Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (http://commonfund.nih.gov/) through the NIH Office of the NIH Director, Office of Strategic Coordination (http://dpcpsi.nih.gov/osc/).  The FOA will be administered by the National Human Genome Research Institute (NHGRI/NIH) (http://genome.gov) on behalf of the NIH.
Funding Opportunity Title	Coordinating Center for an Undiagnosed Diseases Network (UDN) (U01)
Activity Code	U01 Research Project – Cooperative Agreements
Announcement Type	New
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-RM-12-020
Companion Funding Opportunity	RFA-RM-13-004
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.310
Funding Opportunity Purpose	To establish a Coordinating Center for a planned Undiagnosed Diseases Network (UDN) of new Clinical Sites added to and building upon the NIH Intramural Research Program’s Undiagnosed Diseases Program (IRP-UDP).

Posted Date	November 30, 2012
Open Date (Earliest Submission Date)	January 2, 2013
Letter of Intent Due Date(s)	January 2, 2013
Application Due Date(s)	February 1, 2013, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	June/July 2013
Advisory Council Review	October 2013
Earliest Start Date	November 2013
Expiration Date	February 2, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

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

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

This initiative is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress.

The purpose of this funding opportunity announcement (FOA) is to establish a Coordinating Center (CC) for a planned national network of new Clinical Sites added to and building upon the NIH Intramural Research Program Undiagnosed Diseases Program (IRP-UDP). The CC will serve as a resource to assist in the creation, support, inter-site communication and management of this Undiagnosed Diseases Network (UDN).

The purpose of the Network is to diagnose both rare and new diseases, and, through the support of mechanistic studies, to suggest, where possible, management strategies for the patients.  This program will advance laboratory and clinical research building upon the experience and expertise of the IRP-UDP and similar programs to enhance coordination and collaboration among laboratory and clinical researchers across multiple centers and to share resulting data and approaches widely throughout the scientific community.

The CC will be selected and funded as a network member prior to the award of new Clinical Sites (estimated-July 2014) in order to assist and develop with IRP-UDP investigators a preliminary set of protocols and operating guidelines. These draft protocols and guidelines will begin to define an initial framework of common practice across the Network, to be refined and expanded as the Network grows and matures.  To the degree possible, common protocols for data collection and common approaches to patient selection, evaluation, and diagnosis will facilitate pooled analyses and cross-site collaborations, ultimately advancing the clinical approach to undiagnosed diseases. 

For the purposes of this FOA, undiagnosed diseases are considered to be disorders with long-standing symptoms or signs that have not been diagnosed despite extensive clinical investigation.  Undiagnosed diseases include 1) rare, previously described diseases, afflicting less than 200,000 individuals in the United States, that are often not recognized because they are so infrequent; 2) yet-to-be-described disorders, previously unknown to medicine also presumed to be rare; and 3) rare variants of more common diseases.

Rare and yet-to-be-described disorders are a difficult problem for patients, their families and their physicians.  The NIH Office of Rare Disease Research notes that about 6% of patients seeking their assistance have an undiagnosed disease.  For those who were ultimately diagnosed, as many as 15% had persistent symptoms  without diagnosis for at least 5 years, a difficult and costly delay for patient, family (including other afflicted family members), and physicians who struggle to identify and treat these disorders.  This diagnostic odyssey is usually expensive with repeated, sequential diagnostic efforts involving a series of physicians pursuing similar duplicative imaging (with related increased X-ray exposure and other risks) and biomarker investigations.

In addition, these patients present compelling research questions since clarification of the underlying genetics, biochemistry and physiology of these disorders will lead to a better understanding of their disease processes and those of related disorders.  Advances in the science of genetics and genomics in medicine have made it possible to understand the causes and potential targets for treatment of some of these diseases.  Furthermore, as the cost of genotyping and sequencing continues to fall and the accuracy of these methods increases, these approaches become more attractive as potentially standard means to diagnose these disorders.

