Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) National Institute of Allergy and Infectious Diseases (NIAID)
Funding Opportunity Title	Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus: Network Leadership Center (UM2)
Activity Code	UM2 Program Project or Center with Complex Structure Cooperative Agreement
Announcement Type	New
Related Notices	September 12, 2019 - Request for Information (RFI) on the Lessons Learned from the Accelerating Medicines Partnership Rheumatoid Arthritis and Lupus (AMP RA/SLE Program). See Notice NOT-AR-19-039. April 2, 2014 - See Notice NOT-AR-14-019. Notice of Pre-Application Webinar.
Funding Opportunity Announcement (FOA) Number	RFA-AR-14-015
Companion Funding Opportunity	RFA-AR-14-016, UH2/UH3 Phase Innovation Awards Cooperative Agreement
Number of Applications	Only one application per institution is allowed, as defined in Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.846, 93.855, 93.856
Funding Opportunity Purpose	The purpose of this FOA is to solicit applications for the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis (RA) and Lupus Network Leadership Center. The AMP RA and Lupus Network is designed to ascertain and define shared and disease-specific biological pathways in order to identify relevant drug targets for the treatment of autoimmune diseases. This program will involve an enhanced systems-level understanding of gene expression and signaling in target tissues from affected end organs and peripheral blood cells. The Network Leadership Center will: (i) direct and coordinate the scientific activities of the Network; (ii) monitor and evaluate scientific progress and performance; (iii) define Network research priorities; (iv) develop the Network research agenda; (v) provide centralized scientific/technical research resources for data management/coordination, statistical design/analyses and tissue acquisition; and (vi) conduct systems biology and bioinformatics research. A companion FOA will establish the Network Research Sites, including: (i) Clinical Research Sites to assemble patient cohorts and obtain comprehensive clinical and laboratory data and relevant specimens to enable deconstruction of key events in cells and tissues related to disease, disease severity, and response to therapy; (ii) Technology Research Sites to develop, test, standardize and validate advanced and new technologies to identify critical signaling pathways in cells and tissues; or (iii) Combined Clinical and Technology Research Sites to conduct clinical and early validation studies of novel technologies and analytics in rheumatoid arthritis, lupus and related autoimmune diseases. Awardees under both FOAs will work collaboratively to establish the AMP RA and Lupus Network.

Posted Date	March 21, 2014
Letter of Intent Due Date(s)	April 21, 2014
Application Due Date(s)	May 21, 2014
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	July/August 2014
Advisory Council Review	August 2014
Earliest Start Date	September 20, 2014
Expiration Date	May 22, 2014
Due Dates for E.O. 12372

Required Application Instructions

It is critical that applicants follow the instructions in the PHS 398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Looking ahead: NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. See NOT-OD-13-075 and NIH’s Applying Electronically website for more information.

Part 1. Overview Information
Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) is one of two FOAs that implement the Accelerating Medicines Partnership in Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Program (http://www.niams.nih.gov/Funding/Funded_Research/AMP_RA_Lupus/default.asp). The goal of the Program is to ascertain and define shared and disease-specific biological pathways in order to identify relevant drug targets for the treatment of RA, lupus and related autoimmune diseases. The NIAMS and the NIAID, as participating members of the AMP RA/SLE Program, are promoting this goal by publishing two FOAs to solicit applications for the development of a Network Leadership Center (LC) and Network Research Sites (RS). The LC and the RS awardees will work collaboratively within a network structure to implement the AMP RA/SLE Program. The Network will be established by the NIH in collaboration with industry partners that will co-fund, guide and advise on the scientific direction of the project.

This FOA solicits applications specifically for the Network Leadership Center award. Applicants interested in the Research Sites must use the companion FOA.

A critical program goal of the AMP initiative is to advance research in specific disease areas by creating a community resource of data, analyses, and other research resources which are publicly available and accessible to the broad biomedical community. In order to maximize scientific exchange and accelerate research in that field, it is expected that all information, data, protocols, resources, and methods developed by AMP investigators will be shared in a rapid and timely way with other investigators in the consortium and with the research community at-large. Given the amount and complexity of the data, success will require rapid and broad access across the biomedical community to allow for further analyses and collaborative research efforts.

The AMP initiative envisions that all data generated (including processed/analyzed data) will be deposited in a rapid and timely way into a repository that is accessible for use by the broad biomedical community, and that these data will remain available to all qualified investigators, consistent with applicable laws, regulations, and policies and unencumbered by any intellectual property claims. While the NIH encourages patenting of technology suitable for subsequent private investment that may lead to the development of products that address public needs, the NIH discourages premature claims on pre-competitive information that may impede research. It should be recognized that the research supported under the AMP initiative is intended to be precompetitive and will neither make use of proprietary pre-existing intellectual property nor is expected itself to produce patentable findings. Similarly, other research resources developed under the AMP initiative are expected to be made available to the research community.

Research supported and conducted by the NIAMS and the NIAID strives to better understand, treat, and ultimately prevent autoimmune diseases.

Rheumatoid arthritis (RA) and lupus are relatively common, severe autoimmune diseases and are examples of a larger number of such diseases, e.g., multiple sclerosis, Crohn’s Disease, ulcerative colitis, juvenile arthritis, Type 1 diabetes, and psoriasis, among many others. Basic and clinical studies have shown that these diseases share in common abnormalities in adaptive and innate immune function and regulation, resulting in inflammation that impairs end organ function. The ability to target specific immune cells or inflammatory mediators (cytokines) has resulted in the first real advances in treatments for RA in decades. However, the clinical benefit achieved so far is limited. In lupus, no effective targeted therapies exist for the most severe forms of the disease, including CNS lupus and lupus nephritis. Therefore, a major challenge remains to find new targeted therapies that can achieve a high degree of disease activity reduction (i.e., remission) or disease cure, have fewer immunosuppressive side effects, and/or offer oral alternatives to biologics. Progress has been hampered by the current fragmented research focus on peripheral blood immune cells with limited emphasis on changes in affected target organs and few integrated analyses combining findings in multiple cells and tissues.

The NIH, pharmaceutical companies and nonprofit organizations have together created the Accelerating Medicines Partnership (AMP) to develop new models for identifying and validating promising biological targets for new diagnostics and drug development. A major goal is to generate pre-competitive, disease-specific data that will be publicly accessible to the broad biomedical community for further research (http://www.nih.gov/science/amp/).

The partners jointly formed the AMP RA/SLE Steering Committee (see http://www.nih.gov/science/amp/autoimmune.htm), which developed a project plan to address relevant challenges for RA and lupus. Like other autoimmune diseases, these offer a special opportunity for molecular deconstruction because the majority of the complex cellular components of the immune system are available for study in the peripheral blood. In addition, the major target tissues for RA and lupus (including synovium and kidney, respectively, and potentially other tissues) can be biopsied, and emerging technologies allow for a detailed analysis of even small amounts of tissue, down to the single cell level. The overarching vision is that these detailed studies would identify key targets (with initial in vitro validation) that regulate the pathways that drive the diseases. The approach developed here can be subsequently applied to other autoimmune or inflammatory diseases. The central feature of the proposed research program is its ability to compare across autoimmune diseases in which similar immune cells are involved, but where their functions and interactions result in distinct inflammatory outcomes.

This program aims to achieve an enhanced systems-level understanding of gene expression and signaling in target tissues and cells from affected end organs (synovium for RA, kidney, or other tissues such as skin for lupus) and peripheral blood. The initial focus of research will be on RA and lupus, with the flexibility to expand in the future to related autoimmune diseases contingent on scientific feasibility and availability of resources.

The overall goal of the AMP RA and Lupus Network (Network) is to define shared and disease-specific biological pathways in order to identify relevant drug targets for the treatment of RA, lupus and related autoimmune diseases. Towards achieving this goal, a unique and novel infrastructure will be established, that uses a collaborative trans-disciplinary, integrated team science approach, to test high impact ideas that will: lay the foundation for a new and comprehensive understanding of mechanisms driving disease; stimulate early and applied research on cutting-edge technologies; and, advance the research enterprise by accelerating the discovery of disease pathways involved in autoimmune diseases. The initial focus will be on RA and lupus. The Network will be built with the flexibility to expand the scope of research to emerging new technologies and methods for systems analysis and to related autoimmune diseases.

Major outcomes of this collaborative effort include:

• An integrated data set of changes at the molecular level obtained by extensive profiling of gene expression and signaling in immune and tissue-resident cells, potentially including synovium for RA, and kidney and skin for lupus.
• Characterization of modules and pathways, and how they can be used to understand differences between autoimmune diseases, between early and established disease and between responders and non-responders to therapy.
• Identification of changes in circulating cells in blood that correlate with activation of specific pathways in the tissues or predict response to specific therapies, which can be used to improve therapeutic targeting and serve as surrogate biomarkers for diagnostic or treatment decisions.
• A data set shared by the Network and others for exploration of potential therapeutic targets.
• Preliminary steps towards validation of the biological relevance of druggable targets and other key regulatory molecules by in vitro functional assays, RNAi, and other methods.
• Application of existing and development of new computational tools to permit a systematic approach to integration of the datasets into pathways.
• A research model that may be extended to other autoimmune diseases.

Research Phases. The success of this research program will depend on careful progression of individual projects along a predetermined set of steps to ensure standardization of procedures to minimize technical variability. Projects are expected to progress in three phases:

Research Phase 0. Testing of different means of obtaining and prepping tissue and some initial analytic runs will be conducted with the goal of developing standardized methods in small number of homogenous samples in at least two diseases. Samples must include affected organ specimens in addition to peripheral blood and could be newly obtained or already available.

