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

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

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

The purpose of this funding opportunity announcement (FOA) is to stimulate research in the area of PDAC microenvironment with the ultimate goal of understanding the interaction between tumors and the microenvironment. The plan is to design new immunotherapy and combination interventions that would accommodate and build on the distinct characteristics of this interaction. It is expected that the interventions will lead to improved responses in pre-clinical models and clinical evaluation either in NCI-based early phase networks (ETCTN), or by industry or cancer centers.

The companion FOA of the PDAC Consortium includes:

• RFA-CA-17-016, " Resource Center for the Consortium for Pancreatic Ductal Adenocarcinoma (PDAC) Translational Studies (U24) ."

Pancreatic cancer remains a major clinical challenge claiming more than 40,000 lives yearly in the US. Despite many advances in understanding the biology of pancreatic cancer, the disease still imposes challenges in its early detection and effective therapy. Pancreatic Ductal Adenocarcinoma (PDAC) is the most common type and accounts for 95% of cases of pancreatic cancers. Many risk factors including chronic inflammation, diabetes, obesity, and smoking have been established. PDAC is highly resistant to chemotherapy and radiation. The only curative intervention is surgery for localized disease; however, most patients present with locally-advanced disease and are not eligible for curative surgical approaches. The overall 5-year survival is 5%.

After decades of research, new immunotherapy approaches have resulted in unprecedentedly positive results in a subset of many types of tumors including, but not limited to lymphoma, melanoma, renal cell carcinoma, and lung adenocarcinoma. In particular, checkpoint inhibitors have produced long-term survival in approximately 20% of patients, and these findings led to FDA approval of several agents (ipilimumab, nivolumab, pembrolizumab). Cellular therapies with genetically engineered T cells (CAR-T-cells or antigen-specific T cell receptors) or tumor infiltrating lymphocytes (TILs) have also proven to be efficacious in certain hematopoietic malignancies and solid tumors. Therapeutic vaccines have shown some success as well. Immunotherapy, in many cases, provides an alternative to traditional chemotherapy, and often with less severe side effects. The search for reliable predictive markers for immunotherapy is ongoing.

Immunotherapeutic approaches to PDAC, however, have not, for the most part, been successful. PDAC has a low mutational load with few neoantigens (an immunologically quiet tumor); although inflammatory cells have been shown to infiltrate the tumor, these cells promote rather than inhibit PDAC growth. The tumor microenvironment is profoundly immunosuppressive with regulatory T cells, regulatory B cells, myeloid-derived suppressor cells, tumor associated macrophages, and other stromal elements that interact with the tumor and/or secrete suppressive factors. Despite the number of cells that surround and infiltrate the tumor, only a minority of these tumors have naturally occurring effector T cells. However, several groups have recently reported techniques that overcome the immunosuppressive milieu of PDAC and allow the host immune system to react more efficiently against the tumor.

Attempts to create accurate tumor models that include the PDAC microenvironment have been particularly challenging; its dense desmoplastic stroma comprises 90% of the tumor in many cases with a large variety of cells including stellate, fibroblast, endothelial, nerve, and white blood cells, all with different subtypes and functions. In addition, there is an extracellular matrix that includes collagens and fibronectin. It is believed that an important dynamic exists between PDAC and its microenvironment: factors are secreted by the tumor cells that augment the activities of the microenvironment, and growth factors and cytokines are secreted by the cells in the microenvironment that increase the growth and invasion of PDAC, as well as resistance to therapy. Yet, studies that depleted stromal elements in an attempt to decrease PDAC growth led to equivocal results.

No cell lines, genetically engineered mouse models and xenografts, or organoid cultures today encompass the complete PDAC microenvironment. A deeper understanding of the complex PDAC microenvironment including its individual components, their interactions with tumor, and their potential role in facilitating immunotherapeutic interventions is needed. It has been thought that the density of the desmoplastic reaction prevented the influx of T lymphocytes, but it is now well-established that this is not the case; regulatory T cells are abundant within the tumor. The effector T cells are the cells that are excluded.

It is clear that cells in the PDAC microenvironment play a crucial role in PDAC development and progression, and therefore the composition and function of the microenvironment in all stages of the disease need to be better understood. With the use of new staining and microimaging technologies, a better characterization of the microenvironment is possible, allowing in a single specimen or animal the identification and position of all cellular components of the immune response in relation to the tumor. Over the course of the disease, longitudinally obtained specimens could show changes in the cytological signature and position of the cells in the microenvironment. The vascular architecture of PDAC is abnormal; blood vessels are highly disorganized and leaky with sluggish blood flow. Lymphatics within the tumor are compressed. The elevated intra-tumoral pressure results in a decreased opportunity for anticancer drugs to reach their targets.

