NIH's new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically using ASSIST or an institutional system-to-system solution; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

It is critical that applicants follow the Multi-Project (M) 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) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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 Minority Patient-Derived Xenografts (PDX) Development and Trial Centers (M-PDTCs) to join the PDTC Research Network (PDXNet). PDXNet will encompass four PDTCs (awarded under RFA-CA-17-003), a single PDX Data Commons and Coordinating Center (PDCCC) (awarded under RFA-CA-17-004) and two M-PDTC (to be supported by this FOA).

The purpose of the M-PDTCs is expand and diversify the PDXNet, with a required focus upon development and pre-clinical testing of models derived from racial/ethnic minority populations.

M-PDTCs will encompass a research program with demonstrated expertise in

• Cancer health disparity research;
• PDX development;
• PDX drug response testing; and
• Bioinformatics;

Each M-PDTC will be supported by critical cores, including a PDX core, and strong organizational oversight to enable the investigation of novel research questions, development of important resources and models, and outreach to the larger, diverse scientific community.

Alongside PDTC, the M-PDTCs will also be assisted by the PDXNet Data Commons and Coordinating Center (PDCCC) for network interactions and collaborations, bioinformatics, and participation in cross-PDXNet pilot projects. In addition, M-PDTCs will be expected to collaborate closely with the NCI Patient-Derived Models Repository (PDMR) at the Frederick National Laboratory for Cancer Research. M-PDTCs will be expected to incorporate their well-characterized PDX models and optimized standardized procedures available from PDMR into their research programs.

It is anticipated that the collaborative efforts within the PDXNet, concurrent with the focus on racial/ethnic diversity within the M-PDTCs, will benefit cancer patients through optimized integration and translation of data from pre-clinical testing of PDX models.

Patient-derived xenografts (PDX). The term "patient-derived xenograft" 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 can help identify patients who will benefit from the PDX drug combination.

Racial/ethnic minority populations: Populations having the following racial or ethnic backgrounds: American Indian/Alaska Natives, Asians, African Americans, Native Hawaiians/Pacific Islanders, and Hispanic/Latinos.

Cancer Health Disparities. Cancer health disparities are defined by NCI as adverse differences in cancer incidence, prevalence, mortality, survivorship, and burden of cancer or related health conditions that exist among specific population groups in the United States. These disparities represent a major public health concern and have been identified for numerous cancer types. Despite these well-defined cancer disparities, racial and ethnic minority populations remain underrepresented in therapeutic clinical trials. The lack of diverse representation makes it difficult to assess whether the efficacy of cancer therapies is the same, similar, or different for various patient populations. Since a growing body of evidence suggests that biological and genetic factors may contribute to cancer health disparities, increased quantity and quality of available preclinical tools would be valuable to address therapeutic outcome disparities.

PDXNet. The PDXNet is a National Cancer Institute (NCI) program designed to advance the use of patient-derived models in the development of new anticancer agents. The outcomes for the PDXNet are expected to facilitate the optimized design of early phase clinical trials for such agents. For more information on this program see RFA-CA-17-003 and RFA-CA-17-004.

Use of PDX Models for Translational Cancer Research and Cancer Health Disparities. PDXs offer more accurate representations of human cancers than established cell lines and have potential to improve the pre-clinical evaluation of novel anticancer therapies. When properly derived and used, PDX collections can provide the foundation for representative tumor screening platforms to test anti-tumor activity of single agents and drug combinations. In addition, PDXs may be useful in comparing molecular characteristics or tumor signatures between patients, which could be informative not only to evaluating therapeutic responses but also to elucidate biological determinants of cancer health disparities. Unfortunately, PDX models derived from racial/ethnic minority populations are rare.

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). Critical to the success of these efforts is the adequate and diverse representation of racial/ethnic minority populations. Failure to accurately capture these populations within ongoing precision medicine efforts could increase the existing gap and accentuate disparities in cancer outcomes. As such, improved diversity among newly generated cancer models, and inclusion in early phase clinical studies, is a critical need.

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.

The primary goal for M-PDTC investigators will be to develop PDX trial strategies for preclinical testing of single agents and drug combinations, with a focus upon racial/ethnic minority populations. These models are intended to allow determination of optimal treatments (single drugs or combinations) that should be tested in clinical trials in increasingly individualized, molecularly-defined subsets of tumors.

The M-PDTCs must contribute meaningfully to the overall goals of the 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.

In addition, M-PDTCs must be distinctly focused on the use of PDX models for cancer health disparity-relevant issues. Accordingly, to be responsive, applications must conform to several cancer health disparity-related requirements. The major requirements in that context pertain to:

• Scientific focus: At least one of the two required research projects (defined below) must address a cancer health disparity-focused hypothesis to elucidate therapeutic outcome disparities; and
• Model Development: PDX models to be developed must be primarily derived from patients representing racial/ethnic minority populations. Applicants should attempt to achieve no less than 60% level and a programmatic priority may be given to M-PDTCs that will have particularly high proportion of minority patient-derived PDX models.

The M-PDTCs will have a goal to assess efficacy of drug combinations in defined tumor subsets in a context that can feasibly lead to clinical validation of the experimental results. Therefore, M-PDTCs will be required to concentrate 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 (60) 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.