Research Phase I. Analysis of a standardized analytic(s) successfully established in Research Phase 0, in blood and tissue cells, plus trial runs of other selected analytics. The number of samples will be sufficient to inform power calculations and establish the feasibility of larger studies of the tissue analytic and sample type, source and acquisition approach. At least one Research Phase I study in RA and one Research Phase I study in lupus are expected to be completed by the end of the second year of the project. Research Phase I will include analysis of samples from individuals without RA or lupus, such that a systems biology approach can be used to identify pathways that distinguish disease and non-disease tissue.

Research Phase II. Testing in larger patient populations will be conducted as determined by power calculations, priority, and budget. Patient stratification is expected for comparison within a disease (e.g., RA: treatment responder vs. non-responder, early vs. established RA, comparison among disease-modifying anti-rheumatic drugs (DMARD) treated groups; lupus: before vs. after treatment, comparison among types of kidney disease, etc.).

This new research infrastructure will be established using two interrelated FOAs to support the Network Leadership Center (LC), and the Network Research Sites (RS), which together will form the Network. The Network is defined as the consortium of investigators and institutions funded under both FOAs and will provide the framework for the AMP RA/SLE Program. A diagram of the organizational structure can be found at (http://www.niams.nih.gov/Funding/Funded_Research/AMP_RA_Lupus/default.asp).

The LC, to be awarded under this FOA, will lead and coordinate all the scientific activities of the Network and provide key centralized resources and services to the RS projects, pilot and feasibility and other Network collaborative projects.

The RS, to be awarded under the companion FOA, RFA-AR-14-016 will support three additional organizational entities within the Network.

Clinical Research Sites (CRS) will assemble patient cohorts and obtain comprehensive clinical and laboratory data and relevant specimens to enable measurements of key events in cells and tissues related to disease, disease severity and response to therapy.

Technology Research Sites (TRS) will develop, test, standardize and validate advanced and new technologies to identify critical signaling pathways in cells and tissues.

Combined Clinical and Technology Research Sites (CTRS) will support institutions to perform clinical studies and to conduct early validation studies of novel technologies and analytics.

Awards to Network Research Sites will be made using the UH2/UH3 (Phase Innovation Awards Cooperative Agreement) mechanism, a cooperative agreement that supports a phased approach to new research activities. The UH2 (Exploratory) funding period will provide support for Research Phases 0 and I activities in years 1 and 2. The UH3 (Implementation) funding period will provide support for meritorious exploratory and developmental research activities initiated during the UH2 funding period transitioning to Research Phase II in years 3 through 5.

Network Leadership Committee (NLC)

The NLC will serve as the primary governing body for the scientific activities conducted by the Network. The composition and major functions of the NLC are described below.

NLC Composition

Voting members of the NLC may include:

• The Program Directors/Principal Investigators (PDs/PIs) of the Research Sites
• The PD/PI of the LC
• The Directors of the Systems Biology and Bioinformatics Group (SBG) and the Tissue Acquisition Research Group (TRG)
• The NIH Project Scientists (together representing a minority of voting members - not to exceed 1/3 of NLC membership). Other NIH Program staff may attend the meeting as non-voting members.

In addition, outside consultants may be appointed to serve as non-voting NLC members to provide expert advice and assistance with respect to research priorities, specific new and transitioning research projects, technologies, standards, etc. The use of such outside consultants may be recommended by any of the voting NLC members and their participation in NLC scientific activities will require consensus among the voting members of the NLC.

During the first year of the award, the Chair of the NLC is the PD/PI of the LC. Starting in year 2, the NLC will have the option to elect a new chair.

NLC Functions

The NLC will be the primary governing body for all Network scientific activities. The NLC will provide the collaborative environment to coordinate all projects awarded under the two FOAs.

The role of NLC includes:

• Foster collaboration, synergy and sharing among the projects and investigators in the Network.
• Provide the primary mechanism for interactions with NIH.
• Oversee the planning of Network scientific activities, including dynamic adjustment as needs and opportunities arise.
• Guide the development and documentation of the Network standards and guidelines.
• Prioritize the use of LC resources including systems biology analyses and bioinformatics.
• Evaluate progress in the LC and RS and recommend adjustments in approaches if necessary, including implementation of new projects and changes to ongoing studies and termination of projects and sites.
• Foster partnerships and collaborations that will facilitate the extension of the approach to new technologies and their application to related autoimmune disease.
• Review Network Resource Sharing Plan to ensure consistency and appropriateness for achieving the goals of the Network.
• Develop and approve Network-wide intellectual property agreements consistent with the terms and conditions of the cooperative agreement awards, applicable regulations, and the policies and practices of the awardee institutions.

The NLC functions will be supported by the LCMP.

Additional details about the governance structure will be outlined in the Notice of Award.

Leadership Center (LC)

The goal of the LC is to lead the scientific activities of the Network by providing dynamic, collaborative, multidisciplinary approaches, key services and resources to ensure the successful progression of site and network projects along the Research Phases to achieve the expected outcomes of the AMP RA/SLE Research Program.

The scope of research to be supported by the LC includes: (i) clinical research projects involving patients with RA or patients with lupus and specialized methods of collection of tissue specimens, (ii) testing of existing and development of new technologies for analysis of single cells and tissues from affected organs in RA and lupus; and (iii) application of existing and development of new systems biology and bioinformatics approaches for analysis of large datasets generated by the Network Technology and Clinical Research Sites (to be solicited under a separate, companion funding opportunity (RFA-AR-14-016).

The LC will be responsible for a broad scope of activities in support of the Network as a whole, which include: (i) scientific planning, direction and coordination of Network research activities; (ii) defining research priorities to achieve the goals of the Network and the rationale for their selection, including criteria for prioritizing sub-sets of patients with RA or lupus; (iii) developing the research agenda of the Network, identifying potential barriers to success and potential solutions to overcome those barriers; (iv) monitoring and assessing progress and performance; (v) the provision of centralized scientific/technical research resources for all projects undertaken; and (vi) communications with NIH. The LC will develop and operate a central standardized database system for network use and a Network Portal for public data sharing and dissemination.

Leadership Center Research, Coordination, Management and Statistics Program (LCMP)

The LCMP will provide infrastructure for the Network and support the full scope of Network research projects including clinical and tissue analytics studies for all phases. LCMP will work collaboratively within the LC and with the RS to coordinate, standardize and ensure optimization of Network approaches, processes and procedures. The LCMP functions include, but are not limited to:

A. Research Project Management

• Conduct the initial technical review of proposed new, transitioning, pilot and feasibility research projects.
• Coordinate the scientific activities of research sites and research groups to optimze use of critical Network resources.
• Monitor and evaluate scientific progress.

B. Operational Management

• Develop Standard Operating Procedures (SOPs).
• Provide centralized operational/management support for the LC.
• Provide operational, administrative and logistic support for the NLC.

C. Data Coordination and Management

• Implement a central standardized database system for collection, storage, and exchange of Network-generated data, and research protocols.
• In collaboration with the Statistical Research team and the SBG implement a Network Portal to facilitate data sharing and dissemination.
• Generate periodic reports on status of specific studies, sample inventory, data acquisition, etc.
• Establish quality control and quality improvement systems for all clinical and laboratory data.

D. Statistical Research

• Provide centralized statistical support for data analyses and statistical design expertise and support for proposals from the Network RS and for Research Phase 0, I and II studies.
• Conduct research to develop novel statistical approaches to be used by the Network and the RS.
• Review the accuracy and completeness of statistical data for abstracts, manuscripts and presentations reporting on the results of research conducted by the Network.

Systems Biology and Bioinformatics Group (SBG)

The focus of the SBG will be to apply existing and develop new methods and advanced tools for data integration and systems-level analyses of multi-dimensional datasets. The goal is to identify modules and pathways active in specific tissue cell types and define how they differ between diseases or patients with different characteristics. The Systems Biology and Bioinformatics Group (SBG) will conduct research to:

• Apply existing bioinformatics tools to analyze and interpret Network-generated data.
• Conduct research on new informatics approaches to perform integrative analyses and interpret data generated by the Network investigators.
• In collaboration with the Statistical Research and Data Coordination Management teams, establish a central database system to facilitate Network data standardization, data accessibility, archiving and transfer.
• In collaboration with the Statistical Research and Data Coordination Management teams, implement a Network Portal to facilitate data sharing and dissemination.
• Provide scientific, technical support and training about analytical strategies to the Network and to individual RS.
• Conduct Pilot and Feasibility projects.

Tissue Acquisition Research Group (TRG)

The goal of the TRG is to work collaborativelly with the Network RS to identify the most efficient methods for tissue acquisition and prepping, and to develop standard operating procedures to support Research Phase I and Phase II tissue acquisition activities. Effective procurement and utilization of well-characterized tissue are critical to the success of the AMP RA and Lupus Network. The goal is to develop and ensure the consistent implementation of new and existing standardized procedures for procurement, processing, short-term storage, quality control, histopathologic evaluation, and distribution of clinical samples. A centralized specimen storage repository is not part of the scope of work of the TRG.

