Part I Overview Information

Department of Health and Human Services

Issuing Organization
National Cancer Institute (NCI), (http://www.nci.nih.gov)

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

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

Title: Clinical Proteomic Technology Assessment for Cancer (U24)

Announcement Type
New

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

• June 25, 2010 - This RFA has been reissued as (RFA-CA-10-016).
• March 17, 2006 (NOT-CA-06-018) - The National Cancer Institute (NCI), NCI has extended the Letter of Intent Receipt Date and Application Receipt Date for Request for Applications RFA-CA-07-012.
• February 21, 2006 (NOT-CA-06-011) - The National Cancer Institute (NCI), will hold a pre-application meeting for investigators planning to submit applications in response to Request for Applications RFA-CA-07-012.

Request For Applications (RFA) Number: RFA-CA-07-012

Catalog of Federal Domestic Assistance Number(s)
93.392, 93.393, 93.394, 93.395, 93.396

Key Dates

Release Date: February 7, 2006
Letters of Intent Receipt Date(s): April 8, 2006
Application Receipt Dates(s): May 8, 2006
Peer Review Date(s): June/July 2006
Council Review Date(s): September/October 2006
Earliest Anticipated Start Date: September 26, 2006
Additional Information To Be Available Date (URL Activation Date): Not Applicable.
Expiration Date: April 22, 2006

Due Dates for E.O. 12372
Not Applicable.

Additional Overview Content

Executive Summary

• The NCI solicits applications from investigators interested in participation in a collaborative network of up to five Clinical Proteomic Technology Assessment for Cancer (CPTAC) teams to be established under this funding opportunity. Each CPTAC team may include partners from multiple organizations, but this is not a requirement.
• This request for applications (RFA) is a component of the NCI’s Clinical Proteomic Technologies Initiative for Cancer (http://proteomics.cancer.gov) that is aimed at improving proteomic analysis platforms to reliably identify, quantify, and compare proteins and peptides in complex biological mixtures typical of clinical specimens, including generally obtainable body fluids.
• Each CPTAC team will consist of multidisciplinary scientists focused on enhancing proteomic measurement capabilities for clinical cancer research. The emphasis of this initiative is on mass spectrometry (MS) and affinity capture proteomic analysis platforms. Given the need for high-speed sample processing in clinical settings, applications centered on the 2-D gel proteomic platform (which has limited throughput in its current implementations) will not be considered responsive to this funding opportunity. The proposed research projects should be relevant to proteins, peptides, and/or proteomic aberrations that have been implicated in cancer. Examples include molecules and/or proteomic features with already established potentials to serve as diagnostic/prognostic markers or targets for therapeutic intervention.
• The goal of this funding opportunity is to improve the ability to rigorously and reproducibly detect, identify, and quantify proteins and peptides of interest in biological specimens by exploring and improving proteomics technologies and by establishing broadly available research reference resources. Specifically, this program is expected to advance the optimized measurements of proteins and peptides using MS and affinity capture proteomic analysis approaches and to establish a repository of well characterized and comprehensively annotated clinical reference materials along with respective proteomics data sets for these specimens. Multidisciplinary teams will participate in the design of interlaboratory studies aimed at improving reproducibility and comparability of clinical proteomic data.
• This initiative is focused on technology improvement and will not support research on fundamental cellular and molecular mechanisms of cancer or on biomarker discovery and validation. Collectively, the CPTAC teams will function as an interactive network that will be responsible for refining, comparing, and optimizing existing proteomics methods and applications. Improvements are sought in areas such as: sample collection and fractionation, and detection, identification, and quantification of proteins or peptides of interest. In addition, rigorous method/technology validations are needed to ensure reliable and reproducible results for proteomics analyses of complex biological mixtures. The CPTAC program is not designed for an explicit goal of developing new technologies and/or advanced applications. Nonetheless, since the priority in the initiative is the integration of the appropriate scientific expertise and infrastructure, the participating groups of scientists should be capable of efficiently implementing new technologies that might emerge during the life of the program.
• Awards under this RFA will be funded through the NIH U24 cooperative agreement mechanism. The coordination of the CPTAC program will involve a substantial investment of NCI resources and staff effort. Applicants should recognize that there will be significant interactions among the awardee institutions, including comprehensive data and resource sharing.
• The NCI intends to commit approximately $35.5 M in fiscal years 2006-2010 (approximately $8.5 M in fiscal year 2006) to fund up to five 5-year awards.
• Eligible organizations include: for-profit and non-profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; units of State and local governments; eligible agencies of the Federal government; and domestic institutions and organizations.
• Foreign institutions may participate only as subcontractors within a CPTAC team.
• Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his or her institution to develop an application for support.
• An individual can be the Principal Investigator (PI) on only one application submitted under this announcement. However, the PI or other investigators on one application may be listed as participants in multiple CPTAC team applications provided that these applications are discrete research proposals and the individuals are capable of performing one or all of the proposed activities if multiple applications with their involvement are approved for funding.
• Applications must be prepared using the PHS 398 research grant application and forms. Application materials are available from the NIH Office of Extramural Research (OER) at http://grants.nih.gov/grants/oer.htm.
• Telecommunications for the hearing impaired is available at: TTY 301-451-5936.

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 and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
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. Arbitration 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 overall purpose of this funding opportunity is to accelerate the implementation of proteomic analysis technology in monitoring cancer-relevant proteins and peptides in clinical samples. As a part of the NCI’s Clinical Proteomic Technologies Initiative for Cancer, this RFA is designed to establish an interacting network of Clinical Proteomic Technology Assessment for Cancer (CPTAC) research teams. Each CPTAC team may include partners from multiple institutions/organizations, but this is not a requirement. NCI will be involved in the CPTAC team as described below.

The up to five CPTAC teams to be established will serve as a network of proteomic technology assessment centers responsible for evaluating, comparing, optimizing, and standardizing current and forthcoming proteomic technologies, methods, and applications in the context of their applicabilities to clinical cancer proteomics. Improvements are sought in areas such as: sample collection and preparation, and protein/peptide fractionation, detection, identification, and quantification. In addition, rigorous efforts in the area of method/technology validation are needed to ensure reliable and reproducible results for proteomics analyses of complex biological mixtures.

Specifically, the CPTAC program is designed to develop multidisciplinary approaches to the evaluation and implementation of mass spectrometry (MS) and affinity-based proteomics platforms pertinent to clinical cancer research. Given the need for high-speed sample processing in clinical settings, applications centered on the 2-D gel electrophoresis proteomic platform (which has limited throughput in its current implementations) will not be considered responsive to this funding opportunity. The goals of the CPTAC program set the priority on the rigorous optimization and implementation of existing technologies and platforms, not on the development of new technologies and/or advanced applications.

The proposed research projects should be relevant to the detection and quantification of proteins/peptides of known roles in cancer, such as those molecules that have potential to serve as markers for the progression of the neoplastic processes and/or targets for therapeutic intervention. Furthermore, the approaches based on such candidate molecules must be designed with emphasis on their applicability to cancer-relevant clinical specimens, including the development of appropriate experimental procedures, optimization of analysis parameters, and routines for result validation.