The research proposed in response to this FOA 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 NCI's Patient-Derived Models Repository (PDMR). The PDMR is a central component of the PDXNet. This facility, housed with the Fredrick National Laboratory of Cancer Research, 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. M-PDTC investigators will be expected to deposit PDX models generated using this funding within the PDMR so that these models can then be shared with the wider research community. To facilitate collaborative interactions within the PDXNet, the PDMR staff will help to coordinate the development of SOPs both for PDX development and PDX drug response testing in the network, and will approve the SOPs to be used in PDXNet.

All proposed M-PDTCs must have the following characteristics:

Overall Research Focus. Each proposed M-PDTC must focus on testing of novel experimental anticancer agents in large numbers of PDX models (a minimum of 100 models proposed per Research Project) using data integration strategies that relate treatment response with molecular characteristics of individual patients' tumors. Research focus may include:

• narrow selection of drug types to study a broad selection of tumor sub-types;
• broad selection of drug types to study a narrower selection of tumor sub-types; and/or
• drug types and/or tumor subtypes with a therapeutic outcome disparity observed amongst racial/ethnic minority populations

"Tumor sub-types" may be defined not necessarily by tumor organ but also by the shared distinct molecular characteristics (e.g., with KRAS mutation regardless of tumor histology). The proposed research must be highly amenable to future clinical translation leading to early clinical evaluation of new anticancer agents. Furthermore, racial/ethnic diversity must be reflected among the proposed models.

Research Team. Each proposed M-PDTC is expected to involve a research group with appropriately diversified expertise and capabilities needed for the proposed research goals (e.g. medical oncologist, pharmacologist, cancer health disparity researcher, as appropriate). If needed, the involvement of investigators from multiple institutions is encouraged. The team members would also be expected to propose how they will plan to collaborate across the scientific disciplines during the project period to facilitate the successful conduct and completion of the proposed studies.

Organization of each M-PDTC must include the following functional components:

• Administrative Core;
• Research Projects;
• PDX Core;
• Biostatistical Core; and
• Pilot Projects and Trans-Network Activities Core.

The expected characteristics of the required components are summarized below.

Administrative Core. This component is expected to provide a support infrastructure for M-PDTC leadership and handle logistics of interactions within the M-PDTC and with other PDXNet units.

Research Projects. Each proposed M-PDTC must include a minimum of two interrelated and well-developed research projects from one or more of the research areas listed below. A third research project consistent with the theme of the application is optional.

At least one of the projects is required to address a cancer health disparity-focused research problem using a comparative research design between at least two racial/ethnic populations (e.g. American Indian/Alaska Native, Asian, African American, Caucasians, Native Hawaiian/Pacific Islander, and Hispanic/Latino populations). In addition to the required cancer health disparity-focused project, it is strongly encouraged that a second project also addresses cancer health disparity-relevant research questions.

Research projects proposed are expected to be interactive and synergistic, collectively supporting the overarching goal of the M-PDTC and reflecting a trans-disciplinary research program.

The proposed research projects should be designed so that there is a feasible path for subsequent clinical validation of the research results. Research projects that include NCI-IND agents can be clinically validated in the ETCTN.

Research Areas for the required two research projects include, but not limited to:

• Comparative research project (between at least two racial/ethnic minority populations) seeking to identify underlying genetic or epigenetic variations that could explain different therapeutic responses between racial/ethnic minority patient populations.
• Mechanism-based drug combinations in histologically defined PDX models that explore the relation of mechanism of action, tumor characteristics and drug response
• Mechanism-based drug combinations in genetically defined tumor subgroups that explore the relation of the genetic abnormalities to tumor response
• Mechanisms that contribute to the sensitivity or resistance of PDX models to cancer therapeutic agents
• Novel methods for pre-PDX screening using alternate patient-derived models (e.g., organoids, spheroids, etc.)

Models to Study. All research projects must employ large-scale PDX collections, greater than 100 models per project and, if applicable, covering a sufficiently broad range of tumor subtypes differing in their molecular characteristics. It is also expected that research projects addressing cancer health disparities will employ a majority of PDX models obtained from patients representing racial/ethnic minority populations. It is anticipated that both large-scale screening studies would be done across PDXNet, with more disease, target, or population-specific studies be performed at a single center.

Both pre-existing and/or newly developed PDX models may be used. For newly developed models, a minimum of 60% is expected to be derived from racial/ethnic minority populations. A programmatic priority may be given to M-PDTCs that will have particularly high proportion of both established and plans for newly developed minority patient-derived PDX models.

Whereas the focus is on PDXs (required for all projects), a limited use of other patient-derived models, such as organoids, is permissible, if appropriate.

Anticancer Agents. Projects may be focused on testing various molecularly targeted agents alone and in combinations with other agents (which may include, classical, chemotherapeutic drugs, if justified). However, since the goal of the PDXNet is to generate data to support early clinical trials, agents that do not have a clear route to clinical testing, such as compounds that do not have FDA approval for use in humans (approved or Investigational New Drug status), should not be included. Programmatic priority may be given to applications centered on types of agents that are regarded by the NCI as clinically most promising, including specifically those in the NCI-IND portfolio (see https://ctep.cancer.gov/branches/idb/ for a link to the current list of agents). However, other agents may be studied in the PDXNet, but a feasible plan for clinical translation of research results must be described. Cancer immunotherapies, where the target is immunomodulation to manipulate the immune system to attack tumors, are specifically excluded as there are separate initiatives devoted to preclinical development of these approaches.

Preliminary Data. Projects are expected to be supported by strong preliminary data, including, as applicable, relevant data on the development and molecular characterizations of new PDX models, and testing of anticancer agents in PDX models.

