Required Application Instructions

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

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

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

The purpose of this Funding Opportunity Announcement (FOA) is to establish the Pancreatic Cancer Detection Consortium (PCDC). The PCDC is intended to support research to develop and test biomarkers and imaging methods for improved detection of early stage pancreatic ductal adenocarcinoma (PDAC) and its precursor lesion, pancreatic intraepithelial neoplasia-3 (PanIN-3). In addition, the PCDC will develop and test biomarkers and imaging methods to determine which intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are likely to progress to cancer. The research is expected to be conducted by appropriate multi-disciplinary teams, hereafter called "Units".

Clinically useful screening markers should be present in PanIN-3s and early stage PDAC, while absent in those patients without neoplasia, such as pancreatitis. These biomarkers should be readily detectable in easily obtainable biofluids, ideally collected using minimally invasive techniques (e.g. blood, saliva, stool, etc.).

The Units will be supported by individual U01 cooperative agreement awards and will work collaboratively towards the goal of the Consortium. Because each Unit must be multidisciplinary, they should include biologist(s), epidemiologist(s), pathologist(s), statistician(s), clinician(s),a research coordinator and investigators with imaging expertise (if applicable).

The Recalcitrant Cancer Research Act of 2012 calls for the National Cancer Institute (NCI) to develop a scientific framework for research on recalcitrant cancers that have a 5-year relative survival rate of less than 20%, and are estimated to cause the death of at least 30,000 individuals in the United States per year.

Pancreatic cancer is a recalcitrant cancer with a 5-year relative survival rate of less than 7% and resulting in approximately 40,000 deaths per year (SEER Stat Fact Sheets: Pancreatic Cancer). NCI’s 2014 Scientific Framework for Pancreatic Ductal Adenocarcinoma identified four research priorities. These priorities are in part based on the recommendations of an expert panel of extramural scientists convened by the NCI in October 2012 (http://deainfo.nci.nih.gov/advisory/ctac/workgroup/pc/pdacframework.pdf). One of the specific initiatives recommended by this panel was evaluating longitudinal screening protocols concomitant with development of new molecular and imaging biomarkers for patients at high risk for PDAC (because of genetic factors or the presence of mucinous pancreatic cysts) who could be candidates for early surgical intervention.

Pancreatic cancer is the fourth leading cause of cancer death in the United States, and PDAC represents over 90% of all pancreatic malignancies. The majority of PDAC are sporadic, occurring without a family history of the disease. The poor prognosis of pancreatic cancer is primarily due to its advanced stage at diagnosis. Pancreatic cancer does not exhibit early symptoms, and symptoms, when they do occur, are often nonspecific. Consequently, patients often present with locally advanced or metastatic disease. Surgical resection is currently the only potentially curative treatment, but it is only possible for 15-20% of patients, and most patients who undergo surgical resection will have disease recurrence.

Studies suggest an average of approximately 17 years between the occurrence of the initiating mutation and the acquisition of metastatic potential in PDAC. This window of time may offer an opportunity for curative interventions if the disease could be diagnosed at an earlier stage. However, currently, there are no effective early detection or screening methods for PDAC, and no biomarkers measurable in bodily fluids that can accurately and reliably detect early stage PDAC or its precursor lesions.

Although Genome-Wide Association studies (GWAS) have yielded useful information, their utility in measuring PDAC risk is limited due to the lack of functional tests. The challenge is to develop noninvasive or minimally invasive biomarkers with high clinical sensitivity and specificity that can accurately detect PanIN-3 and early stage PDAC. High specificity is particularly important, since a positive test may trigger invasive procedures, which add their own risk of morbidity and mortality. One strategy to achieve specificity could be a combination of molecular markers and imaging for the identification of alterations in exfoliated cells, circulating tumors cells, or secreted molecules (proteins or nucleic acids) which accompany the evolution PanIN-3s and PDAC.

There is a need for the development of molecular, imaging and/or integrated molecular and imaging approaches that are highly discriminating for pancreatic cancer. For patients with a strong clinical and radiological suspicion of PDAC, having a highly discriminating, non-invasive tool may expedite patients workups so they could proceed and receive treatment. Alternatively, for patients with a low suspicion of PDAC on clinical and radiologic imaging, having a highly discriminating, non-invasive tool should obviate additional costly workups. The second area of impact involves those patients with a high risk for developing PDAC, and in need of long-term surveillance.