Background. A proteomic technology is defined in this RFA as an instrument, tool, or device capable of measuring characteristics of peptides or proteins. A proteomic platform is defined as the multistep process for the analysis on proteins/peptides, which uses several technologies and may involve such operations as: sample collection and preparation/processing, separation/capture of proteins and/or peptides of interest, their experimental analysis (typically including protein identification and quantification), as well as post-measurement bioinformatics data processing and data mining.

The existing proteomic platforms, such as those based on MS and protein affinity microarrays, have the potential to serve as clinical tools to interrogate the proteome. However, current implementations of these technologies suffer from inadequately developed procedures for experimental calibration and standardization, reproducible assessment, and rigorous validation and comparison of results across institutions. One of the profound challenges in applied clinical proteomics is the need to handle complex biological mixtures, which are typical of clinical specimens. Moreover, method development is further complicated by a broad variability in protein concentrations that may exceed 10 orders of magnitude. Current proteomic methodologies have not yet been sufficiently demonstrated to be reliable and reproducible in clinical settings to allow for the identification, quantification, and comparison of specific molecules and proteomic data across laboratories or across diverse analysis platforms or instruments.

Developing, refining, and disseminating the proteomic technology platforms and resources are important components in advancing the NCI’s mission to eliminate the suffering and death due to cancer. The NCI recognizes the unexploited potential of applied clinical proteomics to address fundamentally important problems in cancer research, as well as the significant challenges associated with the implementation of proteomic technologies in the clinical setting. To address these opportunities and challenges, the NCI has designed Clinical Proteomic Technology Initiative for Cancer (http://proteomics.cancer.gov), which is an integrated approach to develop and enhance proteomic technologies and their applications pertinent to cancer research. Collectively, these efforts are expected to facilitate the discovery and monitoring of proteins and peptides relevant to clinical cancers and their use as markers of neoplastic changes in research, diagnosis, and treatment.

The NCI Clinical Proteomics Technology Initiative for Cancer will ultimately support three separate programs:

• Clinical Proteomic Technology Assessment for Cancer, which covers the CPTAC teams discussed in this RFA, will characterize and evaluate proteomic technologies, reference standards, reagents, and measurement protocols applicable to clinical cancers and clinical specimens
• Advanced Proteomic Platforms and Computational Sciences program will support investigator-initiated projects concentrated on overcoming current barriers in proteomic technologies and data analysis (RFA-CA-07-005); and
• Clinical Proteomics Reagents Resource will serve as a central source of information and intermediary in the distribution to the members of the scientific community of well-characterized proteomics samples, reagents, resources, reference sets, and standards in various public repositories (to be announced).
• Programs under the auspices of the Clinical Proteomics Technology Initiative for Cancer complement several other NCI resources, including the following initiatives:
• Specialized Programs of Research Excellence (SPORE) (http://spores.nci.nih.gov);
• The Integrative Cancer Biology Program (http://dcb.nci.nih.gov/branchdetail.cfm?branch=1);
• The Cancer Biomedical Informatics Grid (caBIG) (http://cabig.nci.nih.gov);
• The Early Detection Research Network (EDRN) (http://www3.cancer.gov/prevention/cbrg/edrn/);
• The Mouse Models of Human Cancers Consortium (http://emice.nci.nih.gov);
• The Mouse Proteomic Technologies Project, which will share data, biospecimens, and bio-reagents with individual investigators developing proteomic technologies for mouse models of human cancer (http://proteomics.cancer.gov/mouse); and
• The NCI Alliance for Nanotechnology in Cancer (http://nano.cancer.gov).

The funding strategy, generally adopted by the Clinical Proteomic Technologies Initiative as well as by this RFA, stems from the premises that:

(a) clinically relevant and cancer-specific peptides and proteins are known to exist in bodily fluids (e.g., plasma, serum) that are readily available for clinical sampling;

(b) reliable identification/quantification of individual peptides and proteins and/or panels of such molecules can improve specificity and sensitivity of early cancer detection and diagnosis; and

(c) while existing proteomics technologies are capable of monitoring these proteins and peptides, their current implementations can be improved and better adapted to clinical settings.

Integration of the CPTAC teams with the NCI Clinical Proteomics Technologies Initiative for Cancer. Through this funding opportunity, the NCI intends to establish up to five CPTAC teams. Each CPTAC team will participate in standardization of proteomic analyses, sample collection/fractionation, reagent optimization, and routines for data analysis necessary to apply proteomic tools and technologies in cancer diagnosis and therapy. While each CPTAC team will work independently, an overall CPTAC Program Coordinating Committee (PCC, for details, see Section VI.6.2.A Cooperative Agreement Terms and Conditions of Award) will be established to oversee the integration of individual CPTAC teams into a cohesive network. Importantly, guidelines and recommendations to be developed by the PCC (e.g., regarding sample selection, experimental design, and data analysis for interlaboratory comparative studies) will have to be followed by all the CPTAC teams.

To integrate the CPTAC program with the entire Clinical Proteomic Technology Initiative for Cancer, the NCI will coordinate with the PCC and individual CPTAC teams the dissemination of the generated data, reagents, experimental procedures, and other resources, as well as the sharing of these resources with the scientific community at large. Open access of the scientific community to these resources will allow for independent cross-validation of findings and will further advance the strategic goals of the program.

Overview of the Required Expertise and Unique Resources. Close multidisciplinary interactions involving cancer molecular biologists, clinical cancer researchers, proteomic technology specialists, bioinformaticians, and biostatisticians are essential for the success of the anticipated CPTAC teams. Therefore, each group responding to this RFA must have documented current expertise in all these areas. Each group needs to have appropriate instrumental capabilities pertinent to technologically advanced proteomic analysis, computational data analysis, and proteomics-specific bioinformatics. In addition, each group needs to have access to and be capable of properly processing samples from clinically diagnosed cancer patients. To coordinate the multidisciplinary efforts and resources, each CPTAC team will be required to form an Internal Advisory Committee (IAC). Details regarding the required multidisciplinary expertise and capabilities of the applicant team as well as the organization of the IAC are provided in Section IV.6. Other Submission Requirements.

Research Objectives. To facilitate protein/peptide analysis in clinical setting, the CPTAC teams will evaluate and optimize proteomic analysis platforms for clinically-relevant applications, and will develop reference materials, experimental protocols, methodologies, and data analysis/processing routines. It is expected that such integrated effort will significantly improve the overall performance of proteomics tools by identifying sources of experimental error and bias, by improving experimental reproducibility and specificity, and by optimizing protocols for the wide range of protein concentrations typically encountered in clinical samples. In addition, advances are sought in the accuracy of molecular mass determinations by MS-based tools, improved detection and quantification of diverse individual cancer-relevant proteins and peptides, as well as in sample throughput for the various proteomic technologies. Other expected benefits include establishment of a centralized repository of standard reference materials and highly annotated clinical reference sets, in addition to public knowledge resource containing optimized and clinically applicable proteomics protocols and schemes for rigorous validation of proteomic applications in clinical settings.

