet Steering Committee will meet at least one time per year in a face-to-face meeting. A chair of the PDXNet Steering Committee will be selected at the first meeting to coordinate the committee's operation. The PDXNet Steering Committee chair will meet by teleconference with NCI Project Scientists as needed to address program issues.

Additional non-voting members who can serve in an advisory capacity may be added to the PDXNet Steering Committee as needed by a decision of the existing voting committee members. These additional non-voting members may include other NCI and NIH Program Staff members and/or Program Staff members from other Federal agencies.

The PDXNet Steering Committee will have the following primary responsibilities:

• Oversee the overall PDXNet program and review its research progress;
• Review the potential of shared support infrastructure(s) at individual PDTCs to serve the needs of other PDTCs and the entire program;
• Develop procedures for soliciting and evaluating ideas for pilot projects across the PDXNet as well as criteria for their prioritization and approval;
• Ensure that the PDTCs and the PDCCC take advantage of existing NCI and NIH resources and programs;
• Make recommendation for termination of pilot projects that become unpromising or unproductive;
• Participate in the development of the agenda for the annual Steering Committee meeting to present scientific progress and future plans from PDXNet investigators.
• Coordinate the PDXNet evaluation of applications from outside investigators for access to resources in PDXNet centers, and coordinate collaborate with funded investigators when appropriate;
• Establish advisory groups as necessary to ensure the progress of individual Research Centers as well as of the entire PDXNet program;
• Ensure that individual PDXNet members (i.e., PDTCs and PDCCC) accept and implement as appropriate actions (recommendations, directions, etc.) approved by the PDXNet Steering Committee; and
• The PDXNet Steering Committee with conduct performance evaluation of the PDTCs and the PDCCC. The purpose of this endeavor (to be coordinated by the PDXNet Steering Committee Chair) will be to monitor progress and provide feedback to individual PDTCs. Such feedback will facilitate optimization of various aspects of the program and implementation of corrective actions if needed. The overriding goal will focus on identifying approaches to translational research that could not be achieved by individual investigators working separately and, thereby, increasing the likelihood for significant scientific advances.

Dispute Resolution:

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

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

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

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

Email: support@grants.gov

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

Telephone: 301-710-0267

Jeffrey A. Moscow, M.D.
National Cancer Institute (NCI)
Telephone: 240-276-6101
Email: jeffrey.moscow@nih.gov

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

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

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

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