Most imaging strategies for pancreatic cancer include invasive studies such as endoscopic retrograde cholangiopancreatography or endoscopic ultrasound (EUS). Having a safe, highly discriminatory, non-invasive tool to detect PDAC would provide a mechanism for these patients to be screened safely and effectively, with the hope of decreasing mortality from PDAC through early detection. Currently available modalities for screening for pancreatic cancer are mostly anatomical, including traditional cross-sectional imaging such as abdominal ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI), and invasive imaging such as EUS. Traditional cross-sectional imaging has little role in screening for sporadic pancreatic cancer. There have been significant advances in biomedical imaging and related physical technologies that may allow for the detection of PanIN-3s and early stage PDAC. For example, quantitative EUS elastography and microbubble contrast-enhanced EUS, which allow better visualization and delineation of focal pancreatic lesions.

Patients with IPMN and MCN are at high risk of developing PDAC. IPMNs and MCNs can be detected by abdominal imaging because they produce radiographically identifiable ductal dilatations and have been increasingly identified using abdominal imaging such as computed tomography done for workup of non-specific symptoms. However, the natural history of these lesions is not well defined. An estimated 15% of PDAC originate from these lesions. One-third of IPMNs are associated with an invasive carcinoma, and at the time of diagnosis, there is a 40% to 50% chance of the IPMN already being cancerous. MCNs are large mucin-producing precancerous lesions that are less common than IPMNs. MCNs can progress to PDAC, and one-third of patients with resected MCNs have cancer. Resection of IPMNs or MCNs prior to the development of invasive cancer is considered curative, but there are substantial risks of morbidity and mortality associated with surgery. Currently, it is difficult to distinguish precancerous mucinous cysts from benign non-mucinous cysts, the timing and frequency of malignant progression within the mucinous cysts is unknown, and there is a need for accurate biomarkers of high-grade dysplasia and risk of progression.

A major impediment to pancreatic cancer research is limited access to well-characterized and annotated specimens that can be used to discover and validate biomarkers. Pancreatic cancer is often diagnosed at late stages and the rapid demise of patients with PDAC contributes to the difficulty of obtaining well-annotated biospecimens from early stages of the disease. A minority of pancreatic resections are performed in a setting where tissue is routinely banked for research purposes. Even clinical centers with well-established collection protocols have very few specimens from patients with PanIN-3s and early stage PDAC. Addressing this challenge and the establishment of biorepositories with sufficient numbers of specimens will require collaboration among multiple institutions over time. Another shortcoming in the field is the inability of investigators to fully utilize the existing resources of individual facilities across institutions/universities. Several registries and cohorts of patients at high risk of PDAC have been developed, but very few have collected serial, longitudinal samples, which hinders progress in biomarker discovery and development for early detection.

This initiative is intended to support research to develop and test biomarkers and imaging methods for improved detection of early stage PDAC and its precursor lesions. This FOA will also support the collection of longitudinal samples (e.g., tissues, cystic fluids, serum, plasma) and other significant specimens for the non-invasive development of biomarkers. Research projects may include, but are not limited to:

• Development of more accurate and sensitive imaging methods to detect early stage PDAC and PanIN-3s that could be used to select patients for surgical intervention (imaging modalities can be anatomical, functional, or molecular);
• Development and validation of biomarkers to detect early stage PDAC and precursor lesions that could be used to select patients for surgical intervention;
• Development and integration of imaging approaches and multiplexed biomarker panels;
• Development of imageable biomarkers yielding 3D localization of PDAC and high-grade precursor lesions;
• Evaluation of longitudinal screening protocols using patients at high risk of developing pancreatic cancer;
• Evaluation of longitudinal screening protocols of patients with resected PDAC with subsequent follow-ups using imagining modalities;
• Longitudinal collection of samples and images from patients with pancreatic cysts to determine those lesions that are likely to progress to adenocarcinoma within a defined period (e.g. 3 years); determination of cysts with high malignant potential that are resectable;
• Development of novel methods to obtain and interrogate pancreatic tissues containing pre-neoplastic lesions.