As a tangible measure of the collective progress expected to result from the entire CPTAC team initiative, by the end of the 5-year program, it should be possible to reproducibly detect/quantify in clinical specimens at least 1500 features of protein/peptide profiles that are of relevance to human cancers. It is possible that some previously unknown cancer-related peptides, proteins, and/or proteomic features of interest may become revealed through this program. However, this initiative is not designed to support research projects aimed at discovery and validation of novel cancer biomarkers or the development of new proteomic technologies. The overall focus remains on standardizing existing technology platforms so that data generated by future users of these technologies can be compared, validated, and applied in clinical settings.

The CPTAC teams will be established as an integrated network of proteomic technology evaluation and assessment. The entire network collectively as well as each CPTAC team individually will address the following Overarching Objectives:

Objective 1: Evaluate performance of proteomic technology platforms and standardize approaches to developing applications using these platforms;

Objective 2: Evaluate proteomic platforms for their ability to analyze cancer-relevant proteomic changes in human clinical specimens;

Objective 3: Establish systematic ways to standardize proteomic protocols and data analysis among multiple laboratories;

Objective 4: Develop and implement uniform algorithms for sharing bioinformatics and proteomic data and analytical/data mining tools across the scientific community;

Objective 5: Develop well defined and comprehensively characterized sets of standard/reference materials and reagents to serve as resources for the research community.

Given the collaborative nature of the CPTAC program, each application must address all of the five Overarching Objectives adhering to specific areas of focus and requirements that are summarized below.

Scope and Requirements Pertinent to Specific Overarching Objectives:

1. Evaluate performance of proteomic technology platforms and standardize approaches to developing applications using these platforms. To evaluate protocols and procedures, determine technology and platform variability, and perform the interlaboratory comparative studies, all CPTAC teams will analyze a common set of biological samples from the same well characterized mouse model of human cancer. The NCI will coordinate the selection of the specific model, and will assist individual CPTAC teams in establishing this model in their facilities. Also, the NCI will coordinate the procurement of some plasma and/or serum samples from this model. The goal is to cross-compare common sets of samples across instruments and platforms as well as across different laboratories, and to use the results to develop optimized procedures and approaches.

(1a) Eligible technologies. Applicants should propose comparative evaluations of technologies that are capable of high throughput analyses of biological samples. Two-dimensional gel electrophoresis will not be considered in this RFA because of the limited sample throughput inherent to the current implementations of that technology.

The comparative assessment should be proposed for at least two variants of MS technologies differing either in ionization method, or in the analysis technique, or in the integration with other instruments. Examples of such technologies and instrument combinations include: matrix-assisted laser desorption-ionization (MALDI), electrospray-ionization (ESI), time-of-flight (TOF) MS, Fourier transform ion cyclotron resonance (FTICR) MS, tandem MS/MS, and liquid chromatography (LC)-MS. Surface enhanced laser desorption ionization (SELDI) MS will not be considered for this RFA due to its limited ability to comprehensively measure and identify low abundance proteins in serum or plasma considered to be within the dynamic range of proteins released from cancer cells. Thus, applications proposing to use SELDI MS are ineligible for this RFA. Furthermore, applicants should plan for conducting comparative analyses using at least two similar instruments. The instruments to be compared need not to be of the same model as long as they share the same MS technology (e.g., two MALDI instruments). Since awards under this RFA will not support capital equipment purchases, the respective instruments need to be available and operational before the beginning of the award.

Applications should also outline the plans to assess other advanced proteomic technologies with a potential for massively multiplexed analyses, notably approaches based on affinity capture and protein microarray formats. It is realized that at present protein microarray technologies are still largely under development. Nonetheless, the applicants are expected to develop as detailed schemes as possible to rigorously assess examples of such technologies covering similar performance endpoints as outlined for the MS-based platforms. In addition, the applicants should develop plans to assimilate and evaluate promising advancements in proteomic technologies, applications, and data processing that are likely to emerge during the life of this program.

(1b) Experimental Design and Endpoints. Studies should be proposed to assess and compare performance of specific implementations of proteomic technologies. Examples of relevant endpoints to address include, but are not limited to: reproducibility, dynamic range of measurable protein/peptide concentrations, the accuracy of molecular mass determination (in MS-based applications), sample throughput, detection specificity, peptide/protein identification and quantification, and unit cost per assay.

In addition, the proposed investigations could include the systematic examination of a variety of schemes for sample fractionation, quantification of peptide/proteins of interest, and results validation. Plans for technology optimization should provide a rationale for proposed solutions considering, for example, that increased resolution of a technology might be associated with decreased throughput and increased unit cost.

(1c) Statistics and Data Analysis. Essential for the successful and rigorous technology assessment is a thoroughly developed plan addressing statistical and bioinformatics aspects of the proposed experimental design and data processing. Examples of areas that may require particular attention of the applicants in that context include data normalization, statistical measures of confidence, peptide/protein identification and quantification, computational simulation of relevant processes/phenomena, quality control, quality assurance, and data comparison.

For all platforms, plans should be provided to address, if appropriate, performance aspects related to data analysis and/or data mining. Also, provisions must be consistently made in the experimental design to maximize the benefits of feedback from other CPTAC teams using the same set of samples. For example, such parallel determinations should facilitate the identification of experimental factors contributing to measurement variability among platforms and laboratories and accelerate protocols optimization. If applicable, a timeline and specific milestones should be provided.

Whereas applicants are encouraged to outline their vision on the design of interlaboratory analytical studies, they must acknowledge in their applications that eventually it will be the responsibility of the CPTAC team coordinating body (PCC) to identify sample sets to be analyzed and to provide guidelines for study design and data analysis. Therefore, these proposed plans must anticipate that under Objectives 3 and 4 (see below), the CPTAC teams as a network will need to develop uniform standard procedures to compare advantages of diverse proteomic platforms and to standardize proteomic procedures as well as information sharing and data mining.

(1d) Pre-clinical testing of candidate molecule -based approaches. In addition to aiding the primary level of technology assessment, mouse model samples may facilitate pre-clinical testing of some candidate molecule -based approaches (pertinent to Objective 2). While not required, applicants are encouraged to include in their plans the analysis of samples derived from additional mouse models relevant to the cancer site intended for investigation using clinical specimens (Objective 2). The NCI will assist in the procurement of such additional mouse models and/or samples derived from such models. Nevertheless, such studies must adhere to budgetary restrictions stated in Section IV.6. Other Submission Requirements.