The readiness of the scientific community to pursue these types of studies underscores the need for projects that would move discoveries into early phase clinical trials. The proposed FOA will allow the most advanced scientific and clinical teams to perform their work in a more coordinated way with access to common resources and with the option to conduct early clinical trials, particularly with agents developed at the grantee institution or in collaboration with industry.

Studies should be predominantly pre-clinical with the potential for translating the findings into clinical interventions in the future.

The proposed studies must have a laboratory element and a human endpoint, which can be defined as:

1. investigations of specimens from a collaborative early phase clinical trial; or
2. discoveries that shed light on agent response or on patient stratification and development of prediction assays using human specimens or directly in humans as in an imaging study.

Scientific Goals for this arm of the PDAC Consortium

• The scientific goal of the consortium is to deepen the understanding of interactions between pancreatic cancer and its microenvironment including cells of the immune system and to use this knowledge in the design of interventions that would exploit the vulnerabilities of both. The understanding of interactions should extend beyond correlations or cataloging of cell types in the microenvironment.
• Although it is anticipated that the majority of interventions will involve various types of immunotherapeutic approaches, the initiative is open to employing other modalities that will potentiate immune responses including radiation therapy, drugs that affect components of the tumor stroma, vascular system, and other parts of tumor milieu.
• A valid output from these studies will also be the design of suitable and clinically applicable tests, signatures, immunoscoring tools including imaging techniques that will allow better response prediction, and monitoring of the above interventions. Another output may be an agent or combination that could be tested in an early phase of clinical testing.

Research areas of interest for this FOA include but are not limited to:

• In depth characterization of the human PDAC tumor microenvironment over the course of the disease, pre- and post- interventions combined with mechanistic studies beyond correlations or cataloging of cell types in the microenvironment;
• Research on the interactions between immune effectors and suppressors in the human PDAC milieu
• Studies of microenvironment in PDAC metastases
• Novel interventions targeting components of the PDAC tumor microenvironment including stroma, immune response, epithelial-mesenchymal transition, tumor vascularization, etc.;
• Models mimicking the interactions between PDAC and its microenvironment;
• Data generated from Lynch syndrome- and/or microsatellite instability- associated PDAC responses to immunotherapy and their utilization for the design of interventions in PDAC not-associated with this condition;
• Development of prediction assays for PDAC patient stratification in immunotherapy interventions
• Early phase clinical testing of immunotherapy alone or in combination with radiation, chemotherapy, or precision medicine interventions;
• Research in disparities-associated PDAC microenvironment and the potential to use immunotherapy in these populations

An early phase/pilot clinical trial in the later years of the award may be proposed, but is not required, especially in those instances where agents are provided by sources outside of the NCI.

Research areas that will not be considered responsive to this FOA include but are not limited to

• Projects that focus on the tumor microenvironment of other cancers;
• Specimen collection and banking not linked to experimental hypotheses;

Eligibility and Work Scope:

Applicants for U01 grant support should have the capacity to generate pre-clinical data based on preliminary findings in the study of PDAC tumor microenvironment including immune responses, role of different components of tumor stroma, or tumor vascularization. The data obtained should either enable the validation of the stated hypothesis using clinical specimens or amass critical information which could culminate in an early phase clinical trial in the later years of the project.

Transdisciplinary nature of the Consortium

Collaboration among cellular and molecular biologists, immunologists, pathologists, bioinformaticians, surgeons, molecular imagers, and medical and radiation oncologists will be necessary. When necessary, substantial participation of staff involved in clinical trials is also anticipated. Lastly, patient advocates and navigators are invited to contribute to the grant.

It is expected that projects will either start with specimens from a clinical trial (not supported by this grant) or from other sources (e.g., rapid autopsy program, stored tissues, etc.) that will provide material for mechanistic and assay development studies, or begin with laboratory studies leading to an early phase clinical trial in the later years of the project. Studies including biospecimens from underserved patient populations are particularly encouraged.

The consortium will consist of up to 5 U01 grants focused on various characteristics of the PDAC microenvironment that will enable the design of new immunotherapy and other treatment interventions. The projects included in each grant may be carried out by one or more institutions.

