Part I Overview Information


Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH) (http://www.nih.gov/)

Components of Participating Organizations
National Cancer Institute (NCI) http://www.cancer.gov/

Title: Clinical Proteomic Technologies for Cancer Initiative (CPTC): Proteome Characterization Centers (U24)

Announcement Type
Reissue of RFA-CA-07-012

Update: The following update relating to this announcement has been issued:

Request For Applications (RFA) Number: RFA-CA-10-016

Catalog of Federal Domestic Assistance Number(s)
93.393, 93.394, 93.396, 93.397

Key Dates
Release Date:  June 25, 2010
Letters of Intent Receipt Date: August 29, 2010
Application Receipt Date: September 29, 2010
Peer Review Date(s): December 2010-January 2011
Council Review Date: January 2011
Earliest Anticipated Start Date: April 1, 2011
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: September 30, 2010

PRE-APPLICATION MEETING

The NCI anticipates holding a pre-application meeting several weeks prior to the application receipt date deadline to which all interested prospective applicants are invited. NCI program and review staff members will make presentations to explain the goals and objectives for Proteome Characterization Centers (PCCs) in the Clinical Proteomic Technologies for Cancer initiative (CPTC), to discuss the application peer review process, and to answer questions from the attendees. An NCI Grants Management Specialist will be available to answer financial questions. A Notice with the date and time of the meeting will be issued in the NIH Guide for Grants and Contracts (go to http://grants.nih.gov/grants/guide/index.html).

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents


Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
 A. Eligible Institutions
 B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
 A. Receipt, Review and Anticipated Start Dates
 1. Letter of Intent
 B. Sending an Application to the NIH
 C. Application Processing
D. Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
 A. Cooperative Agreement Terms and Conditions of Award
 1. Principal Investigator Rights and Responsibilities
 2. NIH Responsibilities
 3. Collaborative Responsibilities
 4. Dispute Resolution Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives

Purpose

The goal of the Clinical Proteomic Technologies for Cancer initiative (CPTC) is to develop a network of centers that will utilize robust, quantitative, proteomic technologies and workflows to systematically discover and verify protein biomarkers for cancer that can be qualified in clinical studies.

This Funding Opportunity Announcement (FOA) is designed to build a network of milestone-driven Proteome Characterization Centers (PCCs) with experts in proteomics, genomics, clinical chemistry, medical oncology, technology improvement, and bioinformatics. Each PCC proposed in response to this FOA must be focused on the following outcomes:

(a)   Biomarker Discovery: PCCs are to identify and characterize proteins from tumor and normal biospecimens. Within the context of hypothesis-driven cancer biology and potential clinical applications, discovered biomarkers will be prioritized for verification assay development.

(b)   Biomarker Verification: PCCs are to develop analytically validated, multiplex, quantitative assays for verifying the prioritized list of discovered biomarkers in blood (and tissue/proximal fluids when appropriate). These assays will be performed on a large number of clinically relevant biospecimens to ensure sufficient statistical power of the results.  Proteins successfully passing this screen (i.e., verified) are expected to be considered high value targets for translating into other initiatives involved in clinical qualification studies. These biomarkers will be made publicly available through the CPTC Data Center, as will the unbiased discovery data and assay details.

(c)   Technology/Platform Development: PCCs are also expected to pursue improvements in proposed technologies for protein detection, identification, and quantification, actively leveraging the network environment.

Background

The Origins of Clinical Proteomic Technologies for Cancer Initiative (CPTC)

Despite significant progress in understanding cancer at the molecular level, the sheer complexity of the over 200 diseases that comprise “cancer’” is a daunting barrier to developing the interventions needed to diagnose, treat, and prevent cancer. Vital to the progress in these areas is the discovery and understanding of cancer-specific aberrations at various molecular and cellular levels. Although proteins reflecting the genomic changes in cancer have the potential to become clinically meaningful biomarkers, their discovery and validation has proven to be challenging. As a result, few biomarker candidates have translated into clinical utility.

Two key barriers in the early stages of biomarker development are: 1) a limited understanding of the changes in cancer genomes that translate into functional differences at the proteomic level; and 2) insufficient technologies that could be widely applied to reproducibly detect and quantify these aberrant proteomic changes across samples from cancer and control populations. Significant barriers to the development of cancer protein biomarkers include insufficient inter-laboratory reproducibility, lack of standards for proper study design, various analytical barriers, biospecimen collection/handling, data acquisition/analysis, and a notable absence of standards and high quality reagents. The progress in the field has also been slowed by the lack of a coherent “pipeline” to connect biomarker discovery with well-established methods for qualification. Various cancer-related proteomic changes have been identified in numerous published studies. However, these studies mostly came from diverse research groups working independently. Consequently, the findings are typically based on an insufficiently low number of samples to have adequate statistical power needed for rigorous evaluation of the observed protein aberrations as specific, clinically relevant cancer biomarkers.

Recognizing this need for an evidence-based, proteomics pipeline, the NCI launched in 2006 the Clinical Proteomic Technologies for Cancer initiative (CPTC). At that stage (Phase I), the CPTC initiative was focused on removing technical barriers in order to enable the accurate, efficient, and reproducible identification and quantification of a meaningful number of proteins to drive clinically-relevant biomarker qualification studies. Phase I of the CPTC initiative has demonstrated the effectiveness of a multi-disciplinary, multi-institutional approach in addressing long-standing problems of analytical variability in proteomics and ways to overcome the inherent variability of specific analytical platforms in order to uncover and quantify real biological differences.

Although discovery efforts oriented on cancer protein biomarkers identify many hundreds of candidate biomarkers, CPTC investigators recognized that only a few would eventually prove clinically useful. Therefore, it was felt that developmental strategies must allow for an efficient testing of many biomarker candidates to identify and verify those few that would be suitable for further clinical implementation. Addressing this need, researchers involved in the first phase of CPTC initiative designed a two-step strategy (further referred to as the developmental “pipeline”) for the efficient, timely, and cost-effective development of protein (and peptide) biomarkers for qualification studies. The two steps, referred to as “Biomarker Discovery” and “Biomarker Verification”, are outlined below.