2. Evaluate proteomic platforms for their ability to analyze cancer-relevant proteomic changes in human clinical specimens. The knowledge gained from the initial technology assessment (Objective 1) will drive analogous studies using human clinical samples in Objective 2. The emphasis of the CPTAC program that must be reflected by the distribution of the proposed effort is on proteomic determinations using clinical specimens. The goal is to validate pre-optimized platforms for the detection, identification, and quantification of proteins, peptides, or families of such molecules selected based on their relevance to particular types of human cancers. In this protein candidate -based approach, a large number of clinical samples will allow for rigorous evaluation of platform performance. Rigorous evaluation of the protein candidate -based approaches using human clinical specimens and focused on one to three types of human cancer must be a part of research plan in each application.

(2a) Availability of Human Clinical Samples. Applicants must demonstrate access to well-annotated human cancer and normal samples for each of the cancer types proposed to be studied. The application must include explicit plans for procuring prospectively collected samples, but may also include well-characterized, archived samples provided that they have been collected according to standardized and quality controlled protocols. A description of the proposed sample annotation system should be included in the application, keeping in mind that a common system for use across the CPTAC teams will ultimately be implemented.

Each CPTAC team needs to have access and must develop plans for obtaining over the funding period a minimum of 200 individual clinical samples of bodily fluids from patients for each cancer type to be studied. As defined in this RFA, examples of bodily fluids include plasma or serum, urine, serous fluids collected from body cavities, saliva, and ductal lavage, but not cell lysates or tissue culture media. If justified, these human fluid samples can be accompanied by corresponding tissue biospecimens (contingent upon availability of such specimens, e.g., following surgical tumor removal or biopsy). The rationale for the acquisition of such tissue samples should be stated in the application. In addition, samples of biological fluids or tissues from healthy individuals and from patients with conditions that share some symptoms with cancer (e.g., inflammatory diseases) should also be acquired when appropriate.

Each applicant should document the ability to acquire all clinical samples in amounts sufficient not only for their own investigations, but also for comparison, evaluation, and validation studies carried out by the other CPTAC teams. Given that one of the programmatic goals of this funding opportunity is to establish clinical reference sets of biological specimens with high quality proteomic data to serve as a resource for future studies, applicants should anticipate and plan accordingly that additional quantities of the clinical specimens will be needed in order to make them available to other researchers outside of the CPTAC teams at the completion of the program (pertinent also to Objective 5).

It is imperative that appropriate informed consent for the proposed use of clinical samples must have been obtained from individual patients. If archived samples are to be used, the applicant must also have received the appropriate informed consent from patients. The NCI will work with the participating institutions to ensure that appropriate consent forms are developed and used.

(2b) Selection of candidate molecules for technology evaluation using human clinical samples. The selection of proteins/peptides proposed as candidates for platform evaluation using human clinical samples needs to be based on strong scientific rationale and should be appropriate for the selection of cancer types to be investigated. The relevance of candidate molecules to particular type of cancer must be well substantiated by literature data pertinent to cellular signaling pathways, protein expression, and/or changes in physiological processes related to cancer. The candidate molecules should have the potential to serve as markers for the progression of the neoplastic processes and/or targets for therapeutic intervention.

Preference should be given to strategies aimed at the identification of a broader spectrum of candidate molecules, such as families of proteins, or general classes or attributes of such proteins, as opposed to focusing exclusively on identifying aberrations in the expression or post-translational modifications in single, unique proteins.

(2c) Experimental Design, Statistics and Data Analysis. Analogous requirements to those specified for Objective 1 apply also to Objective 2. Hence, studies must be proposed to assess similar endpoints and must include thorough statistical evaluation of data and approaches. In these regards, the experimental plan must account for the feedback from other CPTAC teams that will be analyzing the same set of samples.

Reciprocally, a provision must be made for analyzing clinical samples procured by other CPTAC teams for the endpoints pertinent to their selections of candidate molecules. In this regard, it needs to be expressly acknowledged that such studies will follow the unified guidelines for sample selection, study design, and data analysis to be developed by the PCC.

Plans for the candidate molecule-based approaches must include descriptions of bioinformatics tools/algorithms that will be used to assist in either in predicting or identifying candidate proteins. A timeline and specific milestones should be provided also for this aspect of the project.

3. Establish systematic ways to standardize proteomic protocols and data analysis among multiple laboratories. Standardized protocols for sample preparation, measurements, and data analysis are to be used for proteomic determinations across the entire network as well as shared as a publicly available resource. Since sample quality is a critical factor in all proteomic procedures, particular attention must be devoted to this aspect.

(3a) Developing and testing of reference materials and standards. Applicants should be aware and must acknowledge in their applications that various reference materials will be provided to each CPTAC team for testing. Initially, the CPTAC teams will have to work with measurement proficiency assessment materials (these materials will be provided by the NCI and developed in coordination with the CPTAC program) to establish and document the range of variation among the different proteomic platforms, experimental protocols, and CPTAC teams. As the CPTAC program matures, additional protein mixtures and biological reference samples are expected to be developed, characterized, and recommend for comparative analysis by the PCC. Each CPTAC team will have to cross-participate in the development of reference materials from other groups. Accordingly, studies proposed by each applicant must include analyzing standard reference materials and unknown specimens provided by other network teams, following the PCC recommendations and guidelines.

(3b) Preparation and handling of biological samples for proteomic analysis. Applicants must describe their approaches to ensuring consistent sample quality, including methods of collection and storage of clinical samples required for the project as well as any other samples containing complex protein mixtures. As a part of the sample optimization strategy, factors related to sample collection and handling that influence protein stability and the quality of MS and affinity capture proteomic analyses need to be discussed in detail. Techniques and methods to remove components interfering with measurements and/or to reduce sample complexity should also be proposed for inclusion in standardized protocols. Plans should be outlined regarding the implementation of strictly formalized documentation requirements that would include such elements as: a robust tracking system, full records of the timing from collection to processing to storage, ways of documenting storage conditions (timing, temperature, any freezing thawing cycles, etc.).

(3c) Integration of procedures and approaches among CPTAC teams. The applicants should propose ways by which the CPTAC teams could collectively develop standardized protocols to establish the advantages and disadvantages of the existing technologies. For example, statistical approaches should be discussed to integrate data from all CPTAC teams in order to establish the determinants of experimental variability for all steps of proteomic analysis (i.e., from sample acquisition to actual measurement), as well as propose uniform criteria to assess data processing and reporting.

The applicants are strongly encouraged to present their visions as to how the expected results of technology assessment and evolving standard operating procedures in individual CPTAC teams can or might be integrated into uniform standard methodologies to be eventually adopted by all the CPTAC teams. These plans must strictly conform to the general requirements and obligations pertinent to sharing research information, reagents, and samples (see below).

4. Develop and implement uniform algorithms for sharing bioinformatics and proteomic data and analytical/data mining tools. To maximize the impact of the CPTAC program across scientific and research organizations, it is essential that uniform approaches are developed to processing of proteomics data, their storage, and their analysis using shared data mining tools.