The Intramural Research Program – Undiagnosed Disease Program (IRP-UDP) began in May 2008 and from modest initial recruitment numbers, has over a four-year period received approximately 6,300 inquiries. From these inquiries, the investigators were able to evaluate 2,300 medical records and admit 450 patients to the NIH Clinical Center for thorough, one-week evaluations.  Despite the resource limitations of a new pilot program, NIH investigators over the four years since program initiation have responded each year to an average 1,575 inquiries, evaluated 575 medical records for potential participation and admitted 113 patients for evaluation.  As these data reveal, even without a systematic approach to advertising the program, there is a substantial unmet demand for these capabilities. This justifies the creation of a Network that will be able to address more inquiries, and potentially be more accessible to patients throughout the country who require these services.

Over a four-year period, the IRP-UDP has made diagnoses in approximately 100 patients (20-25% of those evaluated) whose challenging conditions had perplexed and defeated the diagnostic efforts of many skilled physicians. The IRP-UDP has discovered and described two unknown diseases and identified 15 genes not previously associated with human disease.  Much has been learned and many efficiencies gained in the evaluation of patient/family inquiries and of submitted medical records, in diagnostic approaches dictated by organ system involvement, and in engaging the expertise of laboratory scientists studying disease mechanisms.

This funding opportunity and a planned subsequent FOA (for new Clinical Sites) to be issued in early 2013 will create the NIH Undiagnosed Disease Network.  The Network will increase the availability of diagnostic services, expand the geographic distribution of patient access sites, foster opportunities for collaboration between laboratory and clinical investigators, and provide resulting data and protocols to the broader community.  These efforts will lead to new knowledge regarding the biochemistry, physiology, and mechanisms of these diseases and improve diagnostic and management options for patients afflicted with them.

1. Improve the level of diagnosis and care for patients with undiagnosed diseases through the development of common protocols designed by an enlarged community of investigators.

2. Facilitate research into the etiology of undiagnosed diseases, by collecting and sharing standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and documentation of environmental exposures.

3. Create an integrated and collaborative research community across multiple clinical sites and among laboratory and clinical investigators prepared to investigate the pathophysiology of these new and rare diseases and share this understanding to identify improved options for optimal patient management.

This program seeks to provide improved patient access to state-of-the-art diagnostic methods, by expanding the available expertise and facilities serving patients with these unusual disorders and to accelerate discovery and innovation in diagnosing and treating these patients.  NIH intends to create an Undiagnosed Disease Network composed of a CC and 5-7 new Undiagnosed Diseases Clinical Sites in FY 2014 for a total of 6-8 UDN Clinical Sites (5-7 new Sites plus the foundational IRP-UDP).  The IRP-UDP will establish, as an additional element of this overall program, training programs in genomics and genetics of undiagnosed diseases at the NIH Clinical Center and potentially at other sites.

The IRP-UDP investigators will assist in the development of the new Clinical Sites by sharing lessons learned over the past four years in approaches to inquiries, evaluation of medical records, and detailed assessment of phenotype, environment and genotype in patients and families selected for diagnostic investigation.  It is hoped that sharing these lessons will facilitate the development of the new sites and that the infusion of an expanded group of investigators will invigorate and develop new directions and  best practices for use by all.  The CC and new Clinical Sites are anticipated to bring new ideas and alternative approaches to refine and improve upon current IRP-UDP practices and adapt them for use outside the unique setting of the NIH Clinical Center.

It is the intent of this solicitation to establish a Network CC several months prior to the selection of the new Clinical Sites.  This will permit a careful study and codification of the processes used and refined by the IRP-UDP since 2008, for consideration for Network-wide adoption and refinement by the Network Steering Committee once the new sites are awarded.

The award funded under this FOA will be a cooperative agreement (see Section VI.2.A. Cooperative Agreement Terms and Conditions of Award).  Close interactions among awardees and NIH will be required to develop this complex Network.  Shortly after the award, CC staff will meet with IRP-UDP investigators and NIH program staff to plan approaches, identify barriers, and propose solutions for creating and maintaining the UDN. 

The UDN governance will rest with the Network Steering Committee in collaboration with NIH program officials, with advice from an External Scientific Panel, and subject to oversight by a UDP Working Group of the NIH Common Fund.  The Steering Committee may establish subcommittees and working groups to facilitate development, implementation, and monitoring of specific Network functions as needed.

A Steering Committee composed of site Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))from all sites (including the Clinical Sites, CC and the IRP-UDP) and the NIH Project Scientist will be responsible for the scientific direction of the Network.  The Steering Committee will meet quarterly during the first year and two to three times per year or as needed subsequently.  The UDN CC will be responsible for organizing these meetings and teleconferences as needed.