Recent Advances and Challenges for Cancer Proteomics

Recently, significant progress has been made in characterizing and sequencing the genomic alterations in statistically robust numbers of samples from several types of cancer. For example, The Cancer Genome Atlas (TCGA, http://cancergenome.nih.gov) and other similar efforts are identifying genomic alterations associated with specific cancers (e.g. copy number aberrations, rearrangements, point mutations, epigenomic changes, etc.). The availability of these multi-dimensional data to the scientific community sets the stage for the development of new molecularly targeted cancer interventions. Understanding the comprehensive functional changes in the proteome that arise from the genomic alterations or other factors is the next logical step in the development of high-value protein biomarkers that can drive the rational development of new diagnostics and therapies to achieve personalized cancer medicine.

Specific Research Objectives of this FOA

Scope

For the purpose of this FOA, the term proteomics refers to the analysis of the proteins derived from a cancer genome. Distinct changes at the protein level may reflect changes in cancer genomes. Furthermore, factors other than genomic alterations are also involved in shaping the cancerous proteomes resulting in differential expression, post-translational protein modifications, changes in specific activity, and/or aberrant localization in tumor cells. All of these proteomic changes may contribute to the process of carcinogenesis and/or maintenance of the cancerous phenotype. Identifying and understanding the origin of these changes, improving proteomics detection and measurement technologies, and discovering and verifying cancer protein biomarkers are the goals of the reissuance of the CPTC initiative.

Overarching Goals

One of the main goals of this FOA is to leverage the achievements from the CPTC to systematically explore the functional cancer proteome that derives from defined alterations in the cancer genomes or other factors in order to discover and develop verified cancer biomarkers. The FOA also stresses the development and maturation of existing and new proteomic technologies as a goal. Proteomic technologies may offer advantages such as speed (throughput), and/or increased breadth and quality of data to support the discovery of new cancer protein biomarkers. An important goal of CPTC is to provide the cancer research community with comprehensive proteomic characterization data of several tumor types. The CPTC reissuance is designed to support efforts that will utilize data and biospecimens from high-throughput cancer genome characterization and sequencing programs to discover and verify biomarkers that can be transitioned to clinical studies by other NCI programs; e.g., the NCI’s Cancer Therapy Evaluation Program (CTEP, http://ctep.cancer.gov), the Early Detection Research Network (EDRN, http://edrn.nci.nih.gov), the Cooperative Groups (http://www.cancer.gov/cancertopics/factsheet/NCI/clinical-trials-cooperative-group), and the broad cancer research communities.

Overview of CPTC Components

Proteome Characterization Centers (PCCs). The CPTC reissuance under this FOA will create a network of PCCs. Each proposed PCC must have a Discovery Unit and a Verification Unit, which will together implement the 2-step proteomics biomarker developmental “pipeline.”

CPTC Steering Committee. PCC awardees with the participation of the NCI staff members will form a CPTC Steering Committee, which will serve as the primary governing body of the CPTC, and will include a Biomarker Candidate Selection Subcommittee. The Biomarker Candidate Selection Subcommittee will consolidate and recommend to the CPTC Steering Committee the selection of discovered biomarkers for verification studies. For details on the role of these committees see Section VI, 2.A. Cooperative Agreement Terms and Conditions of Award.

Additional Components Directly Sponsored by the NCI (beyond the scope of this FOA). To facilitate the activities of individual PCCs and the entire CPTC Program, the NCI will create and directly support two additional components beyond the scope of this FOA: (1) the CPTC Data Center and (2) the CPTC Resource Center. The CPTC Data Center will serve as the hub and central repository of all data from the PCCs. The CPTC Resource Center will function as a collection and distribution hub for common biospecimens for the PCC Network. The CPTC Resource Center will also provide support for the pipeline verification step through the development of reference materials for assay development, as agreed upon by the CPTC Steering Committee and approved by the NCI.

Integration of CPTC Components. The structure of CPTC is designed to facilitate the efficient implementation of the 2-step developmental pipeline. Briefly, the pipeline originates with the CPTC Resource Center, which will provide a set of high quality, genomically characterized, clinical biospecimens (tumor and normal whenever available) from patients with a single type of cancer. The biospecimens will be from a selection of cancer types, potentially including glioblastoma multiforme (GBM), serous cystadenocarcinoma of the ovary, squamous carcinoma of the lung, clear cell kidney carcinoma, colon adenocarcinoma, and acute myeloid leukemia (AML).

Discovery Units of each PCC will use a set of proteomic technologies to comprehensively analyze the protein composition of this set of biospecimens. To create a comprehensive data set for advancing proteomic research consistent with the goals of this program, all data from the Discovery Units will be shared within the network via the CPTC Data Center. Based on this aggregate dataset, each Discovery Unit will select and prioritize cancer-related proteins for potential use in the verification step.

The selected lists of prioritized proteins by the Discovery Units will be consolidated and collectively prioritized by the Biomarker Candidate Selection Subcommittee. This network-wide subcommittee will consider the clinical, biological, and technical aspects of each protein and develop a verification plan for the proteins, laboratories, and resources involved in the verification step. These verification plans will be subject to final approval by the CPTC Steering Committee, which may include assigning to a given PCC the verification of proteins discovered by another PCC.

The Verification Unit of each PCC will develop targeted assays against corresponding protein targets as assigned by the verification plan. The CPTC Resource Center will facilitate assay development by providing key reagents (reference materials) as required. The Verification Units will then verify the biomarkers by performing these assays in clinically relevant cancer biospecimens (provided by the CPTC Resource Center). The number of biospecimens will be sufficiently large so as to ensure appropriate statistical power (expected to be approximately 500). Data from these verification studies will be shared via the CPTC Data Center. These verified proteins will serve as high value targets to other initiatives involved in clinical qualification studies. Biospecimens under consideration for each step include: Discovery - tumor and normal biospecimens; Verification - blood, and tissue/proximal fluids when appropriate.