4a) Algorithms and data mining tools. To serve the overall purpose of this initiative as a resource, all the proposed solutions must be compliant with Cancer Biomedical Informatics Grid (caBIG, see more details below under General Requirements ) as a unified platform for sharing and disseminating information as indicated in General Requirements. Accordingly, proposed algorithms and bioinformatics tools should be suitable for large sets of proteomic data and utilize well characterized annotation and ontology schemes. The proposed solutions, approaches, and bioinformatics tools must allow for efficient evaluation and implementation of data processing and bioinformatics tools across the CPTAC teams network and ultimately serve as resource to the scientific community.

5. Develop well characterized material and bioinformatics resources for the research community. Working towards Objectives 1 - 4, the CPTAC teams are expected to establish optimized protocols for collection, storage, and annotation of biological and clinical specimens, as well as develop various standard/reference materials and reagents, datasets and bioinformatics tools. In addition, the NCI will coordinate activities of other programs within the Clinical Proteomic Technology Initiative for Cancer to incorporate additional reference materials into the CPTAC program. All these material and information-related products are intended to serve as a well defined and comprehensively characterized resource for the research community. As indicated in General Requirements, all the materials and tools, as well as their characteristics and other associated data will be made available to the research community.

(5a) Preparation of material and information-related products for sharing as resource. Applicants must outline their plans to characterize, document, and prepare for sharing reagents, reference sets, tools, and similar resources that will be generated in the course of the program. Specific Plan for Sharing Research Data, Resources and Intellectual Property must form a separate part of the application (for details, please see General Requirements below and Section 6. Other Submission Requirements).

(5b) Knowledge resource. The CPTAC teams are designed to serve as unique knowledge resources for the scientific community. Therefore, the applications need to include plans and methods for disseminating technological expertise for outreach programs, education, and training, for instance, through workshops, training opportunities, and preparation of resource guides and optimized protocols. The NCI will assist in the coordination of such activities.

General Requirements and Obligations Pertinent to All Objectives:

Sharing research data, reagents, and biological samples. CPTAC teams will be required to share their materials, protocols, data, and resources with other CPTAC teams. In addition, the NCI stipulates that data, proteomic standards, biological samples, reference sets and other resources developed through the Clinical Proteomic Technology Initiative be publicly available. The optimized platform implementations, including standard protocols, algorithms, and tools for data analysis, will be shared among the CPTAC teams and ultimately made publicly available for the scientific community for further validation. Applicants must agree to all these requirements in their applications and must include in their plans timelines for making raw/pre-processed data, biological samples, reagents, and other materials publicly available.

caBIG compatibility. Applicants must consistently plan for analytical algorithms and bioinformatics software tools, ontologies, and data formats to be integrated into caBIG (https://cabig.nci.nih.gov). caBIG is an open source/open access information network for the sharing of cancer research data and related software tools. caBIG has developed four increasing levels of compliance and interoperability (i.e., Legacy, Bronze, Silver, and Gold) that address such aspects as: data format and programming/messaging interfaces, common data elements, information models, and vocabularies and ontologies. The desired degree of caBIG compliance will be determined through coordination and consultation with the NCI’s Center for Bioinformatics. More information on caBIG compatibility is available at https://cabig.nci.nih.gov/guidelines_documentation/caBIGCompatGuideRev2_final.pdf.

Intellectual Property. Since partnerships between the NCI and other institutions are inherent to this RFA, the NCI recognizes the need to address the issues of the intellectual property rights with respect to patentable inventions and other types of intellectual property that are expected to result from the program. Within this context, however, it is the NCI s intention that inventors will work with the NCI to exercise any intellectual property rights retained on inventions developed as part of the program in a way that will promote wide accessibility to and further development of the resources and analysis tools that are generated.

Applicants are required to provide plans for sharing data, resources, and intellectual property. For additional information and guidelines to the preparation of these plans, please see Section 6. Other Submission Requirements.

For general policies related to this announcement, see Section VIII, Other Information - Required Federal Citations

Other Information Relevant to the CPTAC Program

Partnerships with For-profit Private Sector Entities. Collaborations between private sector for-profit organizations and not-for-profit and academic institutions have the potential to further the goals of this RFA. Although a partnership with a for-profit organization is not a required component of the application in response to this RFA, the NCI encourages such collaborations. Investigators from both not-for-profit and for-profit institutions/organizations can submit applications as PIs. Alternatively, for-profit entities may engage in sub-contract relationships with other institutions that are submitting applications. Please see Section 6. Other Submission Requirements for additional information.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the NIH U24 award mechanism. The NIH U24 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator (PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NCI staff being substantially involved as a partner with the PI, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

This RFA is a one-time solicitation.

This funding opportunity uses just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

2. Funds Available

The NCI intends to commit approximately $35.5 M in fiscal years 2006 through 2010 (approximately $8.5 M in fiscal year 2006) to fund up to five 5-year awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will vary. The awards are expected to start by September 2006 and run through 2010. Although the budget plans of the NCI anticipate support for this program, awards pursuant to this funding opportunity are contingent upon availability of funds and receipt of a sufficient number of meritorious applications.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

• For-profit organizations
• Non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of State governments
• Units of local governments
• Eligible agencies of the Federal government
• Domestic institutions

Foreign institutions are not eligible to apply, but may participate as members within a CPTAC team. The PI of the CPTAC team must be based at an institution within the United States of America.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his/her institution to develop an application for support. Individuals from under-represented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing or Matching

Cost sharing is not required for eligibility.

The most current NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

An applicant may submit only one application as the PI in response to this funding opportunity announcement.

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) 710-0267, Email: [email protected].

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

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. 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 DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The DUNS 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 on line 2 of the face page of the application form and the YES box must be checked.

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

Letter of Intent Receipt Date: April 8, 2006
Application Receipt Date(s): May 8, 2006
Peer Review Date: June/July, 2006
Council Review Date: September/October 2006
Earliest Anticipated Start Date: September 27, 2006

3.A.1. Letter of Intent

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

• Descriptive title of proposed research
• Name, address, and telephone number of the PI
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

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 NIH staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Gregory J. Downing, D.O., Ph.D.
Director, Office of Technology and Industrial Relations
Office of the Director
National Cancer Institute
Building 31, Room 10A52, MSC 2580
31 Center Drive
Bethesda, MD 20892-2580
Telephone: (301) 496-1550
FAX: (301) 496-7807
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. 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 delivery; 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
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for express/courier delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: [email protected]

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at http://grants.nih.gov/grants/funding/phs398/labels.pdf.

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, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the NCI. Incomplete and non-responsive applications will not be reviewed. If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

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 this funding opportunity, it is to be prepared as a NEW application. That is, the application for this 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.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks.

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 http://grants.nih.gov/grants/policy/policy.htm.

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 or competing continuation award if such costs: are necessary to conduct the project, and 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 or competing continuation 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 the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Application must be prepared as outlined below. After the submission of application, no additional supplementary material of any kind will be allowed.