Consortium Goals

The PCDC will be structured around individual scientific Units, funded through this FOA. Although the Units will be funded by individual U01 awards and will operate independently, they will be required to interact closely with other Consortium awardees, engage in collaborative activities, and share resources, ideas and expertise beyond the scope of a single research team. Research will require access to samples from existing cohorts of high-risk individuals, prospective collection of biospecimens and imaging. Therefore, collaborative research teams will aid in the recruitment of sufficient numbers of patients, collection of biospecimens, development and/or examination of diverse of imaging modalities, and the sharing of these resources. Teams will collaboratively develop Standard Operating Procedures (SOPs) and Common Data Elements (CDEs) for future sample collections.

Consortium Administrative Structure

Steering Committee: All scientific Units of the Consortium will be linked through a governing body, the Steering Committee. The Steering Committee will include representatives of the Consortium awardees and the NCI Project Coordinator. In addition, Chairs of other NIH programs may serve on the Steering Committee as ex officio members. The responsibilities of the Steering Committee include managing, overseeing and coordinating the integration of efforts among the awardees and all collaborative activities, including uniform standards of specimen and data collections and analysis. The Chair and co-Chair of the Steering Committee will be PDs/PIs of the Cooperative Agreement awards and will be selected by the Steering Committee in consultation with NCI. Further details of Steering Committee composition and responsibilities are provided in Section VI. Award Administration Information. Cooperative Agreement Terms and Conditions of Award.

Consortium Coordinating Unit: Application for the Consortium Coordination responsibilities is optional. The NCI will select one of the funded Units to serve as the Consortium Coordinating Unit, from the Applicants who also apply for this responsibility. Additional funding will be provided (see Section IV. Application and Submission Information. R&R or Modular Budget. for details). These activities may include, but are not limited to:

• Providing logistical and administrative assistance in arranging meetings to allow for efficient interactions, consultations, and oversight functions of the Steering Committee (e.g., preparing, distributing and maintaining minutes);
• Working with NCI Program Staff to develop and maintain an interactive webpage to publicize the activities of the Consortium, to announce the availability of Consortium-supported resources and receive input from investigators;
• Developing and maintaining a "listserv", Consortium documents including Manual of Operations and SOPs, standard procedures/protocols for data and specimen collection;
• Supporting the development, coordination, implementation, and conduct of Consortium collaborative research protocols and monitoring protocol adherence, data collection and submission;
• Creating and managing a patient registry with virtual biorepository that will encompass clinical and demographic information as well as available biospecimens at participating sites;
• Supporting the formation and distribution of Consortium biospecimen sets, biospecimen tracking and analyzing data that result from the use of these specimens;
• Creating and managing infrastructure for data management, bioinformatics, clinical data, and other requirements to support the Consortium Units.

Research projects that are not appropriate for this FOA

This FOA will not support research that is not explicitly focused on risk assessment and detection of early stage PDAC or its precursor lesions.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

Sudhir Srivastava, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute (NCI)
Telephone: 240-276-7028
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions:

• For this specific FOA, the Research Strategy section is limited to 30 pages.

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. In their Unit, Applicants are expected to include a collaborator directly involved in relevant cohort studies.

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

a) PD(s)/PI(s) Effort: The PD/PI must include a minimum of 3.0 person months of his/her time per year. For multiple PD/PI applications, the contact PD/PI must include a minimum of 3.0 person months of his/her time per year and all other PDs/PIs must include a minimum of 1.5 person months of their time per year to the award. This commitment cannot be reduced in later years of the award.

b) Consortium Collaborative Funds: Applicants must set aside $100,000 (direct costs) of their annual budget for Consortium collaborative studies. The set-aside amount should be presented in the Other Direct Costs category under the heading Consortium Collaborative Funds". The use of the set-aside funds will be restricted for collaborative studies proposed post-award. All collaborative studies will be subject to review and approval by the Steering Committee. The release of these restricted funds by the NCI will be contingent upon the recommendation of the Steering Committee.

c) Restricted Travel Expenses Budget: Applicants must budget for travel and per diem expenses for Steering Committee meetings. In the first year, applicants should plan for the PD/PI and an additional senior investigator to attend a Planning Meeting and one Steering Committee meeting. In the second and subsequent years, applicants should plan for the PD/PI and another investigator to attend one Steering Committee meeting per year.

Budget Information Related to Consortium Coordination Activities: Application for the Consortium Coordination responsibilities is optional. For this purpose, applicants interested in coordination responsibilities should provide a separate section for this budget in the Budget Justification , under the heading "Coordination Responsibilities".