PDX Development Core. The PDX Core should encompass the facilities and appropriately skilled personnel to provide direct animal care, conduct intervention studies for the research projects, and operate the storage facilities for PDX models. The Core must adhere to all applicable guidelines, standards, quality control procedures, and ongoing surveillance procedures for animal and human pathogens. The PDX Core must also have the capabilities to perform invasive animal procedures such as implantation of PDX tumors and delivery of antineoplastic agents.

Pilot Projects and Trans-Network Activities Core. It is expected that this Core will lead the development of internal (within the PDTC) pilot projects as well as interact with other Network units in the development of trans-Network collaborative projects, and will also assist non-Network investigators chosen to participate in PDXNet by NCI. This Core should also be capable of conducting other expected trans-Network activities and collaborative non-Network projects. Particularly close interaction will be needed with PDCCC in terms of sharing data regarding PDX demographic information, molecular characterization and response to agents, jointly developing methods to analyze data, etc.

Bioinformatics Core. This core will provide data analytic support for PDX trials conducted in the PDTC. This function will require expertise in statistical methods, trial design, and integration and interpretation of complex data sets, with the goal of correlating genomic characterization data of PDX models used in the research projects with drug response data to identify patient populations that may benefit from a particular drug combination.

Other Requirement and Expectations

Interaction with PDMR. The PDMR is a resource for the PDXNet research investigators that will complement the PDX development activities of PDXNet. Therefore, all M-PDTC's awardees will be expected to enhance that resource by:

• developing and abiding by Standard Operating Procedures and quality control measures for PDX generation and drug response testing;
• donating PDX models developed under the M-PDTC award to the repository; and
• collaborating in the development and testing of methods for cross-validation of studies and testing reproducibility of results within the network.

Governance of the PDXNet. The PDXNet (i.e., M-PDTCs, 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 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.

Non-responsive Applications. The following types of research will be considered non-responsive to this FOA (non-responsive applications will not be reviewed):

• Applications in which none of the two required projects is focused upon cancer health disparity research;
• Projects that do not use sufficiently large collections of PDX models, which means not meeting the required more than 100 PDX models per project;
• Applications that do not propose development of models derived from racial/ethnic minority populations;
• Projects that focus solely on the development of agents that are not FDA-approved or that do not have an Investigational New Drug (IND) designation by the FDA;
• Projects focused on immunotherapy agents in immunocompetent xenograft hosts; and/or
• Projects focused on cancer models other than human, patient-derived models (e.g., genetically-engineered mouse models).

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

Other

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH 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).

A button to access the online ASSIST system is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

Most applicants will use NIH's ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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:

Tiffany Wallace, Ph.D.
Telephone: 240-276-5114
Fax: 240-276-7862
Email: tiffany.wallace@nih.gov

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core (Use for Administrative Core)	6
Project (Use for Research Projects)	12 (each project)
Core (use for PDX Core, Pilot Projects and Trans-Network Activities Core, Bioinformatics Core, and Shared Resources Core)	6 (each core)

Additional page limits 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 a multi-component application.

The application should consist of the following components:

• Overall: required
• Administrative Core: required
• Research Projects: 2 required, maximum 3 allowed
• PDX Core: required
• Pilot Projects and Trans-Network Activities Core: required
• Bioinformatics Core: required
• Shared Resource Core: optional, maximum 1 allowed

When preparing your application in ASSIST, use Component Type 'Overall'.

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

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions. Additional guidance applies.

Facilities and Resources:

In addition to standard items for this attachment, describe in detail the animal facility and relevant veterinary resources available. At a minimum, provide details on the following aspects:

• Facilities that will house immuno-incompetent animals, including all key technical parameters (such as available equipment, facility access design and access control);
• Pathogen surveillance practices (animal pathogens as well as human pathogens), including specific pathogen types tested, the methods used for pathogen screening, screening frequency, etc.;
• Summary of key standard operating procedures for the facility, including (but not limited to);

o the types of xenograft procedures that the facility is capable of doing (e.g., orthotopic, subcutaneous);

o systems for tracking tumor size and animal body weight;

o procedures for review and approval of animal studies at the applicant's Institutional Animal Care and Use Committee; and

o procedures for harvesting tumor samples for cryopreservation and analyses.

Other Attachments: Applicants must provide documentation specified below (uploaded as a separate PDF), using the indicated filename (which will serve as application bookmark).

Attachment 1. Biospecimens for PDX Development (use filename Biospecimens).

In this attachment, provide documentation detailing sources of and access to patient biospecimens that are planned for the development of new PDX model. Preferably in tabular format, provide the basic characteristics of planned biospecimen collections (tumor types, other clinical characteristics, patients racial/ethnic data, etc.). Indicate whether access to these biospecimens has been granted/secured, generally promised, or is potential but without yet formalized commitments.

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Specific Aims: Outline Specific Aims for the proposed Center. Indicate clearly the project(s) that is(are) focused on cancer health disparity research and state their overall goals.

Research Strategy: Provide an overview of the proposed Research Center. Address all the specific aspects indicated below using the sub-sections as defined:

Sub-section A) Research Center Framework and Effort Integration.

• Describe the overarching organizational framework and vision of the proposed Research Center, its scientific focus, strengths, and leadership in the research field.
• Describe how the Center and the investigators team will collectively support the overarching goal of the Center, outlining multi-disciplinary and multi-institutional collaborations, as applicable.

Sub-section B) Research Team.