Submission Requirements

Budget and Budget Justification sections of the PHS 398 must reflect the following;

• No capital equipment costs are allowed;
• Applicant may budget for the acquisition, handling, processing, and maintenance of mouse models pertinent to Objective 1 but related direct costs must not exceed $25,000 per any year and a total of $75,000 per application; and
• Applicants should budget for the attendance of the PI (or an alternative designated representative to the PCC) as well as the principal bioinformatics representative of the CPTAC team in annual meeting in Bethesda, Maryland.

Research Plan. For this RFA, the organization of the Research Plan (sections A-D) in the PHS 398 grant application format is modified as follows

The page limit has been increased from 25 to 75 pages.

Sections A-D of Research Plan in the standard PHS 398 format are substituted by the following new sections: Section 1. Applicant Group; Section 2. Scope of Research; Section 3. Analysis Capacity of the Instrumental Resources; Section 4. Plan for Sharing Research Data, Resources, and Intellectual Property; and Section 5. Participation of Private For-Profit Organizations. These sections must cover the following elements:

Section 1: Applicant Group. The expertise profiles and roles of the participating members of the CPTAC team should be comprehensively described, including any ongoing grant-supported research pertinent to the scientific and technical scope of this RFA. Applicants should emphasize, where applicable, the experience and track record of their group in collaborative programs and activities. In addition, this section should describe the unique resources and supportive infrastructure. Applicants must describe their expertise in technologies proposed for evaluation. The following expertise components and organizational elements must be addressed:

• The cancer biology component must contain information about the level of knowledge and expertise of the team in the molecular biology and genetics of cancer, cancer epidemiology, and cancer pathology. Experience in maintenance of animal models of human tumors as well as collecting, handling, and processing samples from such models must also be described. Researchers involved in the cancer biology component must have a broad understanding of cancer-related signaling pathways, alterations in protein expression, and functional alterations such as mutations or post-translational modifications in cancer-relevant proteins. These researchers are expected to play leading roles in the strategic design of the studies exploring defined proteomic abnormalities associated with neoplastic changes.
• The clinical component must include a description of the expertise of the respective investigators in clinical cancer research, clinical cancer pathology, diagnosis, and treatment; including their proficiency in acquisition and handling of clinical samples for analysis; as well as knowledge of appropriate ethical and legal requirements for clinical studies. The clinical component is essential for procurement of clinical specimens and is expected to provide input into the methodologies and design of studies using these samples, clinical annotation of specimen databases, and the potential applications of proteomics technologies as clinical diagnostic/prognostic tools.
• The technology component must include detailed information regarding the member’s proficiency in the use of proteomic instrumentation, conducting measurements (including quality control and assurance), and interpreting results. This component must also describe already established capabilities in proteomic analysis and validation using MS-based proteomic technology and other massively multiplexed proteomic technologies, such as protein microarrays.
• The statistical design, analysis, and metrology component must contain information on the strengths of statistical and metrics expertise of the members, with emphasis on experimental design, biological variability, data normalization, statistical measures of confidence, validation, and reproducibility of results.
• The bioinformatics component must summarize the member’s experience and capabilities in data analysis, database annotations, and data dissemination. Applicants should provide detailed descriptions of their laboratory information management systems, proteomic analysis tools, data storage, security, and archiving and retrieval systems. The investigator’s track record of integrating, managing, and analyzing data flow from multiple instrument platforms and multiple laboratories should be outlined.
• The planned organization of the Internal Advisory Committee (IAC) must be described. The IAC should consist of individuals from within the CPTAC team as well as other components of the applicant institutions that have been integral partners in developing the experimental design plans for the CPTAC team. The IAC will support the PI in coordinating and monitoring the activities of the CPTAC teams. The proposed IAC must define the chain of responsibility within the CPTAC team for decision-making and administration beginning at the level of the PI and including all key staff. The IAC should work with the PI to establish a time-line for proposed activities and to develop opportunities for information exchange, seminar presentations, and research training opportunities.
• Unique and critical resources and infrastructure. Information should be provided on the unique resources and cores, expert technical or advisory personnel, and information of other components of the supporting infrastructure pertinent to the application (e.g., description of participating clinical cancer center). Detailed descriptions of available proteomic technology platforms, related resources and core facilities (e.g., antibody production, animal facilities, clinical research laboratories for sample collection and processing), and personnel are required.

Section 2: Scope of Research. The applicants must describe in detail experimental and developmental activities addressing all of the five Overarching Research Objectives as outlined in Section I.1 of this RFA. Reviewers will evaluate how well the applicants have fulfilled all the general and objective-specific Requirements and Obligations. In addition, applicants must acknowledge that for the interlaboratory analytical studies in Objectives 1-3, the CPTAC PCC will identify the samples to be analyzed and provide direction on the design and analysis of data.

Section 2 of the application may contain preliminary data, relevant to the proposed models, methods, and/or specific technologies proposed for evaluation. Where appropriate, timelines of the proposed activities and milestones should also be included.

Section 3. Analysis Capacity of the Instrumental Resources. This section of the application must provide an assessment of the analysis capacity needed for each of the objectives. Applicants must demonstrate that they have secured sufficient analysis capacity for each technology to be evaluated. These capacities must be compatible with the planned number of samples to be analyzed for all Objectives, including provisions for replicate runs, multiple fractions, samples provided by other CPTAC teams (where applicable), etc.

In addition to documenting access to appropriate instrumentation, information should be provided on the availability of skilled personnel needed to conduct the experimental analysis as well as data processing and bioinformatics analysis for the proposed number of samples. Respective instruments must be operational and available not later than at the anticipated start of the project. This RFA will not support the purchase or other acquisition costs of capital equipment instruments used in the analysis.

In case of mass spectrometers, a minimum required capacity for all Objectives combined is a full-time-access equivalent defined as a minimum average of ten complete analytical processes or runs per day. This minimal number may reflect either exclusive access to a single instrument or a cumulative partial access to multiple instruments. Applicants should specify throughput capabilities of the available instruments in terms of runs per month for each of the MS technologies included in the platform.

In case of protein microarray and other affinity capture methodologies, applicants must demonstrate in analogous way that they will have the capacity to process the needed number of samples.

Section 4: Plan for Sharing Research Data, Resources and Intellectual Property. Applicants must expressly acknowledge and agree that all data, datasets, algorithms, protocols, standards, reagents, and biological samples generated through the CPTAC teams will be available through the NCI for public use in a manner consistent with respecting the originators rights under the law, regulations, and NIH policies. Sharing/dissemination of intellectual property should also be described in this section. Please see the guidelines for sharing plans below.

Section 5: Participation of Private for-profit Organizations. A private sector for-profit entity is an allowed, but not a required component of the consortium. If no for-profit component is involved, please state Not Applicable in this section. Otherwise, applicants should describe existing as well as planned partnerships with collaborating for-profit entities. The role of for-profit partners in the development of the proposed technologies/platforms should be clearly delineated. This section should also describe any relationship the for-profit entities involved in the CPTAC team may have with NIH SBIR funding, the consumer market targeted for the product(s) associated with the CPTAC teams, and any production and marketing plans associated with the participation in this program. Applicants are encouraged to attach to the application letters of collaboration by the participating for-profit entities succinctly indicating commitment to the program and their roles. (These letters do not count towards the stated 75 page limit).