The UDN Steering Committee will be the operational group through which the NIH UDP Working Group interacts with the UDN.  The UDN Steering Committee will identify scientific and policy issues that need to be addressed at the Network level and develop recommendations to the NIH UDP Working Group for addressing such issues.  Working through the CC, the Steering Committee will monitor all aspects of patient recruitment, selection, and assignment to Clinical Site, as well as imaging and laboratory investigation.  It will also ensure dissemination of program data, clinical protocols, training schedules and other materials to the wider scientific community.

An External Scientific Panel (ESP) will be named by NIH program officials and will be responsible for monitoring Network activities and making recommendations to the UDP Working Group and NIH regarding process and substantive issues that arise during Network operations.

An Interim Executive Committee composed of the IRP-UDP PD/PI, the CC PD/PI, and the NIH Project Scientist will collaborate and communicate on a regular (likely weekly) basis to prepare draft protocols and preliminary materials prior to award of the new Clinical Sites.  Once the new sites are added to the Network, the Chair of the Steering Committee, the PD/PI of the CC, the NIH Project Scientist, and the PD/PI of the IRP-UDP will continue to engage in regular (again, likely weekly) phone conferences to facilitate the program’s maturation from 6-8 individual sites to a functional, integrated and effective Network of investigators.

Data from the UDN are expected to be handled so as to increase the value of the significant public investment in the creation and operation of the Network. Consistent with achieving the goals of the program, NIH expects that the project datasets (phenotypic, environmental, covariate, process, and other relevant data) and associated genotyping data from the Network will be widely shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information.  Information such as study protocols, descriptions, bioinformatic tools, and publications are expected to be made available through an open access section of a database such as dbGAP, other public web sites, and publication in the scientific literature.

Applicants should describe their plans to participate with investigators in preparing yearly reports for the Network leadership, the External Scientific Panel, and the NIH UDP Working Group. The yearly report for FY17 will include a more detailed report which an external group will use to make recommendations on the continuation or shut-down of the UDN effort.

This review group will also be asked to make recommendations for orderly close-out of this project either in FY18/FY19 if the mid-year review determines that close-out is warranted, or for issuing a renewal solicitation to continue the project through final closeout in FY22.

The Network can be envisioned as proceeding in phases involving: 1) network design prior to Clinical Site award; 2) start-up and full network operation; and 3) mid-course review.  Should the mid-course review be successful, a repeat solicitation for Network continuation and eventual close-out will be released; if unsuccessful, modest close-out funding may be provided.

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 scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The total amount of funds available for this award is approximately $1.5M for FY2014 contingent upon receiving scientifically meritorious applications.  One award is anticipated from the solicitation.
Award Budget	Application budgets should not exceed $1.5 million total costs in FY14 and $2.5M total costs per year for FY15-FY17 and must reflect the actual needs of the proposed project.
Award Project Period	The total award period for this FOA is 4 years (FY14 through FY17).

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 not allowed.

Applicant organizations must complete the following registrations as described in the SF424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• System for Award Management (SAM)– must maintain an active entity registration (formerly CCR registration), to be renewed at least annually.  Use the Sam.gov “Manage Entity” function to manage your entity registrations.  See the Grants Registration User Guide at SAM.gov for additional information.
• Grants.gov
• eRA Commons

All Program Directors/Principal Investigators (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 6 weeks prior to the application due date.

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

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

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

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

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

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

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

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

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

• Descriptive title of proposed research
• 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:

Carson R. Loomis, Ph. D.
National Human Genome Research Institute
National Institutes of Health
5635 Fishers Lane, Suite 4076, MSC 9305
Bethesda, MD 20892-9307
Rockville, MD 20852 (courier/FedEx/UPS)
Email: loomisc@mail.nih.gov

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

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

Other Attachments

Please include the following information as an "Other Attachment."

Applicants should indicate their experience and willingness to work collaboratively with other Network investigators in furtherance of Network objectives.  As many of the operational and administrative details can only be defined in broad outline before the new Clinical Sites are selected, applicants should describe their ability to adapt to unique needs and unexpected circumstances that may arise as the Network evolves.  Approaches should be described for facilitating specialization and capitalizing on unique strengths such as systems or disease-specific expertise among Clinical Sites when warranted.