Working collaboratively with the Network Clinical Research Sites and the Combined Clinical and Technology Research Sites, the Tissue Acquisition Research Group (TRG) will:

• Optimize the efficient use of available samples for tissue analytics.
• Ensure that Network investigators work with well-characterized, high-quality tissue specimens, peripheral blood cells, plasma, and serum from patients with RA, lupus and related autoimmune diseases.
• Provide research resources including: (i) consultation with the CRS and CTRS; (ii) SOPs for sample and specimen processing; and (iii) conducting centralized histopathology readings.
• Develop guidelines for distribution of limited tissue samples and make recommendations to the LC and the NLC for tissue acquisition and distribution.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the PHS 398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIH intends to commit up to $1.4 million in total costs in FY 2014 to fund one award.
Award Budget	Application budgets are limited to $2 million per year in total costs for years one and two, and are limited to $3 million per year in years three, four and five.
Award Project Period	The total project period may not exceed five years.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the PHS 398 Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

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

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

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

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS 398 Application Guide.

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

Only one application per institution, normally identified by a unique DUNS number, is allowed,.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS 398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

The letter of intent should be sent to:

Justine Buschman
Division of Skin and Rheumatic Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Telephone: (301) 496-4811
Email: [email protected]

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

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

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

Kathy Salaita, Sc.D.
Chief, Scientific Review Branch
National Institute of Arthritis, Musculosketal and Skin Diseases
DHHS/National Institutes of Health
6701 Democracy Blvd. Rm. 818
Bethesda, MD. 20892
Telephone: 301-594-5033
Fax: 301-402-2406
Email: [email protected]

All page limitations described in the PHS 398 Application Guide and the Table of Page Limits must be followed, in addition to the following page limitations to the Research Strategy section of each component of the application.

• Overall: 30 pages
• Leadership Center Research, Coordination, Management and Statistics Program:

A. Research Project Management: 6 pages
B. Operational Management: 6 pages
C. Data Coordination and Management: 12 pages
D. Statistical Research: 12 pages

• Systems Biology and Bioinformatics Group: 12 pages
• Tissue Acquisition Research Group: 12 pages

The following section supplements the instructions found in the PHS 398 Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: required
• Leadership Center Research, Coordination, Management and Statistics Program: required
• Systems Biology and Bioinformatics Group: required
• Tissue Acquisition Research Group: required

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions, as noted.

Face Page (Overall)

All instructions in the PHS 398 Application Guide must be followed.

Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, Human Embryonic Stem Cells (Overall)

All instructions in the PHS 398 Application Guide must be followed.

Table of Contents (Overall)

All instructions in the PHS 398 Application Guide must be followed, but modify the Table of Contents to include all the following required components of the Leadership Center (LC):

Overall
LCMP
A. Research Project Management
B. Operational Management
C. Data Coordination and Management
D. Statistical Research
SBG
TRG

Detailed Budget for Initial Budget Period (Overall)

All instructions in the PHS 398 Application Guide must be followed.

Budget for Entire Proposed Period of Support (Overall)

All instructions in the PHS 398 Application Guide must be followed.

Biographical Sketch (Overall)

All instructions in the PHS 398 Application Guide must be followed.

PD/PI. A senior physician scientist with (i) extensive and widely recognized scientific achievements in research on rheumatic diseases; (ii) extensive experience and expertise relative to the identification of targets for the development of new and improved treatments for RA, lupus and related autoimmune disorders; (iii) extensive expertise in approaches to assess the role of gene expression and signaling in target tissues from affected end organs and blood cells to define shared and disease-specific biological pathways; (iv) demonstrated capability and experience to plan, implement, track, coordinate, and manage multiple diverse activities in support of large and complex research programs; (v) considerable skill and experience in communicating and interacting effectively with research program sponsors, investigators, research program governing bodies and scientific advisory groups, biotechnology and pharmaceutical companies, patient advocacy groups, and other public and private organizations; and (vi) the ability to manage and assess the performance of a diverse staff of scientific, technical and administrative personnel.

If the application proposes multiple PDs/PIs, the PDs/PIs will select a single PD/PI who has the qualifications indicated above to serve as the Chair of the NLC.

If consortium agreements to other institutions/organizations are proposed to perform any of the LC functions, the application must also include a description of the qualifications of proposed key personnel of those institutions/organizations and documentation of relevant expertise and recent experience in performing such functions for projects of similar size and complexity.

Resources (Overall)

All instructions in the PHS 398 Application Guide must be followed.

1) Document the capabilities of the applicant organization to negotiate and execute agreements (e.g., contracts and sub-awards) with academic institutions and for-profit organizations, including small and large biotechnology and pharmaceutical companies, to arrange for co-funding of the Network and the LC activities, and provide examples of the average length of time required to complete the execution of such agreements.

2) Document the administrative skills and infrastructure necessary to negotiate for appropriate rights (e.g., intellectual property, data, etc.) to maintain, manage, modify and distribute new discoveries consistent with achieving the goals of this program.

Central Institutional Review Board (IRB). Document the experience of the applicant organization with the use of Centralized IRB models and services, including a list of ongoing studies and studies completed over the past five years in which the applicant organization participated using centralized or mixed IRB models. Provide documentation regarding any centralized IRB services provided by the applicant organization and include a list of ongoing and recently completed studies (with participant Institution contact Information) under the oversight of the Central IRB at the applicant Institution.

Research Plan (Overall)

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Specific Aims: Briefly describe the specific aims of the proposed Network Leadership Center (LC).

Research Strategy: The Overall section of the application should provide the following:

Scientific Overview. Provide an overview that succinctly discusses the key scientific aspects of the project. In developing this section, the applicant may wish to review the Concept Development for Tissue Analytics in Rheumatoid Arthritis and Lupus http://niams.nih.gov/Funding/Funded_Research/AMP_RA_Lupus/default.asp.

Include the following:

• The overall scientific goals and research priorities to achieve the goals of the Network.
  
  
• Research agenda of the Network, identification of potential barriers to success, and potential solutions to overcome those barriers.
  
  
• A clear and concise presentation of the evidence supporting the rationale and need for exploration of signaling pathways to identify new therapeutic targets, as well as a discussion of complexities and major obstacles to progress in this area and proposed approaches to overcome/mitigate such obstacles.
  
  
• A general discussion from the network's perspective about the rationale for and feasibility of studying different cohorts of patients with RA or cohorts of patients with lupus (e.g., RA: treatment responder vs. non-responder, pre-clinical, early vs. established RA, comparison among disease-modifying anti-rheumatic drugs (DMARD) treated groups; lupus: before treatment vs. after treatment, comparison among types of kidney disease, etc.); criteria for prioritizing the selection of patient cohorts for short- and long-term studies; and a discussion of at least one related autoimmune disease in which a similar approach to identifying therapeutic targets is scientifically justified and feasible in terms of clinical and tissue resources.
  
  
• A clear and concise overview of: current and emerging approaches to tissue acquisition; methods for preparation of tissues and cells for analysis; and new and emerging methods for tissue analytics and proposed criteria to prioritize the application of technologies to existing and limited supplies of tissue specimens.
  
  
• A brief description of statistical and bioinformatics approaches and methodologies applicable to the analysis of combined omics type data and clinical data, including new and innovative strategies applicable to RA, lupus and related autoimmune disorders.
  
  
• A discussion of strategies to foster a dynamic and collaborative environment to advance the research activities of the Network, enhance communications, and sharing of resources and information.

Overall Structure, Staffing and Governance. Provide proposed plans for the overall structure, staffing and governance of the LC. Include:

• An overall organizational chart showing the required LC infrastructure, including the LCMP functions and Groups and any organizational entities proposed (e.g., sub-groups, committees, etc.).
  
  
• A discussion of the rationale for the proposed mix of expertise and experience represented by the proposed PD(s)/PI(s), Directors of Groups and LCMP, as well as scientific, technical and management personnel.
  
  
• A discussion of how the components of the LC, including key personnel, will interact and ensure efficient cooperation, communication and coordination, and how the proposed organization of the LC will create an integrated entity capable of performing the functions specified in the FOA.

A description of plans to leverage and/or use other NIH supported resources that may enhance the research activities of the Network, improve efficiencies or facilitate data sharing and dissemination plans.

Resource Sharing Plan:Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS 398 Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

• All applications under the AMP will be required to submit a data sharing plan. Applicants and their institutions are expected to describe their plans for making data and other research resources broadly available to the biomedical community. Applicants should include in their data sharing plan the assurance that data will be made available as soon as quality control procedures have been completed at the local institution. Any sharing plans by the institution represent a commitment by the institution (and its subcontractors, if any) to support and abide by the plan. Reviewers will be asked to comment on the plan. After completion of the initial review, NIH program staff will be responsible for any additional administrative review of the plan for sharing data. The adequacy of any data sharing plan will be considered by program staff when making recommendations about funding applications. Any final accepted data sharing plan will become a term and condition of the award of the cooperative agreement. The effectiveness of the data sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report.

Letters of Support. A letter describing the institutional commitment to the resource, any other sources of funding (and amounts) expected to be available to maintain full operation, business plans for actions related to cost recovery, documentation of relevant partnerships, etc.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions, as noted.

Face Page (LCMP)

All instructions in the PHS 398 Application Guide must be followed.

Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, Human Embryonic Stem Cells (LCMP)

All instructions in the PHS 398 Application Guide must be followed.

Table of Contents (LCMP)

All instructions in the PHS 398 Application Guide must be followed.