Plan for Sharing Research Data

All applicants must include a plan for sharing research data in their application. The NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity must include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will factor the proposed data sharing plan into the determination of scientific merit or the priority score.

All data, datasets, algorithms, protocols, biological samples, and reagents developed through or acquired by awarded CPTAC teams must be made publicly available through the NCI and must be open-source programming code, where applicable, to be effectively shared through caBIG. The precise content of the data sharing plan will vary, depending on the data being collected and how the investigator is planning to implement sharing the data. 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 final dataset, the documentation to be provided, any analytic tools provided, and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). The NCI requires that all data, datasets, algorithms, biological samples, and reagents are released to the NCI or are made accessible by the NCI for redistribution to the public scientific community continually throughout each CPTAC award funding period. Investigators choosing to share under their own auspices prior to submission to the NCI may wish to enter into a data-sharing agreement with the partnering institutions or members of the consortium. In addition, each applicant must outline plans to store and maintain the anticipated large amounts of proteomic data in-house or, alternatively, propose appropriate arrangements with the NCI for such storage and maintenance.

It is expected that the actual release of the generated data to the NCI for availability by the broader scientific community will occur as the data become available. Hence, a plan to release the data upon completion of the funding period is not acceptable. Data submission plans should aim for a target of monthly submissions. If this is not possible, applicants must provide an adequate rationale as to why a monthly submission cannot be achieved.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity must include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Guidelines for Preparation of Research Tools Sharing Plan and Intellectual Property Plan. The NIH is interested in ensuring that the research resources developed through grants awarded through this RFA also become readily available to the broader research community in a timely manner for further research, development, and application, in the expectation that this will lead to products and knowledge of benefit to the public health.

The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. This RFA explicitly stipulates that applicants submit a plan that addresses: (1) how they will share the research resources/tools generated (e.g., human biospecimens and novel cancer biomarkers); and (2) how they will exercise intellectual property rights, should any be generated, while making such research resources available to the broader scientific community consistent with this initiative. Research tools sharing plans and intellectual property management plans are needed to ensure that unique research resources will be readily available for research purposes to qualified individuals within the scientific community in accordance with the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/ and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 http://ott.od.nih.gov/NewPages/64FR72090.pdf) ( NIH Research Tools Guidelines Policy ). These documents also: (1) define terms, parties, and responsibilities; (2) prescribe the order of disposition of rights and a chronology of reporting requirements: and (3) delineate the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page (http://www.iedison.gov); see also, 35 USC 210(c); Executive Order 12591, 52 FR 13414 (Apr. 10, 1987); and Memorandum on Government Patent Policy (Feb. 18, 1983). If applicants plan to collaborate with third parties, the research tools sharing plan would need to address how such collaborations would not restrict their ability to share research materials produced with NIH funding. The applicant's institution should avoid exclusively licensing those inventions that are research tools, unless either: (1) the field of use of the exclusive license is restricted to commercial use or (2) the exclusive licensee will make the research tool broadly available on reasonable terms. In the development of any research resource sharing and intellectual property management plans, applicants should confer with their institutions' office(s) responsible for handling technology transfer related matters and/or sponsored research. If applicants or their representatives require additional guidance in preparing such plans, they are encouraged to make further inquiries to the appropriate contacts listed above for such matters. Furthermore, applicants may wish to independently research and review examples of approaches considered by other institutions, such as those described on the NCI Technology Transfer Branch web site (http://ttc.nci.nih.gov/intellectualproperty/). The foregoing guidance is provided by way of example to assist applicants in preparing the expected research resources sharing and intellectual property management plans in a manner that encourages partnerships with industry. While these approaches will likely suit most situations, these approaches are not exclusive and applicants should feel free to submit alternative versions for consideration.

The majority of transfers to not-for-profit entities should be implemented under terms no more restrictive than the Uniform Biological Materials Transfer Agreement (UBMTA) (http://ott.od.nih.gov/NewPages/UBMTA.pdf). In particular, recipients are expected to use the Simple Letter Agreement (SLA) provided at http://ott.od.nih.gov/NewPages/SimplLtrAgr.pdf, or another document with no more restrictive terms, to readily transfer unpatented tools developed with NIH funds to other recipients for use in NIH-funded projects. If the materials are patented or licensed to an exclusive provider, other arrangements may be used, but commercialization option rights, royalty reach-through rights, or product reach-through rights back to the provider are inappropriate. Similarly, when for-profit entities are seeking access to NCI-funded tools for internal use purposes, recipients should ensure that the tools are transferred with the fewest encumbrances possible. The SLA may be expanded for use in transferring tools to for-profit entities, or simple internal use license agreements with execution or annual use fees may be appropriate.

Section V. Application Review Information

1. Criteria

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

The following will be considered in making funding decisions:

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

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score;
• Receive a written critique; and
• Receive a second level of review by the National Cancer Advisory Board.

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

U24 Review Criteria as applicable to this RFA are presented below.

1. Significance:

A. Will the proposed resource significantly advance the overarching goals of the Clinical Proteomic Technologies Initiative for Cancer?

B. Does the proposed plan ensure the integration of the resource with other CPTAC teams?

C. Are the model candidate molecules proposed for analysis significant to the type(s) of human cancer for which clinical samples will be procured?

2. Approach:

A. Is the conceptual framework for the resource well thought out?

B. Are the plans for comparing existing technologies, assimilating new technological developments, acquiring specimens/data and assuring quality control and proper record keeping adequate?

C. Are the proposed plans for sharing and disseminating the materials, samples, data, and tools resulting from this program sufficient and consistent with the stated requirements? Will these plans assure equitable access to the resource by the scientific community at large?

D. Is there sufficient evidence provided that the applicant team can procure (where applicable) and process the required number of specimens over the award period?

F. Are plans for ensuring proper informed consent for clinical specimens clearly defined?

3. Innovation:

A. Does the application propose novel or improved methods, such as more effective means of sample collection and processing, procedure standardization and validation, information storage and retrieval, or innovative resource dissemination and utilization strategies?

B. Does this application propose a new type of specific type of reference or standard material or bioinformatics tools not previously available?

4. Investigators:

What are the qualifications of the resource leader(s) and key personnel to organize and integrate all the required components of the resource, to ensure quality control and equitable access, and to interact with consortium partners.

5. Environment:

Is the infrastructure adequate? For example, assess the adequacy of the facilities and equipment and dedicated core services available for the proposed resource. Evaluate the expertise of scientists who are available to advice the PI on governance, management, and function of the resource.