Achievement of the goals of this reissuance for CPTC will address the growing gap between multi-dimensional data at the genomics and proteomics level needed to support the cancer research community in their efforts to develop new, clinically useful protein biomarkers.

Note: Investigations that employ clinical biospecimens are within the scope of activities that will be considered for support by this initiative. However, this FOA will NOT support new clinical trials.

Overall Research Objectives and General Requirements

Each applicant team proposing a PCC must demonstrate their capability to establish and operate the following critical components (described below) and all components must be included for an application to be responsive to this FOA:

  1. Discovery Unit
  2. Verification Unit
  3. Administrative Core

In addition, applicants must adhere to other general and specific requirements, including:

  1. Other General Considerations (Technology Development Plan; Data Sharing Plan)

Note: The main PCC components and their general requirements are outlined below. Other specific requirements that must be addressed are defined in “Section IV.6 Other Submission Specific Requirements and Information.”

A.        Research Objectives for Discovery Unit

Discovery Unit is expected to comprehensively characterize tumor and normal biospecimens and identify their protein composition in order to systematically identify and prioritize cancer-related proteins for advancement to verification.

Discovery will include analysis of wild-type and mutant proteins, including modifications such as post-translational modifications (PTMs), using validated protein discovery technologies. These types of characterizations should be conducted using analytical methods in a high-throughput fashion and be deployable at the start of the project. All characterization data will be made available to the PCC network and to the public through the CPTC Data Center.

Using the characterization data from across the PCC network, PCCs will identify and establish systematic, comprehensive (protein-wide) criteria for selection and prioritization of cancer-related proteins and their alterations for verification. Since “-omics” discovery approaches generally identify more candidates than can realistically be qualified, a center prioritization strategy is required to enable selection of candidates to advance to the verification unit. Prior to this advancement, a broader criteria for prioritization of the most clinically and biologically relevant proteins for the entire network will be established by the Biomarker Candidate Selection Subcommittee, and approved by the CPTC Steering Committee. Candidates approved by the Biomarker Candidate Selection Subcommittee are what will move forward into each center’s verification unit in a network-coordinated manner.

NCI-provided Biospecimens. The aim is to have all the proteomic characterizations conducted on the same biospecimens for which full genomic and transcriptomic analyses have been performed, as is done in programs for comprehensive characterization of cancer genomes, such as TCGA. This approach will enable achieving optimal analytical integration for data comparability. Achieving the specific goals for the Discovery Unit will require interdisciplinary cooperation among proteomic researchers, cancer biologists, genomic /genetic technology specialists, bioinformaticians, and biostatisticians.

The cancer biospecimens for these studies will be provided by the CPTC Resource Center. Potential cancer types for study include but are not limited to glioblastoma multiforme (GBM), serous cystadenocarcinoma of the ovary, squamous carcinoma of the lung, clear cell kidney carcinoma, colon adenocarcinoma, and acute myeloid leukemia (AML).

Note: Additional details pertaining to the type and number of biospecimens to be provided by the NCI and their distribution across PCCs will be forthcoming.

Investigator-provided Biospecimens. PCCs may also elect to submit human cancer tumor and normal biospecimens other than those supplied by the CPTC Resource Center provided that:

Use of these biospecimens within the PCC network will be subject to approval by the CPTC Steering Committee.

Discovery Unit Objective 1: Comprehensively characterize the protein component of biospecimens provided by the Resource Center using specific high-throughput, metrics-driven, proteomic technologies.

Requirements for Discovery Unit Objective 1:

The CPTC Resource Center will provide tumor and normal biospecimens to the PCCs, with PCC Discovery Units expected to have the appropriate laboratory infrastructure, instrumentation, data and quality control systems to support the technology selected for protein characterization. The Discovery Unit must be able to conduct technologically advanced, comprehensive, and rigorous characterization of proteins to biospecimens provided by the CPTC Resource Center.

General requirements are:

Discovery Unit Objective 2: Establish systematic, comprehensive (protein-wide) data analysis criteria for selection and prioritization of cancer-related proteins and their alterations for Verification.

Requirements for Discovery Unit Objective 2:

General requirements are:

B.        Research Objectives for Verification Unit

Verification Unit is expected to generate accurate, reproducible, sensitive, quantitative, multiplex assays by using optimized and standardized high-throughput technologies for the discovered biomarkers. These verification assays will be performed on a large numbers of clinically relevant biospecimens to ensure sufficient statistical power of the results. Credentialed proteins (identified and selected by the Biomarker Candidate Selection Subcommittee) which continue to show biological and clinical relevance in verification studies are considered verified biomarkers, and high value targets to other initiatives involved in clinical qualification studies.

In the context of this FOA, a protein target is defined as a wild type, mutant, modified, or otherwise aberrant protein resulting from a given “parent” gene. For example, wild-type EGFR may be amplified, or constitute a deletion variant (e.g. EGFRvIII) or contain point mutations (e.g. exon 21). Though all three variations are related to a shared “parent” gene, each of these variations can be treated as a distinct protein target. Consideration of more than one target from a single parent gene for inclusion in the verification phase will require justification based on data from the discovery phase. A goal of the PCC network is to develop assays to protein targets from at least 500 parent genes. To ensure adequate coverage of biologically relevant gene alterations, it is expected that assays be developed for an average of two protein targets from each parent gene. These assays will be optimized and multiplexed for verification in clinical biospecimens.

Biospecimens for Verification will be provided by the CPTC Resource Center. PCCs may also elect to submit biospecimens (tissues and human blood samples/biofluids) other than those supplied by the CPTC Resource Center provided that:

Verification Unit Objective 1. Systematically develop verification assays against corresponding protein targets as identified and selected by the Biomarker Candidate Selection Subcommittee.

Requirements for Verification Unit Objective 1:

The CPTC Resource Center will provide biospecimens (blood, and tissue/proximal fluids when appropriate) to the PCCs, with PCC Verification Units expected to have the appropriate laboratory infrastructure, instrumentation, data and quality control systems to support the technology selected for protein verification.