Modify the Table of Contents to include all the required sub-sections for the Research Strategy of the LCMP:

A. Research Project Management
B. Operational Management
C. Data Coordination and Management
D. Statistical Research

Detailed Budget for Initial Budget Period (LCMP)

All instructions in the PHS 398 Application Guide must be followed.

Budget for staffing of the LCMP should be included and limited to the activities of this Program/component. Infrastructure support related to LCMP functions should be included here as well. The PD/PI of the LC, who is the Chair of the NLC during the first year will be required to commit at least 3 calendar months to the project. If multiple PDs/PIs are proposed, their combined effort should not exceed 5 calendar months. The LCMP Director will be required to commit at least 3 calendar months per year to the project. The Senior Project Manager will be required to commit at least 4 calendar months per year to the project. The Statistical Research team leader will be required to commit not less than 2.4 calendar months per year to the project. The Data Coordination and Management team leader will be required to commit not less than 4.8 calendar months per year to the project.

Additional support for activities covered in SBG and TRG descriptions should be requested in the budgets for those Groups.

In addition, proposed budgets for the activities of the LCMP should be based on the following:

Number of Research Projects. Assume the Network will carry out a total of approximately ten new, and five pilot and feasibility research projects in year 1, and five to ten new, transitioning, and pilot and feasibility research projects per year in years 2-5.

Number of Research Sites. In all years, approximately three Clinical Research Sites, five Technology Research Sites, and three Combined Clinical and Technology Research Sites.

Number of Study Subjects. Assume the network will carry studies involving 80 subjects in the first and second years of the award and average of approximately 150 study subjects per year in years 3-5.

NLC Meetings/Teleconferences. Scheduling, planning, coordination and materials preparation for two face-to-face NLC meetings per year and monthly NLC teleconferences.

Travel for PD/PI, and team leaders to at least two in person meetings of the NLC.

Budget for Entire Proposed Period of Support (LCMP)

All instructions in the PHS 398 Application Guide must be followed.

Assume that the activities of the LCMP will evolve with the Research Phases 0, I and II of the Network research projects.

Number of Research Projects. Assume the Network will carry out a total of approximately ten new, and five pilot and feasibility research projects in year 1, and five to ten new, transitioning, and pilot and feasibility research projects per year in years 2-5.

Number of Research Sites. In all years, approximately three Clinical Research Sites, five Technology Research Sites, and three Combined Clinical and Technology Research Sites.

Number of Study Subjects. Assume the network will carry studies involving 80 subjects in the first and second years of the award and average of approximately 150 study subjects per year in years 3-5.

Biographical Sketch (LCMP)

All instructions in the PHS 398 Application Guide must be followed.

LCMP Director qualifications should include: a senior scientist with (i) demonstrated capability and experience to plan, implement, track, coordinate, and manage multiple diverse activities in support of large and complex research programs; (ii) considerable skill and experience in communicating and interacting effectively with research program sponsors, investigators, research program governing bodies and scientific advisory groups, biotechnology and pharmaceutical companies, patient advocacy groups, and other public and private organizations; and (iii) the ability to manage and assess the performance of a diverse staff of scientific, technical and administrative personnel. The applicants have the option of having the PD/PI of the LC serve as Director of the LCMP.

The LCMP will include a Senior Project Manager with responsibility for overseeing the day-to-day operations for the project as a whole. The qualifications of the Senior Project Manager include relevant education, training, expertise and recent experience. Indicate recent projects of similar scope and complexity and the level and scope of responsibility for each project for the proposed Senior Project Manager.

Qualifications of the Statistical Research team leader should include: (i) a doctorate degree in Statistics or equivalent; (ii) substantial expertise and experience in the statistical design, development and analysis of clinical research, as well as studies using cutting-edge approaches for the analysis of data from human samples, e.g., deep RNA sequencing, single cell RNA sequencing, evaluations of epigenetic changes, multiparameter cell phenotyping, and phospho-flow analysis; (iii) a working understanding of disease pathogenesis and of currently available therapies and prevention strategies for autoimmune disorders and knowledge of the populations affected; (iv) demonstrated capability and experience to plan, implement, track, coordinate and manage statistical and data coordination activities in support of large, complex research programs; (v) considerable skill and experience in communicating and interacting effectively with research program sponsors and investigators; (vi) the ability to manage and assess the performance of scientific and technical personnel.

Qualifications of the Data Coordination and Management team leader should include: (i) a Master’s degree or higher in computer science/information technology or related fields; (ii) extensive experience and expertise in the use of state-of-the-art, computer-based systems for the collection, storage, tracking and management of clinical and laboratory data, as well as data from analyses of samples of human tissues and blood derived through cutting edge techniques; (iii) substantial expertise and experience in operating large, complex databases involving the transmission of clinical, laboratory and analytics data from multiple research sites and laboratories; (iv) expert knowledge of and experience in methods for data validation and system security; and (v) substantial experience and skill in directing and managing technical personnel for the provision of data management and reporting services.

If consortium agreements to other institutions/organizations are proposed to perform any of the LCMP functions, the application must also include a description of the qualifications of proposed key personnel of those institutions/organizations and documentation of relevant expertise and recent experience in performing such functions for projects of similar size and complexity.

Resources (LCMP)

All instructions in the PHS 398 Application Guide must be followed.

Research Plan (LCMP)

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Specific Aims: Briefly describe the specific aims of the proposed LCMP.

Research Strategy: The Research Strategy must consist of the subsections A-D defined below. See page limits listed above for each subsection.

A. Research Project Management.

Review of Proposed Research Projects. Provide plans and procedures for conducting initial reviews of proposed new, transitioning, pilot and feasibility research projects and for making recommendations to the RS and the NLC, including the following:

• Proposed criteria to assess project soundness, relevance, importance and feasibility and the rationale for this selection.
  
  
• Proposed processes and procedures for conducting initial reviews, documenting the outcomes of initial reviews of proposed research projects; communicating recommendations to the NLC; assisting the NLC in reaching consensus on final recommendations for project approval, modification or disapproval; and communicating NLC recommendations to the Network investigators.

Coordination of Scientific Activities of RS, SBG, TRG and the LCMP. Provide plans and strategies to coordinate and optimize the use of critical Network resources including descriptions of the following:

• A system to record the resources (samples, patient cohorts, etc.) generated by the sites and projects, and an approach to the prioritization for the use of central resources and services to be considered by the NLC.
• A process to handle requests, review and recommendations to the NLC for the use of data and specimens by Network investigators.
• A process to coordinate planned and new systems analysis projects.

Monitoring of Network Projects. Provide proposed plans and procedures for the following:

• Monitoring the implementation and conduct of Network research projects.
• Interacting with the NLC to review study progress, address problems and obstacles, and communicate any NLC-recommended actions to the Research Sites.
• Preparing periodic reports on study progress.
• Executing and managing an agreement for the provision of central Institutional Review Board (IRB) services in the event that a central IRB is utilized.

Network and Research Project Timelines and Reporting.

• Provide plans to develop and monitor project and Network timelines and milestones, monitor progress and produce regular reports on the status of Network projects and LC Groups and LCMP activities.

Timeline and Milestones.

B. Operational Management.

NLC Support. Provide proposed plans, processes and procedures for the provision of centralized technical, administrative and logistics support for the activities of the NLC.

LC Operations Support. Provide a description of overall plans for the governance of the LC, including lines of authority and reporting, decision-making processes, and communication processes within the LC and with the NLC, the PDs/PIs of the Research Sites, and senior NIH officials. Propose plans, processes and procedures for the provision of centralized support for the operations and management of the LC, including the following:

• Project management tracking and reporting system(s).
• Information system to support the day-to-day activities of the LC, including hardware and software support.
• Financial management systems to support a high volume of research projects, timely review of expenditures and financial projections, and tracking of LC financial resources.

Processing of Research Projects Submission. Provide plans and procedures for the following activities regarding the submission of proposed research projects:

• Proposed policies, procedures and required documentation for the preparation and submission of proposed research projects.
  
  
• Proposed system for tracking key dates, including submission, initial LC review, final NLC review and recommendations, and communication of recommendations to investigators and key LC personnel.

Describe proposed plans and procedures for development of SOPs governing all key study processes and procedures.

Timeline and Milestones.

C. Data Coordination and Management. Structure and Staffing. Include descriptions of the responsibilities of all proposed functional entities; identification of all personnel with degrees and titles reflecting their role on the project; delineation of lines of authority and reporting among proposed personnel serving in a senior role; proposed processes for decision-making; proposed processes and procedures to ensure timely and effective implementation of the functions across all Network research projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources; and proposed processes for communication with other LC components and Network investigators. The use of tables, diagrams, flow charts and organizational charts is strongly recommended.

Data Management System. Describe in detail the computer-based system (hardware and software) proposed for clinical, laboratory and analytic data, including:

• The central database system for data receipt, entry, validation, processing, correcting, storage, tracking, transmission and reporting.
  
  
• Key system capabilities, e.g., computerized registration and randomization, computerized study forms and systems for remote data entry, report generation features, etc.
  
  
• Provisions for system security and integrity, including an off-site storage facility for system back-ups.
  
  
• Plans to implement a Network Portal to facilitate data sharing and dissemination in collaboration with the Statistical Research team and the SBG.

Data Quality Control. Describe the quality control system proposed for verification of clinical, laboratory, safety and analytic data, including key system capabilities, e.g., computerized validation and error-checking, procedures to ensure uniform, standardized data collection, computerized data query system for aberrant and/or missing data, etc.