A U24 Resource Center (RC) that will have several administrative and resource/ services functions is also proposed. It will serve as the hub for the consortium; individual applicants for U01 grants are encouraged to also apply for the U24 infrastructure grant. The main service function for the RC will be to serve as a bioinformatics center, and to oversee the distribution of tissues and models. Administrative responsibilities of the RC will include support of conference calls and annual meetings of the consortium, and reporting duties to the NCI.

Multi-PI applications for a U01 grant from single or multiple institutions will be accepted and are encouraged. Each U01 grant may include multiple members and disciplines at the same or different institutions to fulfill the need for highly specialized, multidisciplinary expertise.

A Consortium Steering Committee (CSC) will be established to oversee the consortium collaborative activities to maximize the use of resources. The CSC will be composed of the PDs/PIs PDs/PIs of each U01 project, the PD(s)/PI(s) of the RC and 2 NCI representatives. In collaboration with NCI, the CSC will also promote exchange of laboratory methods and scientific findings through use of the RC and coordinate data dissemination and generated resources to the general research community. Additional responsibilities may be included based on the makeup of the newly established consortium. The PDs/PIs of the application should clearly declare commitment to participate in the CSC.

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
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

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).

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

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

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

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

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

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

The letter of intent should be sent to:

Peter Ujhazy, M.D., Ph.D.
National Cancer Institute (NCI)
Telephone: 240 276 5681
Email: ujhazyp@mail.nih.gov

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

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

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

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

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

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

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

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

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

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

Specific aims: In addition to the specific aims and approach(es), applicants should include the relevance of the research to the objectives of this FOA.

Research strategy: The Research Strategy should clearly describe:

• The expected impact to treatment of PDAC if a positive outcome is achieved;
• The significance of the proposed project to future clinical treatment of PDAC. The clinical relevance of pre-clinical models and proposed therapeutic strategies should be explained.
• A research approach that addresses the overall goal(s) of the FOA;
• Collaboration of the multiple sites to achieve the objectives of the consortium through the Resource Center (RC), particularly with respect to governance and decision-making;
• Functioning of the multiple sites within the overall laboratory network;
• A timeline and milestones for achieving the project goals;
• Set-aside funds for collaborative efforts between members of the Consortium are allowed and encouraged.

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 and Resource Sharing Plan.

The plan should also include the usage of the consortium Resource Center (RC). Its functions are addressed in detail in the companion U24 FOA (RFA-CA-17-016) and they include:

• Administrative support of the consortium including monthly conference calls, annual meetings, communication and oversight as specified in organization of the consortium above
• Bioinformatics support that would allow centralization of data resources generated by the consortium
• Biospecimen and model handling capacities enabling centralization and distribution of consortium generated resources as appropriate
• Assistance with the collection of data for the NCI
• Creation and maintenance of the consortium website

Appendix:

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

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

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

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

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

Does the project address an important problem or a critical barrier to progress in the field? 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 concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: Is the project related to immunotherapy of PDAC and how?

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

Specific to this FOA: Are investigators willing to collaborate with members of the consortium and the Resource Center (RC)?

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?

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? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this FOA: Is the relevance of the project to PDAC adequately addressed? Are proposed studies appropriately powered? What project resources could be potentially shared with the consortium and the broader scientific community?

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

Specific to this FOA: Are resources of human specimens adequate for the purpose of the project?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements How will the multiple sites collaborate to achieve the objectives of the consortium through the Resource Center (RC) particularly with respect to governance and decision-making? How will the multiple sites function within the overall Consortium?

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.

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

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

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

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

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

Not Applicable

Not Applicable

Not Applicable

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

Not Applicable

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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

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

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. 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 resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

The PD(s)/PI(s) will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under this program. The PD(s)/PI(s) assume responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the research supported by the U01 award.

Specific responsibilities and rights include:

• Coordinating efforts and cooperating with the other U01 and U24 components of the Consortium and with NCI Program staff. These actions may involve (but will not be limited to) the participation in the appropriate coordinating meetings and/or working groups, and/or teleconferences as needed;
• Overseeing the implementation of the approved data sharing plan and resource sharing plan; Institutions/organizations participating in the Consortium will be expected to share with each other knowledge, data, research materials, and any other resources necessary and relevant to the Consortium;
• Annotation of samples through the use of Consortium-defined Common Data Elements (CDEs).

Each U01 awardee will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

A designated NCI Program Staff member, acting as a Project Scientist, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.