Each PCC is expected to:

Verification Unit Objective 2. Apply verification assays to clinical samples supplied from the CPTC Resource Center - Rigorously verify protein biomarker candidates using quantitative assays developed under Objective 1 on a large number of clinically relevant biofluids (and tissues) to ensure sufficient statistical power of the results. These biospecimens will be specified and provided by the NCI. Objective 2 is expected to generate biomarkers that are verified and of high value to other initiatives involved in clinical qualification studies.

Requirements for Verification Unit Objective 2:

Specific requirements are:

C.        Administrative Core

Each PCC must have appropriate infrastructure for PCC leadership, coordination of center efforts, and participation in overall PCC Network activities (Administrative Core). Administrative Core must provide the following infrastructure elements:

D.        Other General Considerations

Technology Development Plans. Applicants are expected to include a technology development plan to improve the technology/platform(s) used in the PCC consistent with achieving the goals of this program. These efforts may serve the Discovery Unit or Verification Unit or both. The technology development plans should be appropriate to the maturity of the technology, that is, mature and established technologies will require less development than emerging technologies. In general, improvement efforts of technologies/platforms could include (but are not limited to): (a) enhancing detection sensitivity and/or resolution; (b) increasing throughput; (c) optimizing proteome coverage; and (d) reducing unit costs per analysis. The technology development plans may also include any software development related to generation and/or analysis of CPTC data.

Data Sharing Plan. Broad availability of data/information generated by PCCs will be critical to facilitate disease relevant discoveries of clinical significance consistent with the goals of this program. Therefore, sharing all rigorously validated data as a public resource is essential for this FOA. All PCC awardees will be expected to upload all of their data to the CPTC Data Center (serving as the central data repository). All applicants are expected to submit a Data Sharing Plan documenting how and when data obtained throughout the pipeline in Discovery and Verification stages (raw, processed [protein identifications], and analyzed data) will be released and shared, consistent with the goals of CPTC described in this FOA and with NIH data sharing guidelines. See Section VIII, Other Information - Required Federal Citations, for policies related to this FOA. Where appropriate, the proposed data types and outputs must comply with data standards of the cancer Biomedical Informatics Grid (caBIG®, https://cabig.nci.nih.gov) as a unified platform for sharing and disseminating information.

Section II. Award Information


1. Mechanism of Support

This funding opportunity will use the NIH Specialized Center Cooperative Agreement (U24) award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses “Just-in-Time” information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

This funding opportunity will use a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

2. Funds Available

Future year amounts will depend on annual appropriations.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation; see NOT-OD-05-004.

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.

Section III. Eligibility Information


1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed team research as the PD/PI is invited to work with his/her institution 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.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans, policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations, and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Number of Applications: Applicants may submit more than one application, provided they are scientifically distinct and led by different PIs.

Resubmissions: Resubmission applications are not permitted in response to this FOA.

Renewal: Renewal applications are not permitted in response to this FOA

Section IV. Application and Submission Information


1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact Grants Info, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Prepare all applications using the PHS 398 application forms and in accordance with the PHS 398 Application Guide (http://grants.nih.gov/grants/funding/phs398/phs398.html).

Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

For details on application structure, see Section IV.6. Other Submission Requirements and Information.

Foreign Organizations (Non-domestic (non-U.S.) Entity)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from foreign organizations must:

In addition, for applications from foreign organizations:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a – 3h for all PD/PIs. NIH requires one PD/PI be designated as the “contact PD/PI” for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the “Contact PD/PI, et. al.” The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, the section of the Research Plan entitled, “Multiple PD/PI Leadership Plan”, must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: August 29, 2010
Application Receipt Date: September 29, 2010
Peer Review Date(s): December 2010-January 2011
Council Review Date: January 2011
Earliest Anticipated Start Date: April 1, 2011

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Henry Rodriguez, PhD, MBA
Office of Cancer Clinical Proteomics Research
Center for Strategic Scientific Initiatives
Office of the Director, National Cancer Institute
31 Center Drive, Room 10A52, MSC 2580
Bethesda, MD 20892-2580 (for U.S. Postal Service regular or express mail)
Bethesda, MD 20892 (for non-USPS delivery)
Telephone: (301) 451-8883
FAX: (301) 496-7807
Email: rodriguezh@mail.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

3.C. Application Processing

Applications must be received on or before the application receipt date) described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Specific Requirements

PHS398 Research Plan Sections

All application instructions outlined in the PHS 398 Application Instructions are to be followed, with the following additional requirements:

Budget

This FOA uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). 

All foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096.

For the applications submitted in response to this FOA, the standard PHS 398 Research instructions for the application preparation are altered as follows: 

Table of Contents (PHS 398 Form Page 3): Modify Form Page 3 of the PHS 398 (Table of Contents) to include the following sub-sections in Section 3 “Research Strategy” of the PHS 398 Research Plan:
  1. Overview of the Proposed PCC
  2. Discovery Unit
  3. Verification Unit
  4. Administrative Core

Budget (PHS 398 Form Pages 4 and 5): Follow the current PHS 398 instructions to provide a detailed budget (direct costs) for the entire application for the first 12-month period (Form Page 4) and the entire proposed project period (Form Page 5).

Use additional Form Pages 4 and 5 to provide detailed separate budget information (first year and cumulative budgets for the entire project period) for the following individual application components:

RESEARCH PLAN: The standard PHS398 Research Plan is altered as follows:

Other sections of the PHS398 Research Plan remain unmodified and should be completed following standard instructions.

Section A: Overview of the Proposed PCC (limit 12 pages)

Present the overall vision for the proposed Proteome Characterization Center (PCC) including the following items:

If appropriate, preliminary data relevant to the proposed methods and/or specific technologies should be included in the following sections. Applicants should demonstrate an understanding and capability to meet the scientific requirements, including accuracy, reproducibility and high-throughput. Furthermore, there should be evidence for the quality of the data that may be anticipated from the proposed technology platforms when utilized by the applicant.