• Summarize the major collective strength of the research team in the proposed area of research.
• Without repeating information from individual biosketches, explain how the specific expertise of team members (e.g., cancer health disparities, cancer biology, genomics, molecular medicine, computational biology, bioinformatics, others) will be used to advance the proposed research program; describe the environments (e.g., academic or other research) of the research team members and how they will support the mission of the proposed Research Center.

Sub-section C) Overview of Research Projects.

• Identify the overall focus of the M-PDTC research program;
• Outline the rationale for the proposed research projects, and reasons for their inclusions;
• Identify which of the scientific areas listed in Section I, under "Key Requirements for M-PDTCs" are addressed by two required projects.
• Identify the project(s) that is (are) focused on cancer health disparity research.
• If a third research project is proposed, explain how it connects to the other two projects and the overall scientific theme of the proposed Research Center.
• Highlight the innovative aspects of all the proposed projects, as applicable.

Sub-section D) Translational Potential.

• Explain the translational potential and clinical relevance of the proposed research, particularly in relation to response to treatments in PDX models of tumors with specific molecular characteristics;
• Explain how the outcome of the research can be clinically validated, including:
  • which cancer center(s) or cancer clinical trial network(s) could conduct the resulting trial;
  • potential sources of funding for the trial; and
  • how they may be clinically useful to help assign specific cancer therapies to only those patients who would be likely to benefit from them

• Explain the translational potential of the proposed research on addressing therapeutic outcome disparities that exist among racial/ethnic minority population groups.



Sub-section E) Cancer Patient Population.

• Describe plans for ensuring sufficiently high proportion of racial/ethnic minority populations for tumor biopsies that will be used for the development of PDX models.
• The plans should aim at accomplishing at least 60% of all specimens to be derived from racial/ethnic minority populations;
• If the appropriate patient populations are not available at the applicant institution, summarize agreement(s)/commitment(s) established with a different institution(s) to provide adequate access to clinical specimens and/or patients.
• The plans should also be based on reasonable assurances that the patients and human specimens needed for development for the PDX models are readily available from the sources considered and applicants already have or will be granted access to them. (Note that supporting documentation for this Sub-section is requested under Other Attachments).

Letters of Support: All letters of support relevant to the overall application should be included here. Include a letter of support from an institutional official endorsing the proposed M-PDTC and describing available institutional resources to support the Center research. Also, include letters from investigators who will serve as consultants or collaborators but with no measurable efforts. Include letters documenting commitments of applicant institution and/or external institutions that are required to secure access to appropriate patient biospecimens that are proposed to be used for the development new PDX models.

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.

Resource Sharing Plan should be provided only under the Overall component but it should cover all the activities proposed for the M-PDTC.

Specimen Sharing: The plan should explain how the M-PDTC will share biospecimens and related information with other PDXNet investigators and PDMR pursuant to the terms of an informed consent. M-PDTC investigators will be expected to share PDX models used in PDX trials with PDMR as well as all PDX models that will be fully developed under the M-PDTC award. The plan should explain how the M-PDTC would structure an informed consent document including considerations for the wider sharing of data and specimens collected under the M-PDTC award. Furthermore, explain how the M-PDTC would plan to provide information about the availability of PDX biospecimens at their institutions, as well as associated clinical/demographic information, through the patient registry-virtual biorepository that will be created and maintained by the PDXNet Coordinating Center, consistent with achieving goals of the program.

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.

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

When preparing your application in ASSIST, use Component Type 'Admin Core.'

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

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 should account for the efforts of other Core personnel (e.g., Core administrator) and a statistician.

The budget should also include travel funds for the PD(s)/PI(s) and other senior investigators (up to four people) to attend the annual PDXNet Steering Committee meeting and participate in other network-related activities.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: List the main goals of the Administrative Core.

Research Strategy:

Describe the anticipated roles of the Administrative Core. Address the specific aspects indicated below using the sub-sections as defined:

Sub-section A. Core Structure. Outline the organization and function of the Administrative Core, and describe the plans for coordination and communication with the PDCCC and NCI scientific staff.

Sub-section B. Leadership and Center Organization. Outline the organization of the leadership structure and overall Center structure (provide respective organizational diagrams). Describe the lines of responsibility.

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:

Resource Sharing Plans should only be included in the Overall component of the application.

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.

PHS Inclusion Enrollment Report (Administrative Core)

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

When preparing your application in ASSIST, use Component Type 'Project.'

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

SF424 (R&R) Cover (Research Project)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project (Starting with "Research Project 1" or "Research Project 2" or "Research Project 3)
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Research Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Project)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Research Project)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Project)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Research Project)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Project)

Specific Aims: Outline the Specific Aims of the project.

Research Strategy:

Statement of Research Area(s) Relevance. If a given Research Project is one of two required projects, include at the beginning of Research Strategy a statement identifying which of the possible research areas (listed in Section I) is/are being addressed by a given project.

State clearly whether or not this project is the required project addressing disparities that exist for therapeutic outcomes, using a comparative research design between at least two racial/ethnic populations.

If a third, optional research project is proposed, indicate how that project connects to research area(s) of the required projects.

Use the standard subsections of Research Strategy defined in the SF424 Application Guide (Significance, Innovation, and Approach) to describe your project. Emphasis should be placed on explaining why the proposed concepts and approaches are innovative within the context of related research and how the expected outcomes will contribute to clinical trial development, advance cancer precision medicine in general, and/or advance cancer health disparity research. In appropriate sub-sections, address the integration in and contribution of the research project to the overall Research Center program and explain why a given project is essential for achieving the Research Center's overarching goals.