Specifically, the NCI Project Scientists will:

• Coordinate and facilitate the interactions among all the U01 awardees under this initiative;
• Work closely with investigators on Collaborative Research projects to coordinate and facilitate interactions/collaborations among the U01 awardees across the Consortium;
• Serve as liaison between the Collaborative Research awardees (U01 and U24) and NCI staff members and investigators from other NIH or NCI programs, such as the NCI Center for Bioinformatics, if appropriate, facilitating interactions and scientific integration among the U01 awardees and these programs;
• Review of all major collaborations that the awardee might propose with research groups outside the PDAC Consortium and advise on their appropriateness before implementation to assure consistency with the goals of this FOA;
• Provide technical assistance and advice to the awardees as appropriate;
• Assist in avoiding unwarranted duplication of effort with other NCI efforts;
• Monitor institutional commitments and resources to the awardees;
• Suggest reprogramming efforts, including options to modify projects/programs when certain objectives of this FOA are not met -- specifically, the NCI Project Scientist may recommend withholding of support, suspension, or termination of a U01 award for lack of adherence to required policies and/or procedures;
• Develop working groups and trans-project efforts as needed;
• Monitor progress and direction of awardees and working groups as needed; and
• Organize and conduct regular meetings to share progress either by teleconference, videoconference, or face-to-face, as needed between the U01 and U24 awardees of the PDAC Consortium

In addition, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice. The Program Official may also have substantial programmatic involvement (as a Project Scientist) and may be the same person as Project Scientist. In that case, the individual involved will not attend peer review meetings, or will seek NCI waiver according to the NCI procedures for management of conflict of interest.

Areas of Joint Responsibility include:

The NCI Project Scientist and the PD/PIs of the U01 awards funded under PDAC Consortium will be jointly responsible for the coordination of intra-program activities and the scientific integration of individual projects with other appropriate NCI consortia or resources, if required.

Consortium Steering Committee: The Consortium Steering Committee (CSC) will be the main governing body for the Consortium.

The CSC will be composed of the following voting members:

• One representative from each U01 project award (a PD/PI or a designated senior investigator) who will have one vote;
• One representative from the U24 (a PD/PI or a designated senior investigator) who will have one vote; and
• NCI Project Scientists who will have one total vote. The remaining Project Scientists will participate in Steering Committee meetings as non-voting members.

Additional NIH staff members, serving in an advisory capacity, may participate in these meetings as non-voting members. The decision on composition of additional NIH staff member advisors on the CSC will be made by the existing voting members of the Steering Committee. These members may include representatives from NCI extramural divisions and a representative from the NCI CBIIT.

The Chair of the CSC will be selected from the representatives of all awardees.

The CSC will meet once every year, either face-to-face at locations selected by the CSC in consultation with the NCI or by teleconference. The RC (U24) awardee PI(s) will be responsible for arranging the annual CSC Meeting in collaboration with the CSC Chair and NCI Project Scientists.

The CSC may decide to establish sub-committees for specific purposes. The NCI Project Scientists will serve on such sub-committees, as they deem appropriate.

Primary responsibilities of the CSC include, but are not limited to, the following activities:

• Establishing Consortium policies and procedures;
• Establishing policies and procedures for collaborative projects, and protocols.
• Developing guidelines for the collection and distribution of specimen reference sets for collaborative research.
• Serving as a nucleus for a broader outreach to the entire extramural research community investigating PDAC.

Dispute Resolution Process:

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 Consortium 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.

The performance of the consortium will be evaluated by the following criteria:

• Scientific output of pre-clinical studies and their impact on state of science through publications and spin-off of new funded projects (e.g. discovery of new regulatory pathways and mechanistic underpinnings)
• Discoveries that lead to the development of predictive, and response monitoring assays
• Successful initiation of early phase clinical trials (if proposed) with adequate accrual and potential to move to higher stage clinical testing
• Number and quality of collaborative studies among members of the consortium
• Number of resources produced by the consortium (models, shared genomic data)
• Overall novelty of interventions designed

All criteria should be addressed in the future annual progress reports.

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

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

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

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

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

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

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

Email: support@grants.gov

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

Telephone: 301-710-0267

Peter Ujhazy, M.D., Ph.D.
National Cancer Institute (NCI)
Telephone: 240 276 5681
Email: ujhazyp@mail.nih.gov

Jeffrey Hildesheim, Ph.D.
National Cancer Institute (NCI)
Telephone: 240 276 6180
Email: hildesheimj@mail.nih.gov

Kevin Howcroft, Ph.D.
National Cancer Institute (NCI)
Telephone: 240 276 6180
Email: howcrofk@mail.nih.gov

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

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: Crystal.wolfrey@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.