Section B: Discovery Unit (limit 12 pages)

Plan for the Discovery Unit must be organized in two blocks:

Discovery Unit Objective 1: Comprehensively characterize the protein component of biospecimens provided by the CPTC Resource Center using high-throughput metrics-driven proteomic technologies; and

Discovery Unit Objective 2: Establish systematic, comprehensive (protein-wide) data analysis criteria for selection and prioritization of cancer-related proteins and their alterations for Verification.

Details for each block are below.

Discovery Unit Objective 1 - Comprehensively characterize the protein component of biospecimens provided by the CPTC Resource Center using high-throughput metrics-driven proteomic technologies.

a)     Describe the process and the technology platform(s) on which the proposed Discovery will focus. To be eligible, a technology platform must be reproducible and sensitive for proteomic discovery/characterization. For the purposes of this FOA, a Discovery technology platform is considered validated if it meets the following criteria: has successfully been deployed in at least one other site; is capable of generating reproducible results across laboratories in a high-throughput setting; and has been previously published in a peer-reviewed journal. Applicants will outline and describe in detail the plan for the proposed identification of proteins from the supplied biospecimens, including any analysis of PTMs and genetic aberrations. This description will include throughput and enumeration of biospecimen discovery capacity per year, efficiency, sensitivity, number of proteins identified per analysis, error rate of identification, and expertise (personnel) involved in the process. Applicants will describe the amount of biospecimen material needed in order to perform the proposed analysis. Applicants should plan on receiving no more than 10 mg (wet weight) of solid tumor per case for discovery analysis. Applications will be valued on their efficiency in using this material, throughput levels, and protein and PTM identification capabilities.

b)    Analytic Capacity of the Discovery Unit. This section of the application must provide evidence of the analytic capacity to meet the objectives of this FOA for protein discovery/characterization (including post-translational modifications). Applicants must demonstrate the capability to meet throughput requirements. They should also identify their maximal capability and the potential for increasing throughput during years 2–5. Applicants need to define a timeline and milestones specific to the technology platform, which also describe the acceleration of sample throughput rates throughout the course of the project. Applicants must present an explicit, estimated timeline for achieving the operational capacity to conduct protein characterization as outlined in Discovery Unit Objective 1. Automated solutions for increased analysis throughput are highly encouraged. Information must be provided in detail on the involvement of skilled personnel needed to conduct experimental analyses, as well as data processing and bioinformatics analyses for the proposed number of samples. If personnel, equipment and other resources related to operation of a technology platform have a shared commitment to other projects (e.g., core resources, other awards, etc.), applicants need to specify how sufficient access will be guaranteed for the purposes of the project. To meet the project’s goals, it is expected that each Discovery Unit will be able to characterize a minimum of 50 biospecimens in year 1. The characterization methodologies will be expected to yield on the order of hundreds of accurate identifications per tumor sample, adequate to statistically satisfy the end goals of the project. Also, typical error rates for the technology platform need to be described. All capital equipment instruments must be operational and available at the proposed start of the project period.

c)     Describe in detail the Quality Assurance/Quality Control Criteria for Platforms Used. Describe a strategy to ensure and monitor the quality of instrument performance and data generated. Include plans to ensure implementation of metrics for instrument quality control and SOPs for sample storage/processing. Where appropriate, use metrics and SOPs developed by the CPTC, such as the NIST LC-MS/MS metrics for monitoring variability in proteomics experiments (http://peptide.nist.gov/metrics). Examples of such metrics may include: reference material measurements, limits of detection, limits of quantitation, number of protein identifications, signal-to-noise ratio, and other measurements that provide evidence of adequate instrument performance.

Discovery Unit Objective 2: Establish systematic, comprehensive (protein-wide) data analysis criteria for selection and prioritization of cancer-related proteins and their alterations for Verification.

Define evidence-based criteria that will be utilized for prioritization. The criteria must clearly itemize the go/no-go decision and the sequential process and steps that will be taken to arrive at protein Prioritization. Bioinformatic analysis, biological relevance, clinical application, and supporting experimental data (e.g. from model systems or other sources) may be employed to prioritize proteins and aberration products. Examples of protein prioritization criteria were provided in Part II, Section I, but additional evidence-based parameters are encouraged and will be considered.

Discovery Units will be responsible for translational and biologically-informed data analysis and integration for advanced analyses designed to provide biologically relevant results and identify potential translational directions/outcomes from genomic and protein Discovery data. These analyses will integrate all data types available for a set of samples including, proteomic, genomic, and clinical data. Discovery Units will also be involved in coordinating activities at a high level in a network fashion by incorporating transdisciplinary expertise from all PCCs and when appropriate in consultation with specific external authorities in the scientific community. Discovery Units will work together to develop a strategy for data flow through the network via the CPTC Data Center.

Applicants need to describe:

a)     A prioritization strategy for clinically informed and biologically relevant data analysis and integration in their respective PCC. Components are to include (a) a plan for how each type and level of data will be integrated (proteomics, genomics, and clinical); (b) computational tools to be used and developed; (c) analysis of results within the context of disease-relevant conclusions; (d) process (reporting standards and generation of reports) by which the prioritized list of proteins will be shared/presented to the Biomarker Candidate Selection Subcommittee; (e) a timeline for the project, (f) the biological basis for the strategy, and (g) expertise (personnel) involved in the process.

b)    The proposed proteomic data analyses. These elements of proteome analysis must describe the identification and detection of proteins, including: descriptions of data processing, identification algorithms, and error analysis.

c)     Provide an outline of a design document that discusses how their prioritization strategy will be adjusted upon learning the breadth of discovery data types across the PCC Network. The complete document must be generated and submitted to the NCI within the first three months of the project.

d)    A strategy to contribute to a cancer proteome database with proteogenomic correlation, to be developed by the CPTC Data Center. This database will serve as a resource to the cancer research community.

Section C: Verification Unit (limit 12 pages)

Plan for the Verification Unit must be organized in two blocks:

Verification Unit Objective 1: Systematically develop verification assays against corresponding protein targets as identified and selected by the Biomarker Candidate Selection Subcommittee; and

Verification Unit Objective 2: Apply Verification assays using clinical samples.