Under the Approach subsection, clearly describe the number of PDX models that will be used per project, ensuring the minimum requirement of 100 PDX models per project is proposed. Provide characteristics of these models, including their sources/availability (whether previously established or to be developed), distribution of cancer types, racial/ethnic background, etc.

Resource Sharing Plan: Resource Sharing Plans should only be included in the Overall component of the application.

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.

PHS Inclusion Enrollment Report (Research Project)

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

When preparing your application in ASSIST, use Component Type 'Core'

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

SF424 (R&R) Cover (PDX Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project (use "PDX Core")
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (PDX Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (PDX Core)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (PDX Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (PDX Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (PDX Core)

Budget forms appropriate for the specific component will be included in the application package.

In the budget include (showing appropriate break down in Budget Justification):

• Personnel costs for the DVM-level staff member(s) and other skilled animal technical staff (for individuals who are not Key Persons--explain briefly their roles and skills under Budget justification);
• The costs for obtaining and maintaining immunocompromised mice for the research plans; and
• The costs involved in PDX collection, storage, and quality control characterization.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (PDX Core)

Specific Aims: Outline the Specific Aims of the PDX Core.

Research Strategy:

Address the following aspects using the sub-sections as defined:

Sub-section A) Outline of the Core.

• Explain the overall capabilities of PDX Core, with examples including:

o terms of the scale of operation;

o types of xenograft procedures used and types of drug testing conducted;

o collective skills/expertise (without repeating information in individual Biosketches but including essential skills provided by individuals who are not covered by biosketches); and

o other relevant aspects relating to capabilities;

• Outline plans to conduct comprehensive surveillance for pathogens to ensure facilities are free of pathogens (including viral, bacterial, fungal, and parasitic agents) that are commonly regarded as unacceptable for such facilities (if the facility has allowable murine or human pathogens, please provide a list);
• Since Corynebacterium bovis is not part of most standard pathogen screens, please provide a statement regarding facility status of this pathogen;
• Explain any other steps planned to ensure that PDX models to be shared as a key feature of PDXNet are free of rodent pathogens;
• Describe PDX screening practices for human pathogens (such as HIV); and
• Describe other current approaches and plans for quality assurance/quality control of the Core operations and procedures.

Sub-section B) Core Collections.

• Describe the collections of PDX models and associated data at all the participating sites in the M-PDTC;
• Describe the racial/ethnic diversity within the PDX collections and the plans to meet the required at 60% of new models originating from patients representing racial/ethnic minorities;
• Indicate whether the specimens are available for collaborative research studies with PDXNet as well as outside investigators;
• Describe any unique human cell lines/organoid collections available at the Center to support PDXNet research; and
• Describe PDX quality control procedures, such as steps taken to compare each passage generation to the original tumor

Sub-section C) Support for the Center Projects and PDXNet activities.

• Describe the role of the Core in facilitating the projects of the M-PDTC as well as possible contributions to collaborations with other M-PDTCs, PDTCs, and non-Network investigators; and
• Describe how this Core will share and accept models from other M-PDTCs, PDTCs, and the PDMR to allow cross-validation of experimental results and to enhance the diversity of tumor models among the PDXNet.

Resource Sharing Plan: Resource Sharing Plans should only be included in the Overall component of the application.

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.

PHS Inclusion Enrollment Report (PDX Core)

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

When preparing your application in ASSIST, use Component Type 'Core'

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

SF424 (R&R) Cover (Pilot Projects and Trans-Network Activities Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project (use "Pilot Projects and Trans-Network Activities Core")
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Pilot Projects and Trans-Network Activities Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Pilot Projects and Trans-Network Activities Core)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Pilot Projects and Trans-Network Activities Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Pilot Projects and Trans-Network Activities Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Pilot Projects and Trans-Network Activities Core)

Budget forms appropriate for the specific component will be included in the application package.

The budget request should account for the efforts of the Core Leader and other Key Persons and staff.

The budget should also include restricted funds for pilot studies in the amount of $100,000 in direct costs per year, starting in year 2 of the project period. The funds include $50,000 in direct costs per year for pilot studies within Center and $50,000 in direct costs per year for Cross-PDXNet pilot studies. The release of these restricted pilot funds will be recommended to the PD/PI by the PDXNet Steering Committee and approved administratively by NCI staff, respectively. These amounts should be presented in the Other Expenses category under the heading "Restricted Pilot Project Funds."

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Pilot Projects and Trans-Network Activities Core)

Specific Aims: Outline the main goals of the Core.

Research Strategy:

Address the following aspects using the sub-sections as defined:

Sub-section A. Pilot Studies Development and Evaluation. Outline the Research Center's overarching vision for development of Pilot Projects and cross-PDXNet Projects. Pilot projects may serve, for example, as a mechanism to develop methods of experimental validation and reproducibility assessments across M-PDTCs and PDTCs. Outline the mechanisms/procedures that will be employed by the Core for soliciting, reviewing, prioritizing, and monitoring these projects. In the description, include general criteria for selecting pilot projects. Also, include key scientific capabilities, which the applicant Center can provide to support such projects. (NOTE: As specific Pilot Projects or cross-PDXNet Projects will be developed and selected post-award, no such specific projects should be listed in the application.)