2.A. Additional Review Criteria

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing some research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant award recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and at http://ott.od.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity must include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing of some resources is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

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 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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

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 (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the 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 Notice of Award. 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 PI 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 is a cooperative agreement (U24), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NCI scientific and/or programmatic involvement with the grantee is anticipated during performance of the activity. Under the cooperative agreement, the NCI supports and/or stimulates the recipient's activity by being involved in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI as summarized below.

2.A.1. Principal Investigator Rights and Responsibilities The PI will coordinate project activities scientifically and administratively at the awardee and collaborating institutions, including research design and protocol development, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications. The PI will have primary responsibility for defining the details for the projects within the guidelines of this RFA and for performing all scientific activities. The PI will agree to accept the close coordination, cooperation, and participation of the NCI Program Director, NCI Project Scientist, and the CPTAC Coordinating Committee in those aspects of scientific and technical management of the project as described below.

Specifically, the PI will:

• Determine experimental approaches, design protocols, set project milestones, and conduct experiments;
• Propose protocol modifications as required;
• Analyze and interpret research data;
• Provide goals for assay optimization, screening throughput, quality, and cost to the NCI Program Director, usually at the outset of the award and in 6-month progress reports, but also at other times if requested;
• Periodically release data, datasets, algorithms, protocols, biological samples, and reagents to the NCI and other members of other CPTAC teams according to the approved plans for timely sharing of research resources and data generated through the award, and publish results, as agreed upon by the CPTAC PCC;
• Ensure that data and assay protocols are deposited in a centralized database and compliant with caBIG, according to the timeline implemented by the NCI;
• Serve as voting member on the CPTAC PCC (or appoint an appropriate designee to do so) and attend annual PCC meetings;
• Comply with and implement the policies and procedures approved by the PCC for all the participating CTPAC teams
• Provide information to the NCI Program Director concerning progress by submitting periodic progress reports in a standard format, as agreed upon by the NCI;
• Share with the NCI and other CPTAC teams resources, tools, and data of interest to those facilities, as directed by the CPTAC PCC; and
• Be prepared for annual administrative site visits by NCI staff.

In addition to the PI’s responsibilities, each CPTAC team will designate one of its investigators as its bioinformatics representative. The designees will assist the PCC in the coordination of bioinformatics-related activities and will be required to attend an annual meeting with other bioinformatics representatives in Bethesda, MD.

2.A.2. NCI Responsibilities An NCI Project Scientist will be assigned to serve as the coordinator of the CPTAC program. The Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

Specifically, the Project Scientist will:

• Attend and participate as a voting member in all meetings of the CPTAC PCC, and will provide liaison between the PCC, the CPTAC teams, and the NCI.
• Attend CPTAC team meetings as appropriate;
• Assist in avoiding unwarranted duplication of effort among CPTAC teams;
• Help coordinate collaborative research efforts that involve multiple CPTAC teams;
• Assess progress of the project toward the accomplishment of specified milestones, and recommend if further funds should be released for the project;
• Facilitate the establishment of contact and collaborations between awardees of the CPTAC program and other organizations supported by or interacting with the NCI whose participation will assist with the accomplishment of project goals;
• Review and comment on critical stages in the research program before subsequent stages are implemented; and
• Assist in the interaction between the awardee and investigators at other institutions.

The NCI Project Scientist will also assist the NCI Program Director in stimulating broader NCI program interactions to accelerate the translation of research resulting from the CPTAC teams efforts towards clinical applications of proteomic technologies. In order to carry out these duties, the NCI Project Scientist may consult with other NCI and NIH staff as well as non-NIH experts.

Additionally, an NCI program official (a Program Director) will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

2.A.3. Collaborative Responsibilities

Program Coordinating Committee (PCC) will be established as a CPTAC governing body that sets policy and approves procedures that all the participating teams will have to follow. In addition, PCC will oversee the integration of the CPTAC teams as part of the entire Clinical Proteomic Technology Initiative for Cancer. Voting members of the PCC will include the PI (or a PI-designated senior scientist) from each CPTAC team and one person representing NCI Program staff (the NCI Project Coordinator). Additional representatives from NCI extramural divisions and from the NCI Center for Bioinformatics may participate as non-voting members of the PCC. Additional non-voting members with specific scientific expertise in disciplines not readily provided by the PCC members may be added to ensure an adequate review of the research infrastructure.

On at least a semi-annual basis, the PCC will assess the progress made by the participating CPTAC teams, make recommendations regarding strategic decisions and program goals, and provide guidelines regarding experimental design, sharing of protocols and reagents, and the allocation of resources. The assessments and recommendations of the PCC will be included in written semi-annual reports and delivered to each of the PIs and the NCI. The PIs generally will be expected to accept and implement the recommendations. The PI will need to provide a thorough explanation to the PCC and the NCI for any situation that prevents the implementation of the recommendations.

Other activities of the PCC will include the following items:

• Prioritization of materials/reagents for further characterization and standardization by the participating CPTAC teams;
• Evaluation of proteomic standards, reference materials, standard protocols, and bioinformatics tools/standards developed or adopted by the individual CPTAC teams and recommendations for incorporating respective resources/procedures etc. into the research efforts of the other CPTAC teams and broader scientific community;
• Monitoring of concurrent developments in clinical proteomics external to the CPTAC team network;
• Facilitating communication and data sharing among the CPTAC teams;
• Coordinating the compatibility of generated data and bioinformatics tools among participating CPTAC teams with caBIG;
• Establishing an interactive web site providing both open public access and password-protected access for CPTAC team participants;
• Organizing conference calls and meeting for participating investigators; and
• Coordinating efforts with the NCI to ensure that resources, technologies, and knowledge gained from the program are made publicly available and widely disseminated throughout the cancer research community.

2.A.3. Arbitration 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 arbitration. An Arbitration Panel composed of three members will be convened. It will have three members, including: 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 arbitration procedure in no way affects 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 PHS Non-Competing Grant Progress Report, Form 2590, annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

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:

Gregory J. Downing, D.O., Ph.D.
Director, Office of Technology and Industrial Relations
Office of the Director
National Cancer Institute
Building 31, Room 10A52, MSC 2580
31 Center Drive
Bethesda, MD 20892-2580
Telephone: (301) 496-1550
FAX: (301) 496-7807
Email: [email protected]

2. Peer Review Contacts:

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service express or regular mail)
Rockville, MD 20852 (for express/courier delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: [email protected]

3. Financial or Grants Management Contacts:

Ms. Kathryn Dunn
Grants Management Specialist
National Cancer Institute
6120 Executive Boulevard, EPS Room 243, MSC 7150
Bethesda, MD 20892-7150 (for U.S. Postal Service express or regular mail)
Rockville , MD 20852 (for express/courier delivery)
Telephone: (301) 846-6829
FAX: (301) 402-3409
E-mail: [email protected]

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); and 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 (see the NIH Policy for Data and Safety Monitoring in the NIH Guide for Grants and Contracts at 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. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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-02-005.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. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from: 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

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. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to 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 PA 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 or Health Systems Agency review. 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 2 years to the research. For further information, please see http://www.lrp.nih.gov.