Details for each block are below.

Verification Unit Objective 1: Systematically develop verification assays against corresponding protein targets as identified and selected by the Biomarker Candidate Selection Subcommittee.

a)     Describe the technology (-ies) for Verification. To be eligible, technology platforms must be validated for biomarker verification studies. Technology platforms are considered validated if they meet the following criteria: (1) are multiplexed and high throughput; (2) minimize sample handling and preparation; (3) are metrics-driven and standardizable by using SOPs, reference materials, etc.; (4) the results will quantitatively measure protein/peptide concentrations in the range of low femtomole/microgram (protein) and picogram/milliliter to low nanogram/milliliter in tissues and biofluids, respectively; (5) demonstrate the repeatability and reproducibility of data obtained from within and across laboratories with CVs of =20%; (6) are capable of sampling the depth of proteomes studied that spans a wide dynamic range. At present, Multiple Reaction Monitoring Mass Spectrometry (MRM-MS) is the predominant quantitative technology platform standardized by CPTC initiative (phase I of this initiative) and will be used as a reference point for criteria such as throughput, sensitivity, specificity, multiplex capability, reproducibility, and portability. Other platforms/technologies are encouraged pending they meet the specified requirements.

b)    Describe the process for Verification assay development. Describe the process for assay development to be used in Verification studies. Attributes to be included are throughput (assays developed per year), quality control, total cost per assay, reagents needed, timeline, and expertise (personnel) involved in the process. Also describe the quality metrics (go/no-go decisions) that will render an assay suitable for full deployment in Verification studies involving clinical samples. Provide current and anticipated capacity (number of assays developed per year) for the technology proposed.

Verification Unit Objective 2: Apply Verification assays on clinical samples.

a)     Describe the process for Verification assay deployment. Applicants are to include a detailed plan that describes the process for Verification assay deployment on a sufficient number of clinical samples to ensure statistical power needed (approximately 500 samples per cancer type). Provide evidence of the analytic capacity to meet the objectives of CPTC reissuance for protein verification. Demonstrate that quantitative assays developed under Verification Unit Objective 1 are able to target protein candidates in highly complex clinical samples provided by the CPTC Resource Center. Applicants must define milestones specific to the technology/platform chosen for sample analysis, which also describe the acceleration of sample throughput during the course of the project. Applicants will be expected to present an explicit, estimated timeline for achieving the operational capacity to conduct protein verification to meet the goals of the project. Automated solutions for increased analysis throughput are highly encouraged. Information must be provided in detail on the involvement of personnel needed to conduct experimental analyses, as well as data processing and bioinformatics analyses. If personnel, equipment and other resources related to operation of a technology platform have a shared commitment to other projects (e.g., core resources, other awards, etc.), the applicants need to specify how sufficient access will be guaranteed for the purposes of the project. All capital equipment instruments must be operational and available at the proposed start of the project period.

b)    Data Analysis and Integration for Verification. Applicants must describe how data from Verification studies will be analyzed, visualized, and interpreted.

c)     Implementation of Quality Assurance and Quality Control Criteria. Applicants are to describe the implementation of SOPs for sample storage and preparation, metrics and reference materials used for instrument quality control (go/no-go decisions) during Verification assay deployment. Additionally, quality assurance of data to be deposited into the CPTC Data Center must be described.

Section D: Administrative Core (limit 6 pages)

Applicants must describe the organizational infrastructure to support and coordinate project administration within the individual PCC and participation in the CPTC Steering Committee and its subcommittees. In this section, applicants must address the following elements:

a)     Timeline for the project and milestones (jointly for both Discovery and Verification Units).

b)    Description of the structure of PCC communication strategy, program management structure, and strategies for communication in PCC Network research projects.

c)     Data management system. Include a detailed description of the laboratory information management system, proteomics analysis tools, data storage, security, archiving, and retrieval systems. Applicants must also describe standardized formats for data reporting and the validation process for data prior to submission to the CPTC Data Center for public access. This standardized system of data reporting is required in order to provide a common basis for data evaluation and data mining across the PCC network. Applicants also need to describe how data will be made caBIG® compliant, where appropriate, for deposition into the CPTC Data Center for public access.

d)    Pilot projects. This is to include mechanisms to carry out pilot projects, to be determined and approved by the CPTC Steering Committee that will enhance specific PCC’s efforts in its overarching framework. Pilot projects could include, but are not limited to innovative approaches to discovery and verification approaches, and computational tools for proteogenomic data integration and analysis. No pilot projects are to be proposed in the applications submitted in response to this FOA. A minimum of $50,000 in direct costs per year will need to be allocated by each PCC specifically for pilot projects.

e)     A scientific project manager for the center to manage the day-to-day operations. This individual is to have education and experience in project management or equivalent; knowledge of both theoretical and practical aspects of project management; knowledge of project management techniques and tools; direct work experience in project management capacity; and proficient in project management software. In addition, a scientific project manager is expected to maintain periodic interaction (as defined by NCI program staff) with the CPTC Resource Center (biospecimen management) and provide updates regarding research milestones and timelines; maintain proper record keeping; oversee timely submission of data to the CPTC Data Center; coordinate site visits and annual CPTC meetings for the PCC leadership; and describe interaction with technology transfer groups at the applicant’s institution.

f)     Internal Management Committee (IMC): The planned organization of the IMC must be described. The IMC should consist of individuals from within the PCC (including the scientific project manager) as well as other components of the applicant institutions that have been integral partners in developing the experimental design plans for the PCC. The IMC is to also include one NIH/NCI Project Scientist to be assigned by the Office of Cancer Clinical Proteomics Research and one or more patient advocates (see item “g” below). The IMC will support the PI in coordinating and monitoring the activities of the PCC and will define the chain of responsibility within the PCC for decision-making and administration beginning at the level of the PI and including all key staff. The IMC should work with the PI to establish a timeline for proposed activities and to develop opportunities for information exchange, seminar presentations, and research training opportunities. The IMC will meet at least twice per year, and as needed, to ensure PCC progress.

g)    The applicants considered for funding will be required (as a Just-in-Time requirement) to identify at least one patient advocate as an IMC member. For assistance in identifying such individuals, applicants are encouraged to contact the NCI Office of Advocacy Relations (http://advocacy.cancer.gov/about/staff).