Sub-section B. Collaboration with non-PDXNet Investigators. Outline the M-PDTC's plans to enhance collaboration with non-PDXNet investigators in specific pilot studies. Outline the Center's vision for any other activities that could have a synergistic effect on the outcomes of the PDXNet Program.

Resource Sharing Plan: Resource Sharing Plans should only be included in the Overall component of the application.

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.

PHS Inclusion Enrollment Report (Pilot Projects and Trans-Network Activities Core)

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

When preparing your application in ASSIST, use Component Type 'Core'

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

SF424 (R&R) Cover (Bioinformatics Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project (use "Bioinformatics Core")
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Bioinformatics Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Bioinformatics Core)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Bioinformatics Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Bioinformatics Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Bioinformatics Core)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Bioinformatics Core)

Specific Aims: Describe the goals of the Bioinformatics Core.

Research Strategy:

Address the following aspects using the sub-sections as defined:

Subsection A. Capabilities

Describe how the Bioinformatics Core has the capacity to support study designs and data analysis for trials within the M-PDTC and, when needed, across the other PDTCs, and in conjunction with the data management personnel of the PDCCC. Examples of relevant capabilities may include, but are not limited to:

• Established statistical and computational methodologies for interpretation of the complex data generated from molecular characterization of PDX models, from PDX responses to agent and agent combinations, and measurable differences between population groups.
• Systems to track progress of PDX trials (available or possible to design and implement)

Subsection B. Approaches

Describe how the Bioinformatics Core can develop novel approaches to study designs and data analysis for trials within the M-PDTC and, when needed, across the other PDTCs, and in conjunction with the data management personnel of the PDCCC. Examples of relevant capabilities may include, but are not limited to:

• Approaches to create algorithms for different data types including Omics data (e.g., genomics, RNAseq, etc.)
• Developing approaches to integrate PDX molecular characteristics with PDX response data to generate both hypothesis-testing preclinical studies and proposals for human clinical trials.
• Developing approaches to determine and integrate genetic ancestry information of patients used to derived PDX models.

Resource Sharing Plan: Resource Sharing Plans should only be included in the Overall component of the application.

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.

PHS Inclusion Enrollment Report (Bioinformatics Core)

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

When preparing your application in ASSIST, use Component Type 'Core'

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

SF424 (R&R) Cover (Shared Resources Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Shared Resources Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Shared Resources Core)

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Shared Resources Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Shared Resources Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Shared Resources Core)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Shared Resources Core)

Specific Aims: Describe the goals of the Shared Resource Core. Indicate which specific Research Projects will be served by this Core.

Research Strategy: Justify why the Shared Resource Core is needed and how it will facilitate M-PDTC research projects. (The Shared Resource Core must support at least two M-PDTC Research Projects.) Any additional services, support, and/or resources to be provided to other Research Center components (if applicable) should be clearly defined.

Resource Sharing Plan: Resource Sharing Plans should only be included in the Overall component of the application.

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.

PHS Inclusion Enrollment Report (Shared Resources Core)

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

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) using ASSIST or other electronic submission systems. 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.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads 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.

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 (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

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

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

For this FOA, note the following:

Reviewers will provide an overall impact score for the entire M-PDTC application. In addition, assigned reviewers will provide individual "criterion scores" for the Overall criteria but not for the other components.

All other components of the Center [i.e., Administrative Core, Research Projects, PDX Core, Bioinformatics Core, and optional Shared Resource Core] will be evaluated but each will receive only one overall adjectival (not numerical) rating.

For the evaluation of the M-PDTC application, the Research Projects will be emphasized as the scientific base of each Center, with additional components enhancing and integrating the overall research/outreach program.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the M-PDTC 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 Center 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 M-PDTC that by its nature is not innovative may be essential to advance a field.

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

Specific for this FOA: What is the likelihood that the M-PDTC research, as proposed, will help advance cancer precision medicine? What is the likelihood that the M-PDTC research, as proposed, will help advance cancer health disparities research? How will the proposed concepts and approaches help provide preclinical evidence to guide the clinical development of new promising anticancer agents, and NCI-IND agents in particular? How will the proposed M-PDTC meaningfully contribute to and facilitate the PDMR goals of developing PDX models and associated data to share with the larger research community? How will the proposed M-PDTC contribute to the racial/ethnic diversity represented in the overall PDXNet?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the M-PDTC? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the Center 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 Center?

Specific for this FOA: Are the backgrounds, expertise, and commitments of the PD(s)/PI(s) and other key persons sufficient for the proposed scope of activities and in line with the overall goals of the PDXNet? How have the M-PDTC investigators demonstrated expertise in the development and characterization of large-scale PDX collections? How well have the investigators demonstrated expertise in PDX development, including development of both orthotopic and subcutaneous PDX models? Have the investigators demonstrated expertise in conducting trials of agent and agent combinations in groups of PDXs, including administration of drug by oral, intravenous (IV), and intraperitoneal (IP) methods at human-relevant dosing preclinical drug testing on PDX models? Have the investigators demonstrated expertise in conducting cancer health disparity research?

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

Specific for this FOA: Does the proposed M-PDTC employ novel concepts, approaches, and/or methods to use PDX models for preclinical testing of cancer therapies? Does the proposed M-PDTC have novel strategies for integrating and cross-validating molecular characterization and pre-clinical therapeutic data from diverse datasets? Does the proposed M-PDTC have novel strategies for identifying or investigating the causes of cancer therapeutic outcome disparities experienced by racial/ethnic minority populations? Are the M-PDTC's goals original and innovative?