Training of Research Site Personnel. Discuss proposed plans for providing training to RS personnel on the design of data collection instruments and procedures for data collection, entry, management, validation, quality control and submission.

Timeline and Milestones.

D. Statistical Research.

Structure and Staffing. Include descriptions of the responsibilities of all proposed functional entities; identification of all personnel with degrees and titles reflecting their role on the project; delineation of lines of authority and reporting among proposed personnel serving in a senior role; proposed processes for decision-making; proposed processes and procedures to ensure timely and effective implementation of the functions across all Network research projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources; and proposed processes for communication with other LC components and Network investigators. The use of tables, diagrams, flow charts and organizational charts is strongly recommended.

Briefly State the Goals and Objectives.

Statistical Design. Provide discussions of the following:

• Statistical design and analysis considerations relevant for the full scope of research to be conducted by the Network.
• Methodologies considered to be high priority for the statistical design and analysis of the clinical studies and analytics for RA, lupus and related autoimmune disorders and the rationale for their selection.
• Common statistical design and analysis problems and difficulties associated with clinical and analytic research using human samples in general and in relation to differences among these diseases and the populations affected.
• Approaches recommended to overcome and/or improve identified problems/difficulties and optimize the yield from experimental strategies.
• Emerging methodologies for the statistical design and analysis of clinical research and their applicability to the types of research projects to be conducted by the Network.

Statistical Analysis. Provide proposed plans and procedures for performing statistical design and analysis functions for the full scope of clinical and analytic research to be conducted by the Network, including:

• Assisting in the preparation and/or review of the appropriateness and adequacy of statistical designs for proposed research projects from the RS.
• Participating in developing and refining study designs and statistical analysis plans for Research Phase 0, I, and II studies.
• Participating in the review of draft and revised study protocols and recommending improvements and modifications in statistical design and analysis plans, including proposed plans and procedures for collaborating with Network investigators.
• Obtaining and documenting input, and deliberating and achieving consensus on appropriate modifications/refinements to produce final documents.
• Preparing interim and final statistical analysis of all study data in collaboration with Network investigators.
• Participating in the preparation of scientific manuscripts and reports and reviewing the accuracy and completeness of statistical data and data analyses for abstracts, manuscripts and presentations.

Timeline and Milestones.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS 398 Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions, as noted.

Face Page (SBG)

All instructions in the PHS 398 Application Guide must be followed.

Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, Human Embryonic Stem Cells (SBG)

All instructions in the PHS 398 Application Guide must be followed.

Table of Contents (SBG)

All instructions in the PHS 398 Application Guide must be followed.

Detailed Budget for Initial Budget Period (SBG)

All instructions in the PHS 398 Application Guide must be followed.

If consortium agreements are proposed to conduct any SBG activities, include budget information here. Budget information for proposed consortium agreements is required.

Budget for staffing of the SBG should be included and limited to the activities of this Group. The SBG Director will be required to commit at least 3.6 calendar months per year to the project.

Include the SBG portion of the costs associated with the building of a Network portal/database for data review and analyses as well as displays of sample storage (done in collaboration with the LCMP).

In addition, proposed budgets for the activities of the SBG should be based on the following:

Number of Research Projects. Assume the Network will carry out a total of approximately ten new, and five pilot and feasibility research projects in year 1, and five to ten new, transitioning, and pilot and feasibility research projects per year in years 2-5.

Number of Research Sites. In all years, approximately three Clinical Research Sites, five Technology Research Sites, and three Combined Clinical and Technology Research Sites.

Number of Study Subjects. Assume the network will carry studies involving 80 subjects in the first and second years of the award and average of approximately 150 study subjects per year in years 3-5.

Travel of Key Personnel to two annual NLC meetings in the Bethesda MD/Washington DC area.

Budget for Entire Proposed Period of Support (SBG)

All instructions in the PHS 398 Application Guide must be followed. Assume that the activities of the SBG will evolve with the Research Phases 0, I and II of the Network research projects.

Number of Research Projects. Assume the Network will carry out a total of approximately ten new, and five pilot and feasibility research projects in year 1, and five to ten new, transitioning, and pilot and feasibility research projects per year in years 2-5.

Number of Research Sites. In all years, approximately three Clinical Research Sites, five Technology Research Sites, and three Combined Clinical and Technology Research Sites.

Number of Study Subjects. Assume the network will carry studies involving 80 subjects in the first and second years of the award and average of approximately 150 study subjects per year in years 3-5.

Travel of Key Personnel to two annual NLC meetings in the Bethesda MD/Washington DC area

Biographical Sketch (Systems Biology and Bioinformatics Group (SBG) Component)

All instructions in the PHS 398 Application Guide must be followed.

Qualifications of the SBG Director should include: (i) a Ph.D. degree in bioinformatics, biomedical informatics, biostatistics, or related quantitative sciences (computer sciences, mathematics, physics and engineering) with at least 5 years of relevant work experience; (ii) evidence at a senior level of experience and expertise in integrating and interpreting large datasets of biomedical data, such as genomics, proteomics, metabolomics, imaging data and clinical study data; (iii) in-depth technical knowledge and experience of bioIT areas, including programming, systems and database architecture, high performance computing and networking technologies; (iv) considerable skill and experience in communicating and interacting effectively with research program sponsors and investigators; and (v) the ability to manage and assess the performance of a diverse staff of scientific, technical and administrative personnel in a complex customer-oriented environment.

If the application proposes a single PD/PI, that individual will serve as the Director of the SBG. If the application proposes multiple PDs/PIs, the PDs/PIs will select a single PD/PI who has the qualifications indicated above to serve as the SBG Director.

In addition, if consortium agreements to other institutions/organizations are proposed to perform any of the SBG functions, the application must also include a description of the qualifications of proposed key personnel of those institutions/organizations and documentation of relevant expertise and recent experience in performing such functions for projects of similar size and complexity.

Resources (SBG)

All instructions in the PHS 398 Application Guide must be followed.

Research Plan (SBG)

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Specific Aims: Briefly describe the specific aims of the SBG.

Research Strategy:

SBG Structure, Staffing and Governance. Describe plans for the structure, staffing and governance of the SBG. Include descriptions of the responsibilities of all proposed functional entities within the SBG; identification of all senior personnel with degrees and titles reflecting their role on the project; delineation of lines of authority and reporting among proposed SBG personnel serving in a senior role; proposed processes for decision-making.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

Research Designs. Describe the rationale, preliminary data and approach for the application of existing bioinformatics tools to analyze and interpret Network-generated data. Discuss pitfalls and alternative approaches. Describe the innovation and feasibility aspects of the proposed research strategies to identify and test new bioinformatics approaches to identify key signaling pathways.

Describe plans to establish and maintain a technologically up-to-date toolset that can be readily used for systems-level analyses of data generated by the Network. Emphasis should be given to systems biology and other emerging computational approaches that can contribute to understanding, visualization, integration and analysis of multi-dimensional data, envisaged to be essential for the goals of the Network. Include:

• Innovative high level integrative analysis with careful consideration of statistical biases and confounders.
• Approaches to advanced statistical analyses of high-throughput data sets generated by the Network. This includes established techniques for statistical genetics and transcriptomics (e.g. principal components analysis, data normalization, smoothing, clustering, association testing, eQTL mapping etc.). Examples of the types of analyses include: pipelines for genome-wide analysis and interpretation of RNA-seq and single cell RNA-seq data; pipelines and methods for interpretation of mass cytometry data, etc.
• Novel approaches to perform systems-level analyses of multiple different datasets (e.g. genetic, epigenetic, immunological, proteomic or clinical) and define clinically relevant modules and nodes that form tissue-specific networks.

Bioinformatics Tools and Software Development: Describe in detail the strategy for the developmentof tools and software for the integration, annotation, analysis, retrieval, and presentation of data and meta-data from Network clinical and analytic studies.

Consider building flexibility to allow incorporation of new, diverse data types.

Primary and Secondary Analyses. Provide plans for:

• Interactions with Network investigators, LC and NIH scientists for the development, review and implementation of proposed studies/sub-studies, including assessing feasibility and suggesting appropriate technologies to use.
• Collaborations with domain specialists or investigators bioinformatics staff on in-depth analysis of clinical, laboratory and analytics study data.
• Meta-analysis across multiple studies for the purposes of developing best practices, generating summaries/reports, or identifying patterns and trends beyond the primary goals of individual studies.
• Collaboration with LCMP. Describe how the SBG will work with the Data Coordination and Management and the Statistical Research teams to create necessary computational infrastructure and tools to facilitate systems-level understanding of disease. Specifically, include descriptions of at least the following collaborative functions:
  
  1. Development and maintenance of a database for storage and retrieval of data generated by the Network. The database must be able to store multi-dimensional data, such as image, numerical and multi-omics, and integrate those data with experimental (protocol) and clinical descriptive data as well as other existing datasets and to facilitate correlational and meta-analyses.
  2. Development of criteria or templates for uniform data collection, data standardization, data exchange and integrative modeling across multiple data types. Consider use of existing biological ontologies as the basis for defining data standards.

Consultation. Provide consultation to the Network investigators to address questions and needs in the bioinformatics area and, where feasible, work with the Network investigators to develop novel and innovative solutions to identified needs/problems. When possible, the Group should consider leveraging resources (e.g. data standards, novel tools or software) that will be made available through the NIH BD2K (http://bd2k.nih.gov/#sthash.4zsfC8Dw.dpbs).