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 :

Overview

Outline the overall theme of the proposed research, as well as the Significance and Innovation of the proposed studies. Propose research on the identification and testing of biomarkers measurable in bodily fluids for early detection of PDAC or its precursor lesions; determine which pancreatic cysts are likely to progress to cancer; develop molecular- and/or imaging-based approaches for screening populations at high risk of PDAC; conduct biomarker validation studies; and collect longitudinal biospecimens for the establishment of a biorepository.

For research on biomarkers, applicants are encouraged to refer to an article on a five-phase approach to biomarker development for successfully translating research on biomarker applications from the laboratory to the bedside (http://edrn.nci.nih.gov/docs). Analytical studies to establish and compare the sensitivity and specificity as well as the predictive accuracy of biomarkers in a clinical context, including inter- and intra-laboratory may also be proposed.

Define during the initial phases of development the intended clinical context in which a biomarker will be used and the likelihood of its use in routine clinical practice, if shown to be efficacious. This will also entail the modeling and analysis of the cost-benefit effect of its implementation in the clinic. Such modeling and analysis is intended to aid the optimized combination of the developed biomarker with other existing modalities to increase their combined impact on the targeted population.

Research Approaches

It is essential that each Unit identify and concentrate resources on the most promising scientific opportunities, studies be completed as planned, and methodologies employed are sound, and where appropriate, innovative. For each of the proposed research approaches, the following strategies should be used, wherever relevant.

• Prospective, cross-section or case-control studies to determine the sensitivity and specificity of a defined biomarker or biomarker panel in clinically appropriate populations (Early Detection Research Network [EDRN]-defined Phase 2 study);
• Determine the specificity of a defined biomarker or biomarker panel to detect preclinical disease (EDRN-defined Phase 3 study);
• Determine the accuracy of a biomarker or panel of biomarkers to predict progression from a precancerous lesion to cancer;
• Determine the accuracy of biomarkers to predict the extent or severity of disease;
• Perform comprehensive studies in targeted, high-risk populations for validation and potential integration of novel detection strategies;
• New imaging modalities to detect high risk precursor lesions (e.g., PanIN-3)
• Integration of imaging and molecular markers to detect early stage PDAC and PanIN-3 or to predict progression from IPMNs or MCNs to PDAC.

Study Design

The proposed study may initially involve the analysis of biospecimens from patients with neoplastic lesions versus respective control biospecimens (case-control or cohort samples) and with adequate follow-up information. A study may involve the use of retrospectively and/or prospectively collected specimens. However, detailed eligibility criteria in reference to incidental or screen-detected or symptom-detected, must be defined and described. If the mode of detection was noted from other than the existing database, such as using questionnaire in face-to-face interview to collect demographics and mode of detection, the process should be described. Details should also be provided as to how the ascertainments were made for screen-detected or symptom-detected cases. If using retrospective cohorts (screening or treatment), criteria for eligibility and cohorts details must be provided along with detailed clinical information, such as data on follow-up: median (max) length of follow-up, which endpoints were ascertained (cancer progression, death, cause of death) and how the endpoints were ascertained; patient age; disease stage; tumor size; lymph node status; and any other relevant treatment details. In case, specimens are being assembled from different sources and populations in terms of geography, demographics, ethnicity, etc., applicants should address the possibility of potential biases in the study design to minimize such biases.

A clear statement on how statistical power is defined in multiple tests and what sample size is required to achieve this power is required. Examples of power definition: (a) the probability to detect at least one of possible true non-zero effects; (b) the probability to detect all non-zero effects; and (c) true discovery rate, etc. Also, in case-control designs, clear descriptions of whether matching is involved and what cofounders are adjusted for and why, are required.

A multi-center validation study will not commence until the protocol is reviewed by the Steering Committee and approved by the NCI. To avoid bias and make best use of resources, the proposed biomarker validation studies should follow the principles of the prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) study design (http://edrn.nci.nih.gov/docs) or a similar study design. The criteria include the randomized selection of case patients and control subjects from a well-defined prospective cohort that is relevant to the intended clinical application, rigorous protocols that precisely define data items and procedures to measure them, and mechanisms to ensure that biomarker and outcome assessments cannot influence each other. Wherever possible, an evaluation study should be conducted for biomarkers that show promise in discovery studies that use the same clinical context and population. The evaluation of the performance of a marker or marker combination can be undertaken by using a PRoBE design and randomly splitting the dataset into a training set for discovery and a test set for evaluation.