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

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

Specific for this FOA: How well are all components of the M-PDTC integrated to support the proposed research? Have the investigators presented adequate plans to address relevant biological and technical variables inherent in early-passage PDX models across multiple sites? Do the Centers test multiple combinations of anticancer agents, including NCI-IND agents, in large-scale populations of PDX models, and a strategy to correlate molecular characterization of PDX models with drug response data? For the proposed health disparity project, is their design appropriate to determine differences in response, or identify contributing mechanisms to therapeutic outcome disparities, between racial/ethnic minority population groups? If patient-derived models other than PDX are proposed, is their use appropriate and well justified in the context of the main thrust of effort on PDX models? Does the research plan demonstrate how PDX models will be used to develop the rationale for novel ETCTN clinical trials using combinations of agents to treat molecularly-defined tumors?

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 Center proposed? Will the Center benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Specific for this FOA: Is there evidence for sufficient institutional support for the M-PDTC? Will the scientific environment at the participating institutions stimulate trans-disciplinary research collaborations? Does the institution(s) have appropriate access to racial/ethnic minority cancer patients for the development of PDX models? How will the proposed M-PDTC be able to make consistently rigorous and meaningful contributions to the entire PDXNet and the participating institutions (in particular PDMR) e.g., in terms of contributing innovative PDX models that are well-characterized and rigorously screened for pathogens before sharing? How well will the proposed M-PDTC take advantage of the infrastructure for PDXNet and existing resources at the participating institutions, and in particular PDMR?

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

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

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

When the proposed M-PDTC 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 M-PDTC 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 .

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.

Reviewers will provide only one overall adjectival rating for the Administrative Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• As described for the Administrative Core, is there adequate evidence for the managerial and collaborative capabilities of the proposed leadership? How appropriate are the proposed plans to coordinate and communicate with the PDCCC and NCI scientific staff? How appropriate are the leadership structure and activities of the proposed M-PDTC in terms of facilitating: achievement of the overall goals of the M-PDTC; integration of multiple institutions participating in a given M-PDTC (as applicable); and collaboration in cross-PDXNet activities?

Reviewers will provide only one overall adjectival rating for each Research Project (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

Significance

Does the project address an important problem or a critical barrier in preclinical testing of new anticancer agents? Does the project address an important issue that may explain or address cancer health disparities? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the clinical approaches to matching treatments with molecular characteristics of individual patients' tumors? How well is this project connected to other project(s) proposed for the Center?

Investigator(s)

Are the Project Lead, collaborators, and other researchers well suited to the project? If the project is collaborative, do the investigators have complementary and integrated expertise?

Innovation

Does the project propose novel methods for testing anticancer agents in PDX models and/or innovative pre-PDX screening? Does the project propose novel methods for investigating cancer health disparities?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? How sufficient are quality assurance and quality control measures to ensure that PDX models used for studies are free from microbiological contaminations? If focused upon cancer health disparities, is the project adequately designed to evaluate differences between diverse racial/ethnic population groups? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? Are the PDX and other models proposed appropriate and sufficient for the Project goals (e.g. appropriate statistical power, racial/ethnic minority populations represented, if applicable)? How feasible is the proposed project in terms of availability of the models proposed (already established and available models versus models to be developed by PDX Core)? If the agents to be tested include non-NCI-IND drugs, how feasible will be the path to clinical validation of results for such agents?]

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 M-PDTC environment including the Cores and Projects?

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 based on 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 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.

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.

Reviewers will provide only one overall adjectival rating for the PDX Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

How well is this Core integrated in the proposed M-PDTC? What is the likelihood that the Core, as proposed, will be able to provide Research Projects with the needed numbers of models (at least 100 per research project) while also achieving appropriate racial/ethnic diversity within the newly-developed models? Are the veterinary resources, animal holding facilities and quality control procedures adequate for high-quality PDX therapeutic trial testing and for collaborative PDX research projects? Will the facility's infection control procedures and pathogen surveillance and screening practices minimize the risk of contamination of facilities that receive shared PDX models? Does the Center outline its intent to collaborate and share specimens and cell models within the M-PDTC and across the PDXNet program as appropriate and consistent with achieving the goals of the program? Is the clinical annotation for PDX models described?

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 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.

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.

Reviewers will provide only one overall adjectival rating for the PDX Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

Are the overall vision and specific plans for pilot projects well thought out and realistic? Are the solicitation procedure and criteria for pilot project selection appropriate? Is sufficient attention given to planning for the participation in trans-network collaborations as well as potentially engaging non-PDXNet investigators? Is an appropriate plan proposed for the Core to solicit, review, prioritize, and monitor the pilot and cross-PDXNet projects?

Reviewers will provide only one overall adjectival rating for the PDX Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

How well is this Core integrated in the proposed M-PDTC? Does the Core provide expertise and appropriate capabilities to interpret complex data generated from molecular characterization of PDX models and from PDX responses to agent and agent combinations? Can it help develop approaches to create algorithms for different data types including Omics data? Can it assist in the development and implementation of systems to track progress of PDX trials?

Reviewers will provide only one overall adjectival rating for the optional Shared Resources Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

How well matched is the proposed Shared Resources Core to the needs of the overall Research Center? Will the proposed Core meaningfully enhance the Center's research program? Are the services of the Shared Resources Core essential to the goals of more than one Research Project? Are the qualifications, experience, and effort commitment of the Shared Resources Core Director(s) and other key personnel adequate and appropriate for providing the proposed facilities or services? Will the proposed Shared Resources Core provide cost-effective services to the Research Center, prevent duplication, and/or increase efficiency?