Additional Requirements

Plans for Technology Development.
Applicants are expected to include plans for technology development to improve the technology/platform(s) used in the PCC by the Discovery Unit and/or Validation Unit. In general, improvement efforts of technologies/platforms could include (but are not limited to): (a) enhancing detection sensitivity and/or resolution; (b) increasing throughput; (c) optimizing proteome coverage; and (d) reducing unit costs per analysis. The technology development plans should be appropriate to the maturity of the technology, as mature and established technologies will likely require less development than emerging technologies. The technology development plans must address relevant needs of the discovery and/or verification platforms, as well as any software development related to production or analysis of CPTC data. These descriptions must be included within the page limits for the Discovery Unit and/or Verification Unit (as appropriate).

Capital equipment requests. In general, capital equipment, defined as equipment whose unit costs exceed $5,000, may NOT be budgeted under this FOA.

Site visits. Because of the complexity of the PCCs, NIH/NCI program staff members will conduct annual administrative site visits. PCC applicants should be prepared for annual visits and should budget appropriately (including travel for collaborators and other necessary costs).

Costs of participating in CPTC meetings

Applicants should budget for the PIs and/or alternative designated representatives (in aggregate, up to 5 members of each PCC) to attend annual CPTC investigator meetings.

Costs of PCC participation in the activities of CPTC Steering Committee and other CPTC Network Activities. Include in the budget a minimum of $50,000 reserved for the CPTC Pilot Projects (to be decided by the CPTC Steering Committee). Also include funds appropriate for support of the PCC participation in the activities of the CPTC Steering Committee (two face-to-face meeting per year and other expenses as appropriate).

caBIG® compatibility. Where appropriate, applicants must adhere to the formats and standards of the NCI’s Cancer Biomedical Informatics Grid (caBIG®, http://cabig.nci.nih.gov). caBIG® requires that data be represented as aggregations of Common Data Elements (CDEs) that are registered in the NCI’s Cancer Standards Data Repository (caDSR, https://cabig.nci.nih.gov/concepts/caDSR). These data elements are, in turn, defined using concepts codes that are maintained in the NCI’s Enterprise Vocabulary System (EVS). Data submitted to the CPTC Data Center must be unambiguously analyzable into CDEs.

Appendix Materials

All paper PHS 398 applications must provide appendix material on CD only, and include five identical CDs in the same package with the application (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.)

Do not use the Appendix to circumvent the page limitations. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this should be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Additional considerations specific to this FOA to address in the Data Sharing, Resources, and Intellectual Property Plan

Data Sharing: Consistent with achieving the goals of this program, it is expected that all data (raw, processed [protein identifications], and analyzed), datasets, and algorithms generated through the PCC network during this five-year funding period will rapidly be submitted to the CPTC Data Center (within 30-60 days) and become available through the CPTC Data Center for public use pending Quality Assurance as determined by the CPTC Steering Committee. PCC applicants are expected to acknowledge the need for comprehensive data sharing.  The precise content of the data sharing plan may vary, depending on the data being collected. Nevertheless, all the PCC awardees will be expected to adhere to the general data sharing principles established such as in the Amsterdam Principles (http://www.ncbi.nlm.nih.gov/pubmed/19344107).

Applicants should include a description of the criteria for data evaluation, submission, and storage. Applicants should describe briefly the expected schedule for data sharing, the format of the datasets, the documentation to be provided, and any analytic tools provided. This section must describe the type(s) of data that will become available through the proposed center as well as a rigorous timeline and frequency for when the data will become available. Applicants should describe their vision of an optimal reporting format and system. However, they must also acknowledge that a uniform data reporting standard may be implemented across the PCC centers. A reporting system should allow for performance evaluation and optimization and should facilitate data mining as part of an integrated bioinformatics infrastructure. All the proposed data types and outputs should comply with data standards of the Cancer Biomedical Informatics Grid (caBIG®, https://cabig.nci.nih.gov) as a unified platform for sharing and disseminating information, where appropriate.

Resources Sharing: Consistent with achieving the goals of this program, it is expected that all resources (standards, reagents, and SOPs) generated through the PCC Network during this five-year funding period will rapidly become available through the CPTC Resource Center for public use as specified by the CPTC Steering Committee. Resource sharing plans would be expected to describe the type(s) of resources that will become available through the proposed center as well as a timeline for when and with what frequency the resources will become available.

CPTC Intellectual Property Policy: Consistent with achieving the goals of this program and maximizing the benefit of all research funded as part of the CPTC initiative for the improvement of public health through discoveries of the scientific community, CPTC Data Sharing and Data Release policies expect a broad freedom-to-operate for all users of CPTC data (e.g., by rapidly placing all data in the public domain). In addition to data, computer algorithms produced specifically to analyze CPTC data, software source code or other resources (reagents) made possible under the auspices of CPTC are expected to be made broadly available. It is expected that any data producer in the PCC Network (whether supported by a grant or contract mechanism) will make all information available, without requirement for licensing, for applications such as, but not necessarily limited to, the use of markers in developing assays or targets for therapeutics and diagnostics. All PCC Network members and affiliated institutions must acknowledge agreement to the CPTC Intellectual Property Policy. Investigators and their institutions must expressly acknowledge and agree to abide by this policy.

Specific Instructions for Foreign Applications

All foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096.

Section V. Application Review Information


1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Review Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National Cancer Institute and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact.

Reviewers will provide an overall impact/priority 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 five scored review criteria, and additional review criteria (as applicable for the project proposed).

Scored Review Criteria.

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

Significance. Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator (s). Are the PD/PIs, 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?

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

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

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

In addition to the above review criteria, the following criteria will be applied to applications in the determination of scientific merit and the impact/priority score.