Establishment of Biorepository

Applicants should describe plans for collection of prospective, longitudinal specimens from high-risk individuals (i.e. familial and hereditary registries), other appropriate cohorts, sporadic cases of early stage PDAC (Stage IA, IB, IIA and IIB), pancreatic cancer precursor lesions (PanINs), cystic lesions (IPMNs and MCNs), and benign pancreatic conditions (i.e. acute and chronic pancreatitis, biliary obstruction) in accordance with Steering Committee-developed protocols. Types of samples to be collected may include plasma, serum, DNA, stool, urine, duodenal/pancreatic aspirates, cystic fluid, diagnostic biopsies, pancreatic resections, image-guided samples, such as EUS- or secretin-stimulated magnetic resonance cholangiopancreatography (S-MRCP)-guided biospecimens.

Applicants must document the ability to recruit patients, procure specimens prospectively, collect epidemiological and clinical data using CDEs, and to process, track, and store specimens. Applicants should describe in detail any proposed retrospective and/or prospective specimen collections that will be used for Consortium activities. The description should include information on the types of patients and control subjects to be accrued, clinical information to be collected, and types of specimens to be collected.

Autopsy specimens, especially for indolent and early stage cases, can also be used in experimental designs. In cases where autopsy samples are proposed, procedures for acquiring samples and obtaining clearances from State and regulatory authorities, including those from an institutional review board (IRB), must be submitted. A portion of the samples collected during the tenure of this funding must be deposited in the Central Repository at NCI-Frederick for establishing reference sets and use as a shared-resource.

Collaborative Responsibilities

Each Unit should provide plans for working collaboratively with the other Consortium Units to facilitate the discovery, clinical validation, and clinical application of biomarkers through participation in multi-institutional studies. The Units will provide expertise on cohorts, protocol development, and pathological assessment, and will participate in data quality control, analysis, and interpretation of validation studies.

The applicants should also describe plans to provide archived specimens to other Units for discovery and/or validation studies. Prospectively collected specimens can be used for one or more of the following: (1) validation studies proposed in the application; (2) collections to be shared with other members of the Consortium; and (3) requests from other Consortium investigators that have been recommended by the Steering Committee and approved by the NCI. Collaboration with cooperative groups with ongoing trials that can provide a unique opportunity for prospective longitudinal collection of specimens for PDAC is also encouraged. Restricted set-aside funds may be used to support specimen collections to be shared with other members of the Consortium and to support requests from other investigators. All specimen collection and storage should follow the guidelines provided in the NCI Best Practice for Biospecimen Resources (http://biospecimens.cancer.gov/practices/default.asp).

Letters of Support: In addition to the standard items, please provide letters from collaborators documenting access to appropriate samples.

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, should provide a Data Sharing Plan.

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

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

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

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow our Post Submission Application Materials policy.

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

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? 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?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? 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 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?

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? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

In addition, specific to this FOA: If the proposed study is a biomarker validation study, does it incorporate principles of the PRoBE (or a similar) study design? Is there a feasible and appropriate strategy for longitudinal collection of biospecimens?

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?

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

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact 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 five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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.

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

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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

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

As part of the scientific peer review, all applications:

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

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

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

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

The PD/PI (or multiple PDs/PIs, if applicable) under the Consortium auspices will have primary responsibilities in the following areas:

• Defining objectives and approaches, overseeing planning and conducting experiments, analyzing and interpreting results, and publishing reports of studies conducted under this award;
• Assuming responsibility and accountability to the applicant organization and to the NCI for the performance and proper conduct of the research in accordance with the terms and conditions of the award;
• Serving as voting members of the Consortium Steering Committee. In accordance with this cooperative agreement, the PD/PI and another senior investigator (or two PD(s)/PI(s) for multi-PD/PI awards) from each Consortium award (U01) will be required to attend Steering Committee meetings once a year;
• Accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee to the extent consistent with applicable grant regulations;
• Coordinating efforts and cooperating with the other components of the Consortium and with NCI Program staff;
• Overseeing the implementation of the approved data sharing plan;
• Ensuring that experimental data and their format, analytical algorithms, computational modeling and visualizations, and other bioinformatics tools resulting from this FOA are compatible with the NIH-approved bioinformatics platforms, such as those designed and implemented by the NCI Center for Bioinformatics (http://cbiit.nci.nih.gov);
• The PDs/PIs and their awardee institutions will be accountable for implementing the approved research resource sharing plan;
• All 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;
• Each Consortium awardee and the entire Consortium programmatic initiative will be subject to external evaluation (coordinated by the NIH). Consortium Awardees will be expected to participate in such evaluations.