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NCI} in accordance with NIH peer review 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. Programmatic priority may be given to:
• Applications centered on types of agents that are regarded by the NCI as clinically most promising, including specifically those in the NCI-IND portfolio;
• M-PDTCs that will have particularly high proportion of minority patient-derived PDX models; and
• Particularly high merit of the proposed cancer health disparities research .

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

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

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

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

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

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

• Determining the M-PDTC's directions, coordinate research approaches and procedures, and oversee the analyses and interpretation of research data;
• Overseeing the timely release and sharing of specimens and data according to the approved plans;
• Participating in the development and evaluation of pilot projects, cross-PDXNet Projects, and cross-PDXNet activities that will cross-test novel projects;
• Participating in the annual PDXNet Steering Committee meeting, and periodic conference calls organized by the PDXNet Coordinating Center;
• Cooperating with NCI Project Scientists in the program evaluation process;
• Accepting and implementing all scientific and practical decisions approved by the PDXNet Steering Committee to the extent consistent with applicable grant regulations;
• Providing information to the NCI Program Directors concerning progress by submitting annual progress reports in a standard format;
• Preparing for administrative site visits by NCI staff members; and
• Taking advantage of collaboration with other NCI and NIH initiatives and programs, as appropriate for advancing the Center research and the PDXNet program.

The following additional responsibilities will also apply for each M-PDTC awardee:

• Each M-PDTC 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). M-PDTC 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 DHHS, PHS, and NIH policies;
• All institutions/organizations participating in a Research Center will be expected to share with the PDXNet program knowledge, specimens, data, research materials, and any other resources necessary and relevant to the M-PDTC award, consistent with achieving the goals of the program;
• Participating in the evaluation of applications from outside investigators for access to resources in PDXNet centers, and collaborate with funded investigators, if applicable.
• Each M-PDTC is expected to operate under SOPs developed by the consortium in collaboration with PDMR 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;
• Each M-PDTC is expected to provide all new PDX models developed under the M-PDTC award to PDMR without encumbrance;
• 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; and.
• The applicants are expected to accept (to the extent consistent with grants regulations) the overall governance of the program, and program policies including, as applicable, policies on: the use of common protocols, publication of study results, collaborative procedures, confidentiality, and data sharing plans to be developed by the PDXNet in collaboration with NCI.

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 NCI staff members include the following activities:

• Serving as the NCI lead Project Scientists and voting members of the PDXNet Steering Committee;
• Assisting in avoiding unwarranted duplications of effort across the PDXNet program;
• Helping coordinate collaborative research efforts that involve multiple M-PDTCs and PDTCs;
• Monitoring the operations of the PDXNet M-PDTCs and make recommendations on overall project directions and allocations of funds. NCI staff will perform periodic (at least annual) site visits to the M-PDTCs to review scientific and administrative progress and to ascertain that SOPs and other agreed upon procedures are implemented and being followed;
• Reviewing the progress of individual M-PDTCs and specific activities shared among the Research Centers and Coordinating Center;
• Participating in the development and evaluation of cross-PDXNet Projects;
• Co-organizing and participating in the annual PDXNet Steering Committee meeting;
• Participating as Collaborators of the PDXNet investigators in some shared activities, if appropriate;
• Assisting 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;
• Providing clinical background on agent clinical development to guide the development of PDX trials;
• Providing 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
• Evaluating 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 serves as the main governing board of the PDXNet program that the M-PDTCs will join.

After the M-PDTCs join PDXNet, the Steering Committee will consist of the following voting members:

• The PD(s)PI(s) of each awarded PDTC and M-PDTC who will have one vote for each center, regardless of the number of PDs/PIs designated;
• The PD/PI of the PDCCC and a designated senior investigator who will collectively have one vote;
• The NCI/CTEP/CRCHD Project Science Officer(s) who will collectively have one vote; and
• The NCI/PDMR liaison who will have one vote.

The PDXNet Steering Committee will meet at least one time per year in a face-to-face meeting. 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 has the following primary responsibilities:

• Overseeing the overall PDXNet program and review its research progress;
• Reviewing the potential of shared support infrastructure(s) at individual PDTCs to serve the needs of other PDTCs and the entire program;
• Developing procedures for soliciting and evaluating ideas for pilot projects across the PDXNet as well as criteria for their prioritization and approval;
• Ensuring that the M-PDTCs, PDTCs, and the PDCCC take advantage of existing NCI and NIH resources and programs;
• Making recommendations for termination of pilot projects that become unpromising or unproductive;
• Participating in the development of the agenda for the annual Steering Committee meeting to present scientific progress and future plans from PDXNet investigators;
• Coordinating the PDXNet evaluation of applications from outside investigators for access to resources in PDXNet centers, and coordinate collaborate with funded investigators when appropriate;
• Establishing advisory groups as necessary to ensure the progress of individual Research Centers as well as of the entire PDXNet program;
• Ensuring that individual PDXNet members (i.e., M-PDTCs, PDTCs and PDCCC) accept and implement as appropriate actions (recommendations, directions, etc.) approved by the PDXNet Steering Committee; and
• The PDXNet Steering Committee will conduct performance evaluation of the M-PDTCs, 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 RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

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

Tiffany Wallace, Ph.D
National Cancer Institute (NCI)
Telephone: 240-276-5114
Email: tiffany.wallace@.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.