Review Criteria for PCC Integration and Administrative Core

1.     How strong is the scientific leadership of the proposed PCC in terms of capability to provide scientific and organizational integration of all PCC components? Will proper project management approaches be adequately implemented as requested (including a qualified scientific project manager and an Internal Management Committee (IMC)?

2.     Are the PCC milestones adequately comprehensive, quantitative, and realistic allowing accurate and informative evaluation of the progress of the activities proposed?

Review Criteria for Discovery Unit

1.     How appropriate and efficient (including throughput, breadth, accuracy, and sensitivity) are the technologies and computational approaches proposed for protein characterization in cancer biospecimens?

2.     How rigorous is the quality control/quality assurance strategy for analytical approaches to discovery? Are the metrics and standards proposed adequate as the basis of the quality assurance strategy?

3.     What is the likelihood that the proposed strategy for protein prioritization will succeed in selecting proteins showing biological importance and clinical biomarker potential?

Review Criteria for Verification Unit

1.     How appropriate and efficient (in terms of reproducibility, throughput, and sensitivity) are the technologies proposed for quantitative, multiplexed, protein verification?

2.     How appropriate is the overall approach for verifying a cancer biomarker candidate in a clinically relevant number of biospecimens?

3.     How rigorous is the quality control/quality assurance strategy for developing and testing verification assays on hundreds of samples? How appropriate are the metrics and standards of the quality assurance strategy?

Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Protection of Human Subjects from Research Risk. 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.

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information, see http://grants.nih.gov/grants/olaw/VASchecklist.pdf.

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

Resubmission Applications. Resubmissions are not allowed for this FOA.

Renewal Applications. Renewals are not allowed for this FOA.

Revision Applications.  Revisions are not allowed for this FOA.

Additional Review Considerations

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

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

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

Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

Specific to this FOA: Are the proposed plans for sharing and disseminating the data and other tools resulting from the program sufficient and consistent with the stated goals and considerations related to the needs of a broadly available repository of comprehensive tumor proteomic data?

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

Selection Process

The following will be considered in making funding decisions:

NIH considers the following in evaluating Center grant applications:

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information


1. Award Notices

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.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

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. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2. A. 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.

2. A.1. Principal Investigator Rights and Responsibilities

The Principal Investigators will have the primary responsibility for:

The primary PCC awardee institution and all other institutions participating in a given PCC must agree to share knowledge, data, research materials, and any other resources necessary and relevant to the PCC’s award.

Each PCC award and the entire PCC Network will be periodically evaluated by the NIH. Awardees will be expected to participate in such evaluation.

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.

2. A.2. NIH Responsibilities

A NCI Program Director(s) (acting as a Project Scientist(s)) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. These NCI Staff Members will provide substantial input in terms of overall program coordination and directions and collectively serve as a voting member of the CPTC Steering Committee.

Additional NIH staff members (e.g., from the NCI Center for Biomedical Informatics and Information Technology, NCI CBIIT) may also have substantial involvement in the CPTC Steering Committee and assist in operational issues as needed.

NCI Program Director(s) 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. A Program Official may also have substantial programmatic involvement (as a Project Scientist). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications, or will seek NCI waiver.

NOTE: The NCI reserves the right to award reduction or suspension of funds for a PCC that is unable to meet its milestones.

Additionally, an agency program official or IC program director will participate in the normal scientific and programmatic stewardship of the award and will be named in the award notice.

2.A.3. Collaborative Responsibilities

CPTC Steering Committee. CPTC Steering Committee will serve as the primary governing body of the CPTC. The Committee will be jointly established by all the awarded PCCs and NCI program staff members. The CPTC Steering Committee will provide strategic coordination for the activities of the PCC Network.

Voting members of the CPTC Steering Committee will include:

The CPTC Steering Committee will elect one of the PCC representatives as its chair for a pre-determined time length.

Non-Voting Members:

Subcommittees:

It is anticipated that the CPTC Steering Committee will formulate strategic decisions and policies for network-wide activities. The CPTC awardees will be required to accept and implement these decisions and policies to the extent consistent with applicable grant regulations. NCI retains the rights to disapprove of decisions by the CPTC Steering Committee if they deviate from NIH policies and applicable grant regulations.

The activities of the CPTC Steering Committee will include the following:

Biomarker Candidate Selection Subcommittee. The members of the Biomarker Candidate Selection Subcommittee will include a set number of members of the CPTC Steering Committee (or their nominees); NIH/NCI Program staff members; and additional scientific experts as deemed necessary by the subcommittee.

The activities of the Biomarker Candidate Selection Subcommittee will include the following:

Recommendations by the Biomarker Candidate Selection Subcommittee will be reviewed and approved by the CPTC Steering Committee.

2.A.4. 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 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.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts


We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Henry Rodriguez, PhD, MBA
Office of Cancer Clinical Proteomics Research
Center for Strategic Scientific Initiatives
Office of the Director, National Cancer Institute
31 Center Drive, Room 10A52, MSC 2580
Bethesda, MD 20892-2580 (for U.S. Postal Service regular or express mail)
Bethesda, MD 20892 (for non-USPS delivery)
Telephone: (301) 451-8883
FAX: (301) 496-7807
Email: rodriguezh@mail.nih.gov

and

Chris Kinsinger, PhD
Office of Cancer Clinical Proteomics Research
Center for Strategic Scientific Initiatives
National Cancer Institute
31 Center Drive, Room 10A52, MSC 2580
Bethesda, MD 20892-2580 (for U.S. Postal Service regular or express mail)
Bethesda, MD 20892 (for non-USPS delivery)
Telephone: 301-451-8883
FAX: (301) 496-7807
Email: kinsingc@mail.nih.gov

2. Peer Review Contacts:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

3. Financial or Grants Management Contacts:

Rebecca Brightful
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, Suite 243, , Mail Stop 7150
Bethesda, MD 20892-7150 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Phone: (301) 846-6703
FAX: 301-846-5720
E-mail:
brightfr@mail.nih.gov

Section VIII. Other Information


Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-116.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.


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NIH Funding Opportunities and Notices


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