Training and Outreach. In collaboration with the other functional components of the LC, organize training workshops and community outreach activities to enhance awareness and proficiency in usage of the Network resources and to collect feedback for improvement. Provide proposed plans for training and consultation on using LC-supported data, software, SOPs, and computing resources to the end users.

Pilot and Feasibility Project (P&F). Applicants must state the rationale they will use to develop P&Fs. P&Fs may be proposed when the approach (i) requires additional resources to be provided by the Network, (ii) is at a very early stage of development, or (iii) it represents an alternative to the approach originally proposed. Description of specific P&F projects will not be included in the application. This section is limited to half page.

Timeline and milestones.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS 398 Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

It is expected that this plan will include a description of timely data and software dissemination and public sharing plans that follow community standards, ensure reproducibility, and contribute to NIH-sponsored and public data databases and portals. It is also expected that this will include a description of computing infrastructure and administration plans to provide sufficient system security, computing power and data transfer capacity.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions, as noted.

Face Page (TRG)

All instructions in the PHS 398 Application Guide must be followed.

Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, Human Embryonic Stem Cells (TRG)

All instructions in the PHS 398 Application Guide must be followed.

Table of Contents (TRG)

All instructions in the PHS 398 Application Guide must be followed.

Detailed Budget for Initial Budget Period (TRG)

All instructions in the PHS 398 Application Guide must be followed.

Provide a unified budget for the staffing and related costs necessary to carry out the functions of the TRG for all Network research projects. The TRG Director will be required to commit not less than 1.8 calendar months per year to the project.

If consortium agreements are proposed to conduct any TRG activities, include budget information here. Budget information for proposed consortium agreements is required.

In addition, proposed budgets for the activities of the TRG should be based on the following:

Number of Research Projects. Assume the Network will carry out a total of approximately ten new, and five pilot and feasibility research projects in year 1, and five to ten new, transitioning, and pilot and feasibility research projects per year in years 2-5.

Number of Research Sites. In all years, approximately three Clinical Research Sites, five Technology Research Sites, and three Combined Clinical and Technology Research Sites.

Number of Study Subjects. Assume the network will carry studies involving 80 subjects in the first and second years of the award and average of approximately 150 study subjects per year in years 3-5.

Number of Patient Specimens. (i) in the first and second years of the award period, a total of 320 specimens (80 subjects, 4 specimens per subject, (ii) in years 2-5 of the award period, an average of 400 specimens per year (100 subjects, 4 specimens per patient. Specimens may include, blood, biopsy tissue, stool, urine, etc).

Travel to two annual NLC meetings in the Bethesda MD/Washington DC area.

Budget for Entire Proposed Period of Support (TRG) All instructions in the PHS 398 Application Guide must be followed.

Assume that the activities of the TRG will evolve with the Research Phases 0, I and II of the Network research projects.

Number of Research Projects. Assume the Network will carry out a total of approximately ten new, and five pilot and feasibility research projects in year 1, and five to ten new, transitioning, and pilot and feasibility research projects per year in years 2-5.

Number of Research Sites. In all years, approximately three Clinical Research Sites, five Technology Research Sites, and three Combined Clinical and Technology Research Sites.

Number of Study Subjects. Assume the network will carry studies involving 80 subjects in the first and second years of the award and average of approximately 150 study subjects per year in years 3-5.

Number of Patient Specimens. (i) in the first and second years of the award period, a total of 320 specimens (80 subjects, 4 specimens per subject), (ii) in years 2-5 of the award period, an average of 400 specimens per year (100 subjects, 4 specimens per patient. Specimens may include, blood, biopsy tissue, stool, urine, etc).

Travel of Key Personnel to two annual NLC meetings in the Bethesda MD/Washington DC area.

Biographical Sketch (TRG)

All instructions in the PHS 398 Application Guide must be followed.

If the application proposes a single PD/PI, that individual will serve as the Director of the TRG. If the application proposes multiple PDs/PIs, the PDs/PIs will select a single PD/PI who has the qualifications indicated above to serve as the TRG Director.

TRG Director qualifications should include: a senior scientist with (i) demonstrated capability and experience to conduct research on tissue acquisition strategies, (ii) experience on planning, implementation, tracking coordination, and management of multiple diverse activities in support of large and complex tissue acquisition research programs; and, (iii) experience in communicating and interacting effectively with research program sponsors, investigators, research program governing bodies and scientific advisory groups.

In addition, if consortium agreements to other institutions/organizations are proposed to perform any of the functions, the application must also include a description of the qualifications of proposed key personnel of those institutions/organizations and documentation of relevant expertise and recent experience in performing such functions for projects of similar size and complexity.

Resources (TRG)

All instructions in the PHS 398 Application Guide must be followed.

Research Plan (TRG)

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Specific Aims: Briefly describe the specific aims of the TRG.

Research Strategy:

TRG Structure, Staffing and Governance. Describe in detail plans for the structure, staffing and governance of the TRG. Include descriptions of the roles of all proposed functional entities with the TRG; delineation of lines of authority and reporting among proposed TRG personnel serving in a senior role; proposed processes for decision-making; proposed processes and procedures to ensure timely and effective implementation of TRG functions across all Network research projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources; and proposed processes for communication within the TRG, between the TRG and the LCMP, the SBG, the NIH scientific staff and Network investigators. The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

Specimen Acquisition and Handling. Provide plans and procedures for ensuring that RS work with well-characterized, high quality tissue, peripheral blood cells, plasma and serum and other tissue specimens. Propose standardized procedures for procurement, processing, storage, quality control, and histopathologic evaluation. Discuss proposed approaches to be used for handling specimens for analysis, identify new approaches/technologies for specimen handling and describe their relevance and applicability to the scope of research to be carried out by the Network.

Centralized Histopathology Readings. Provide a statement of capability, but do not include a budget for, proposed plans and procedures for performing centralized histopathology readings for all Network research projects.

Distribution of Patient Samples. Discuss approaches to ensure maximum efficiency in the use of available samples for tissue analytics; identify those approaches most likely to promote efficiency; and provide proposed guidelines for the distribution of limited samples.

Sample Tracking. Describe in detail the proposed computerized database system(s) for tracking all samples from patient consent to tissue acquisition and distribution to appropriate Research Sites. Include descriptions of key system features to allow for: inclusion of or linkage to clinical information on all patients and characteristics of patient samples; maintaining site- and study-specific reconciliation of physical samples and reconciliation of data results corresponding to physical samples, tracking and reporting of specimen collection, sample processing, inter-laboratory shipping and receipt, and final specimen disposition; sample availability; integration with data produced by tissue analytics projects; analysis across studies; etc.

Provision of Materials for Laboratory Testing. Provide proposed plans and procedures for the purchase, packaging and shipping of kit materials required for protocol-specific specialized laboratory tests and for ensuring intact receipt. Describe proposed methods for maintaining a computerized inventory of all materials distributed and, where appropriate, methods to streamline and centralize handling of all processes and provisions requiring material transfer agreement, interstate shipments, and collaborations with foreign Research Sites providing specimens.

Timeline and milestones.

Regulatory Considerations. All applicable laws and regulations for shipment should be satisfied. For example, ISBER Best Practices and International Air Transport Association (IATA) regulations (ISBER 2008; IATA 2009) should be consulted for information concerning international transport regulations and classifying samples for shipment. Variation in national and regional standards regarding biospecimen transport should be considered when shipping biospecimens to or from an international location.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS 398 Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS 398 Application Guide.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS 398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

This initiative is not subject to intergovernmental review.

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

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

Applications must be received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will not be reviewed.

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

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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

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

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

Significance

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

Specific to the FOA: Are the overall goals and research priorities significant? Is the proposed Network research agenda comprehensive, well organized, and feasible in achieving the scientific goals of the Network? Is there strong rationale for the proposed research priorities? Does the application include a Network research agenda? How well do they identify complexities and address key roadblocks for exploring signaling pathways to identify new therapeutic targets? Does the application provide a scientifically sound justification for prioritizing patient cohorts and demonstrate the importance of various approaches to tissue analytics, statistical design and the use of bioinformatics methodologies? Does the application demonstrate the potential to lead the identification of relevant drug targets through an enhanced systems-level understanding of gene expression and signaling in target tissues in the diseases of focus?

Investigator(s)

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

Specific to the FOA: Are the qualifications of the PD/PI proposed to serve as the contact PD/PI and Chair of the NLC in year one well documented and appropriate for directing, managing and coordinating the LC’s scientific, technical and operational responsibilities, particularly for large, complex and multifaceted research programs focused on autoimmune diseases? Will this individual devote adequate time and effort? For applications proposing multiple PDs/PIs, are the roles and responsibilities of PD(s)/PI(s) not proposed to serve as the LC Director clearly defined and well justified relative to the full scope of LC responsibilities? Do these PD(s)/PI(s) have well documented qualifications to perform the responsibilities proposed, and will they devote adequate time and effort? Is the proposed mix of expertise and experience of Directors and senior personnel for the LCMP functions well justified and well suited to the scope of the LC's scientific, clinical and technical functions?

Innovation

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

Specific to this FOA: Does the application as a whole demonstrate innovative approaches to data management, statistical design, tissue acquisition, systems biology and bioinformatics, particularly in relation to RA, lupus and related autoimmune diseases?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the LC ? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

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

Environment

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

Specific to this FOA: Does the application include feasible plans to provide and use a central IRB?

Research Project Management

Note: This criterion will receive one individual score; the subcategories listed will be assessed but not scored separately.