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

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

A designated NCI Program staff member serving as Project Coordinator will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additionally, an NCI Program Director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Program Officials may also have substantial programmatic involvement (as Project Scientists).

Main NCI Project Coordinator responsibilities include the following:

• Overarching coordination of the Consortium and the various activities of the Consortium Steering Committee;
• Monitoring the scientific progress of the entire Consortium and the entire program;
• Promoting collaborative research efforts that involve interactions with other NCI-sponsored programs, projects, and centers;
• In cooperation with the NCI Center for Bioinformatics, ensuring that there are effective mechanisms to enable electronic communication among the Consortium Units, and between the Consortium and the NCI;
• Coordinating external evaluation of the Consortium;
• Serving as liaison between the Consortium investigators and NCI staff members;
• Assisting the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require coordinated action;
• Developing working groups and trans-project efforts as needed.

The NCI reserves the right to adjust funding, withhold, suspend, or terminate the support to those consortium awardee institutions that are unable to meet the performance requirements set forth in these Terms and Conditions of Award, or significantly change the level of performance.

Additionally, an NCI 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 Responsibility include:

Steering Committee: The Steering Committee will be the main governing body for the Consortium. The Steering Committee will be composed of the following voting members:

• Two representatives from each Consortium award (the PD(s)/PI(s) or a PD/PI and a designated senior investigator) who will have one vote each; and
• NCI Project Coordinator (who will have one vote).

Assigned 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. This decision 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 Steering Committee will be selected from the representatives of all awardees.

In addition, Chairs of other NIH programs may serve on the Consortium Steering Committee as ex officio members.

The Steering Committee will meet once every year, at locations selected by the Steering Committee in consultation with the NCI.

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

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

• Establishing Consortium policies and procedures;
• Establishing policies and procedures for collaborative projects, protocols, and Consortium-defined projects;
• Develop guidelines for the collection and distribution of specimen reference sets for collaborative research;
• Setting the overall research priorities for the Consortium and identifying emerging research opportunities which can be best explored through a joint collaborative effort via the Consortium;
• Serving as a nucleus for a broader outreach to the entire extramural research community investigating indolent versus aggressive cancers or cancers detected via existing screening programs or based on the appearance of clinical symptoms;

Joint Consortium Activities

A significant part of the Consortium will be Joint Consortium activities. While each funded Unit will be largely self-sufficient, investigators will be expected to devote a portion of their effort to participating in collaborative activities with other Consortium members. The individual Unit will have access to resources, information, technologies, ideas, and expertise that are beyond the scope of any single research Unit. Awardees will be charged with developing collaborative projects, resources for the community, and where possible, Consortium-sponsored outreach activities. These efforts will require interaction and collaboration among Consortium-funded investigators and/or with other investigators. Support for these collaborative activities will be provided by the restricted funds of each U01 award. The plans to use these restricted funds will be subject of review and approval by the Consortium Steering Committee and final approval by the NCI to release specific funds from the individual U01 awards.

The Consortium will:

• provide an appropriate venue for close interactions among investigators;
• facilitate exchange of data and comparison of results obtained across a variety of tumors; and,
• disseminate expertise that may be initially concentrated within a single Unit.

The NCI will ensure common access to Consortium-generated resources and reagents for the broader cancer research community. The NCI will also encourage the Consortium members to interact with existing NCI-supported multidisciplinary Unit, such as the Early Detection Research Network (EDRN) and the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer Clinical Centers.

To facilitate communications among the participants in the Consortium and between the Consortium and the NCI, the NCI will establish and maintain an internet-based information technology solution for rapid data and document transmission and electronic communications for the Consortium.

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 regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

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

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

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

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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: https://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Sudhir Srivastava, Ph.D., M.P.H.
National Cancer Institute (NCI)
Telephone: 240-276-7028
Email: [email protected]

Jo Ann S. Rinaudo, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7133
Email: [email protected]

Sharmistha Ghosh-Janjigian, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7122
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: [email protected]

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

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