Review of Proposed Research Projects

Are the criteria to be used in initial reviews to assess soundness, importance, relevance and feasibility of proposed research projects well articulated and well suited for the scope of investigations to be performed; will they be effective in ensuring recommendations to promote sound scientific priority setting and the flexibility to integrate new strategies and technologies?

Are plans and procedures for conducting and documenting the outcomes of initial reviews of proposed research projects clear and appropriate?

Are plans and procedures for monitoring the implementation and conduct of research projects comprehensive and effective? Does the application provide effective methods for assessing study progress, identifying problems/obstacles, and developing recommendations for their resolution? Are the reporting plans adequate?

Coordination of Scientific Activities of RS and LC Groups

Are plans for coordinating the the use of critical Network resources sound and clear? Is there evidence of adequate consultation with the NLC in these plans and decision-making?

Standard Operating Procedures (SOPs)

Are proposed plans and procedures for assisting in the development of SOPs governing key study processes and procedures clearly articulated, efficient and effective? Are they likely to contribute to achieving standardization across participating Research Sites?

Operational Management

Note: This criterion will receive one individual score; the subcategories listed will be

assessed but not scored separately.

Is there an effective plan to provide technical and administrative support for the operations and activities of the NLC including management of meetings/teleconferences?

Are proposed project management and tracking systems clearly defined, feasible and appropriate for overseeing effective planning and implementation of the full scope of LC activities?

Are proposed plans for managing LC resources, including financial management capacity and systems, fully defined and feasible; will they contribute to maximizing the efficient use of available resources across all LC functions?

Does the application propose effective, efficient and reliable information management system(s) to support day-to-day LC activities and study-specific collaboration portals?

Data Coordination and Management

Note: This criterion will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed structure clearly defined and does it provide for effective and efficient planning, direction and management of the scientific, technical and operational activities of the Group as a whole? Are proposed processes for decision-making, resolving technical and operational issues, and communication clearly articulated and appropriate? Do the proposed team leader and other staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Is the proposed data management system effective, efficient and reliable? Does it provide for the full range of necessary system capabilities?

Are appropriate quality assurance/quality control procedures in place and is the data quality control system proposed comprehensive, efficient and reliable? Does it provide for standardization in data collection and other necessary system capabilities?

Are proposed data collection and validation standards and procedures clearly defined, comprehensive and user oriented?

Are there clear strategies to manage the interactions with RS investigators and data management teams and the SBG?

Training of Research Site Personnel

Are appropriate plans in place for training Research Site personnel on the use of the data management system, including standardized procedures for data collection, entry, management, validation, submission and quality control?

Statistical Research

Note: This criterion will receive one individual score; the subcategories listed will be

assessed but not scored separately.

Structure and Staffing

Is the proposed structure clearly defined and does it provide for effective and efficient planning, direction and management of the scientific, technical and operational activities of the Group as a whole? Are proposed processes for decision-making, resolving technical and operational issues, and communication clearly articulated and appropriate? Do the proposed leader and other senior staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Statistical Design and Analysis

Does the application demonstrate a sound and comprehensive understanding of the statistical design and analysis considerations of particular relevance and importance for the full scope of research to be carried out by the Network?

Are statistical design and analysis methodologies identified scientifically sound and well justified for the type of studies?

Does the application demonstrate a sound and thorough understanding of common statistical design and analysis problems and difficulties in the diseases and technologies of interest?

Are plans and procedures proposed for performing the full scope of statistical design and analysis functions clearly defined?

Are there clear strategies to manage the interactions with RS investigators and statistical teams and the SBG?

Are there plans for consensus building with the Network investigators in study protocol development and statistical analysis?

Training of Research Site Personnel

Are appropriate plans in place for training Research Site personnel on the use of the data management system, including standardized procedures for data collection, entry, management, validation, submission and quality control?

Note: This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Specific Aims

Are the aims consistent with the overall goals of the LC?

SBG Structure and Staffing

Is the proposed SBG structure clearly defined and does it provide for effective and efficient planning, direction and management of the scientific, technical and operational activities of the Group as a whole? Are proposed processes for decision-making, resolving technical and operational issues, and communication clearly articulated and appropriate? Do the proposed Group Leader and other senior SBG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Research Strategy

Are there a strong rationale and preliminary data supporting the proposed plan for the application of existing bioinformatics tools to analyze and interpret Network-generated data?

Are the proposed research strategies to develop and test new bioinformatics approaches to identify key signaling pathways innovative and feasible? Is there adequate discussion of pitfalls and alternative approaches?

Is there a strong plan to establish and maintain a technologically up-to-date toolset that can be readily used for systems-level analyses of data generated by the Network?

Is there a clear strategy for development of new advanced approaches for integrative analyses of high-throughput data sets generated by the Network?

Bioinformatics Tools and Software Development:

Does the application propose a sound, feasible, effective and efficient system for the development of tools and software for the integration, annotation, analysis, retrieval, and presentation of data and meta-data from Network clinical and analytic studies?

Do the proposed computing infrastructure and administration plans provide for sufficient system security, long-term maintenance and survival of data and the data system, computing power and data transfer capacity?

Primary and Secondary Analyses

Does the application provide well defined, appropriate and effective plans for interacting with the Network Research Site investigators, investigators bioinformatics staff, domain experts, and NIH scientific staff to develop, review and implement studies/sub-studies?

Are there sound and appropriate plans for conducting meta-analyses across multiple studies to develop best practices, generate summary reports, and/or identify patterns and trends beyond the primary goals of individual studies?

Does the application provide appropriate plans for training and consultation on use of Network-generated data, software, SOPs, and computing resources to end users?

Collaboration with LCMP

Is there a well thought out plan to collaborate with the LCMP to achieve efficiency, synergy and avoid duplication of effort?

Consultation

Is there a clear plan to provide consultation to the Network investigators?

Training and Outreach

Are there appropriate plans in place for training and outreach to Network investigators and other potential users?

Does the application include a rationale for the development of Pilot and Feasibility Projects?

Note: This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Specific Aims

Are the aims consistent with the overall goals of the LC?

Research Strategy

TRG Structure, Staffing and Governance

Is the proposed TRG structure clearly defined and does it provide for effective and efficient planning, direction and management of the scientific, technical and operational activities of the Group as a whole? Are proposed processes for decision-making, resolving technical and operational issues, and communication clearly articulated and appropriate? Do the proposed Group Leader and other senior TRG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

TRG Functions

Are there sound and appropriate plans for the operation and management of oversight of specimen acquisition, processing, shipping, tracking, testing, storage, and quality control? Given that a centralized specimen storage repository is not part of the scope of work of the TRG, is there a sound plan and system for inventory processing?

Is the proposed computerized database system(s) for tracking and reconciling all samples and their distribution efficient and reliable? Will it provide for integration with data produced by tissue analytics projects, analyses across studies, etc.?

Are there appropriate and efficient plans and procedures for the purchase, tracking, packaging and shipping of kit materials for specialized laboratory tests?

Are proposed approaches to maximize efficiency in the use of available samples sound, practical?

Does the application propose relevant alternative or new approaches for tissue acquisition and for handling tissue and cells that will be analyzed using new technologies?

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Sample and Biospecimen Shipping

If applicable, is there sufficient consideration of issues related to shipment and receipt of samples and biospecimens from overseas sites?

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

As part of the scientific peer review, all applications:

• Will receive a written critique.

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

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

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

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

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

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

Awardee-selected projects that involve clinical trials or studies involving greater than minimal risk to human subjects require prior approval by NIH prior to initiation.

• The awardee institution will provide NIH with written study protocols that address risks and protections for human subjects in accordance with NIH s Instructions for Preparing the Human Subjects Section of the Research Plan.
• The awardee institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

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

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

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

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

The PDs/PIs will have the primary responsibility for the scientific and administrative leadership and coordination of the project at the awardee institution. The PDs/PIs will have primary responsibility for defining the details for the projects within the guidelines of this FOA and for performing all scientific activities. The awardee institution will agree to accept the close coordination, cooperation, and participation of the NIH Project Scientists (PS) and the NIH Program Official (PO) in those aspects of scientific and technical management of the project as described below.

• Determine experimental approaches, design protocols, set project milestones, conduct experiments, and analyze and interpret research data.
• Provide goals for projects and protocols and costs to the NIH PO and PS, at the outset of the award, following re-negotiation of the milestones after the first meeting of the NLC and at six months intervals thereafter.
• Ensure that all projects involving human subjects have the appropriate clearances (e.g., IRB, FWA, human subject’s research training, and other required documentation) prior to implementation.
• Serve as a voting member of the NLC, and participate, along with critical staff, in NLC meetings including two face-to face meetings in the Bethesda-MD/metropolitan Washington, DC area.
• Adhere to Network guidelines and other policies that might be established, as agreed upon by the NLC, and the PO to the extent consistent with the applicant’s submitted statements and applicable grant regulations.
• Apprise the PO and the PS of any potential impediments to execution of the goals of the Project.
• Ensure that primary and secondary data, protocols, and procedures are made available to Network participants to meet the goals of the Network (e.g., deposited in a centralized database, as specified by the PO and the PS) according to a timeline agreed upon by NLC and the PO and to the extent consistent with the applicant’s submitted statements and applicable grant regulations.
• Agree not to disclose confidential information obtained from other members of the Network.
• Be prepared for annual administrative site visits by NIH staff.
• Be solely responsible for the timely acquisition of all appropriate proprietary rights, including intellectual property rights, and all materials needed for the awardee to perform the project.
• Be required to report to the U.S. Government all inventions made in the performance of the project, as specified by 35 U.S.C. Sec. 200-212 (Bayh-Dole Act).
• Before, during, and subsequent to the award, the U.S. Government is not required to obtain for the awardee any proprietary rights, including intellectual property rights, or any materials needed by the awardee to perform the project.
• The PD/PI is responsible for selecting and implementing Pilot and Feasibility Projects in accordance to guidelines developed and approved by the NLC, by the PS and by the PO.

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

NIH Project Scientists (PS)

The role of the PS in the cooperative agreement is to support and encourage the recipient's activities by substantial involvement as partners and facilitators in the process without assuming responsibilities that remain with the PD(s)/PI(s). The PS will:

• Work closely with the PD(s)/PI(s) and other Network investigators to facilitate collaborations and to leverage the resources available to the sites and the network. They will assist in the integration of the individual RS and LC components into a collaborative research network.
• Monitor the progress of the LC, help coordinate research approaches, and contribute to the shaping of research projects or approaches as warranted. The PS will support and facilitate this process but will not direct it.
• Assist in avoiding unnecessary duplication of effort across the Network, and help coordinate collaborative research efforts that involve multiple sites.
• Keep the PDs/PIs informed about other ongoing studies supported by NIH to avoid duplication of effort and encourage resource sharing and collaborations. The PS will coordinate access to other NIH resources, as well as assist the research efforts of the LC and RS by facilitating access to fiscal and intellectual resources provided by industry, private foundations, NIH intramural scientists and other federal government agencies as appropriate.
• Serve as voting members of the NLC and assist in developing the network priorities and research agenda, operating guidelines and consistent policies for dealing with situations that require coordinated action.
• Retain the option to recommend to the PO the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of the award or fails to comply with the Terms and Conditions of the award.
• Serve as scientific liaison between the awardees and other NIH program staff.
• Review and comment on critical stages of the Network progress.
• Share opportunities and discuss strategies and potential avenues of collaborations (such as with industry, private foundations and/or NIH intramural scientists).

NIH Program Official (PO)

The PO is responsible for the normal scientific and programmatic stewardship of the award. The PO will:

• Provide approval for transition of projects to Phase II.
• Have the option to recommend, following consultation with the Network, NIH PSs and NIH officials, the possible withholding, reduction, or reallocation, as appropriate, of support from any center component that substantially fails to achieve its goals according to the milestones agreed to by the center at the time of the award or fails to comply with the Terms and Conditions of the award, at the appropriate times.
• Have the option to recommend, following consultation with the PS and the NIH officials, an increase in support to engage in further research efforts within the original research scope, as appropriate, for any center component showing that additional research would be substantially exceeding its goals according to the milestones agreed to by the center and substantially improving state-of-the-art capabilities, at the appropriate times.
• Participate in the NLC meetings as an ex officio (non-voting) member.
• Retain the option to recommend, with the advice of the NIH PSs re-allocation of NIH support among awardees, as scientific goals evolve.
• Carry out continuous review of all activities to ensure objectives are being met.
• Serve as the official NIH representative in all communication with the NLC.

Areas of Joint Responsibility Include:

The NLC will be the primary governing body for all Network scientific activities. The NLC will provide the collaborative environment to coordinate all projects awarded under these FOAs and recommend the projects that should progress from Research Phase I to Phase II. The voting membership of the NLC will include: one PD/PI from each award made under this and the companion FOA, the Directors of the SBG and the TRG. During the first year of award, the Chair of the NLC is the PD/PI of the LC. Starting on year two, the NLC will have the option to elect a new Chair that will serve for a period of one year. Face-to-face meetings of this committee will occur at least twice a year. At least a portion of the NLC meeting will be open to the public.

The role of NLC includes:

• Foster collaboration, synergy and sharing among the projects and investigators in the Network.
• Provide the primary mechanism for interactions with NIH.
• Oversee the planning of Network scientific activities, including dynamic adjustment as needs and opportunities arise.
• Guide the development and documentation of the Network standards and guidelines.
• Prioritize the use of LC resources including systems biology analyses and bioinformatics.
• Evaluate progress in the LC and RS and recommend adjustments in approaches if necessary, including implementation of new projects and changes to ongoing studies and termination of projects and sites.
• Foster partnerships and collaborations that will facilitate the extension of the approach to new technologies and their application to related autoimmune disease.
• Review Network Resource Sharing Plan to ensure consistency and appropriateness for achieving the goals of the Network.
• Develop and approve Network-wide intellectual property agreements consistent with the terms and conditions of the cooperative agreement awards, applicable regulations, and the policies and practices of the awardee institutions.

Responsibilities of the NLC include:

• The NLC will convene at least two 1 to 2 day in person meetings annually in the Bethesda MD-Washington DC area. Additional regular meetings will be conducted by teleconference or videoconference. Prior to each meeting, teleconference or videoconference, the NLC Chair will prepare an agenda for review and approval, and distribute to members of the NLC and the LC. Following these meetings a list of participants and summary of discussion, action items, and recommendations will be prepared and submitted to the PO. Part of these meetings may be open to the public. The NLC Chair may convene additional teleconferences, videoconferences, or electronic reviews to avoid delays in addressing key issues that cannot be evaluated at the regularly scheduled meetings.
  
  
• Regularly scheduled NLC meetings will be convened in order to:
• Review progress of Network-sponsored ongoing clinical and technology and tissue analytics studies; review progress of standardization and validation studies, other performance assessments, and future plans and take remedial actions to address delays or other problems.
• The NLC may establish subcommittees or project-specific working groups, or assign responsibility to key staff for other specific Network-related activities.
• Review new tissue acquisition and analytics studies.
• Oversee protocol development for projects approved for implementation by the NLC. Identify need for protocol amendments and/or remedial actions to ensure adequate patient accrual and retention, adherence to protocol requirements and overall progress of studies in collaboration with the NIH PSs; make recommendation to the NIH staff for appropriate actions.
• Coordinate data collection and analysis. Assess requirements for data collection, validation, analysis and security. Make recommendations to the LC about the Network informatics and data and/or information management processes.
• Review and approve outreach and dissemination efforts as proposed by the LC.
• Review governance and fiscal policies and procedures; enforce conflict of interest procedures and policies. The NLC should engage with the PO to ensure that identified conflicts are appropriately addressed.
• Manage publications and communications. Review and approve policies and procedures for authorship, preparation, review, and final approval of manuscripts resulting from Network studies, and for submission of manuscripts for publication in peer reviewed journals.
• Review Data and Safety Monitoring Plans. For each clinical study, the NLC will review recruitment and the Data and Safety Monitoring Plans to ensure adequate enrollment and monitoring of human subjects research. The LC, working with the Network investigators, will solicit, prepare and distribute reports and information for review by the NLC. The LC will follow up on the recommendations of the NLC regarding data and safety monitoring to ensure their adequate implementation.
• Review the data and resource sharing statements, consistent with achieving the goals of the Network. The NLC will review and summarize Network IP management, and develop agreements to be approved by the NLC consistent with the terms and conditions of the NIH awards and applicable regulations. The NLC will work in consultation with the NIH PSs as well as institutional officials from the participating institutions to ensure the effectiveness of any such agreements.
• Awardee members of the Network will be required to accept and implement policies approved by the NLC.

Data Sharing:

• The data sharing plan will be referenced as a term and condition of award. Applicant organization must comply with the Public Health Service (PHS) policies relating to distribution of unique research resources produced with PHS funding and sharing of research data and other research resources, as well as the grantee’s data sharing plan subject to decisions of the Network Leadership Committee. For further information, see the NIH Data Sharing Policy at http://grants.nih.gov/grants/policy/data_sharing/.
• The effectiveness of the data sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report.
• The NIH intends for the resource sharing plans for the data generated under the AMP initiative to follow the policy and goals stated in the FOA. Specifically, consistent with achieving the goals of the AMP program, all data generated (including processed/analyzed data) are expected to be deposited in a rapid and timely way into an accessible repository for use by the broad biomedical community, and for these data to remain available to all qualified investigators, consistent with applicable laws, regulations, and policies and unencumbered by any intellectual property claims. The NIH, in consultation with the Network Leadership Committee for this project, will make all final decisions concerning data deposition and data access policies, and all policies are subject to change by the NIH as deemed necessary to sustain program principles and priorities, or to ensure the highest standards for responsible research conduct within the project.
• Applicant organization will comply with and implement the recommendations and decisions of the Network Leadership Committee with respect to the sharing of information, data, protocols, resources, and methods developed by AMP investigators under the AMP initiative.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the NLC chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

Additional details about the governance structure will be outlined in the Notice of Award.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590 or RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

Reporting requirements for both progress and financial reports may be requested more frequently, under the AMP Program, than the standard annual reporting requirements. The details for the reporting requirements will be outlined in the Notice of Award.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
TTY: 301-451-5939
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY 301-451-5936
Email: [email protected]

Su-Yau Mao, Ph.D.
National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5032
Email: [email protected]

Yan Wang, M.D., Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Telephone: 301-594-5032
Email: [email protected]

Nancy Coulter
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-496-1886
Email: [email protected]

Kan Ma, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-451-4838
Email: [email protected]

Andrew Jones
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-435-0610
Email: [email protected]

Leslie Boggs
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-6450
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.