Applicants should describe how they will encourage the autonomy of the Network Steering Committee (SC) to define a mode of operation that best matches the capabilities of the selected sites, within broad guidelines of parity, openness, cost-effectiveness, timeliness, and optimal patient care, as defined by the SC, the NIH, and its advisors.

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

In this FOA, as in all FOAs related to the UDN, applicants are encouraged to creatively engage the scientific and operational problems that will need to be addressed for the Network to be a success.  NIH recognizes that the approach to diagnosis and investigation developed by the IRP-UDP is only one model, albeit a successful one, that may be challenging to adapt outside the unique setting of the NIH Clinical Center.  New ideas and alternative approaches proposed by the CC and eventually all Clinical Sites are likely to refine and enhance the care of patients and the science generated from careful study of their cases. Within the framework of this FOA there are a variety of approaches to Network creation and subsequent function that may ultimately be adopted by the Steering Committee and NIH.  Applicants should discuss alternatives and defend the approaches they favor.

Specific Aims

List each aim for your CC and how it supports the Objectives of this Research Program described above.

Research Strategy

Describe how you will provide the following responsibilities in the development of this UDN CC:

• Observing the operations and reviewing the past history of the IRP-UDP to gain a thorough understanding of its methodologies, procedures, strengths and weaknesses.
• Documenting current IRP-UDP methods and assisting in streamlining data management and deposition.
• Drafting, in collaboration with IRP-UDP investigators, preliminary protocols and operating guidelines that will define an initial framework for common approaches to patient selection, data collection, laboratory investigation, and ultimate diagnosis, and serve as a base for further refinement by all Network investigators.
• Assisting new Clinical Sites in refinement and implementation of the resulting consensus framework Network-wide.
• Aiding Clinical Sites in rigorous collection of phenotypic, covariate, and exposure data, as in standardizing laboratory and imaging approaches, defining and monitoring data quality standards, and collecting short and long term follow-up data.
• Planning for, establishing, and maintaining efficient data systems necessary for timely collection, submission, and analysis of high-quality phenotypic, exposure, and genomic and other specialized clinical and laboratory data.
• Providing statistical expertise and advice to the Network Steering Committee regarding optimal approaches to the analysis of UDN data.
• Supporting investigators as needed in preparing abstracts, presentations and publications and in assisting Network leadership in making the public aware of the program.
• Managing site-to-site interactions including logistics of advisory and steering committees and Network meetings, facilitating patient selection, and creating a secure mechanism for exchange of patient information and inter-site data management.
• Disseminating resulting data and protocols consistent with patient privacy, confidentiality, and existing regulations on management of health information (such as HIPAA).

The creation of an integrated and collaborative Network is an essential task for all investigators who are chosen to participate; the CC is a critical component in creating and sustaining this goal.  The following recommendations should be considered when describing your concept of the UDN CC:

• Applicants should indicate their willingness to cooperate with other awardees in the development and design of research approaches, procedures, policies and strategies to be applied to this program.
• Applicants should describe prior experience in working as part of a research network or other collaborative activities to meet individual and group goals.  They should also describe their experience with and proposals for putting into operation a central IRB.
• Describe the overall strategy, methodology, and analyses to be used to accomplish the specific aims of the project.
• Applicants should detail their experience/expertise, proposed approaches and potential alternatives to performing the various CC tasks summarized below.  Additional tasks not detailed here but in the applicant’s view essential to Network operations should be noted and potential approaches described.
• Applicants should describe their plans for coordinating, facilitating and supporting the activities of the Network in collaboration with the other Network investigators and NIH program officials.
• Applicants should articulate their plans for collaboration with other Network investigators in the design of data collection and management including the creation of data forms, web based data submission, informed consent documents, creation of CC policies and procedures for data collection, management, quality control, storage, analysis and security.  This will involve process variables such as recruitment rates, timely and accurate submission of data by the Clinical Sites and scientific variables such as phenotype, genotype and environmental data. These plans should also include, prior to the selection of the new sites, a pilot effort in the collection of data from the IRP-UDP investigators to test plans for data submission on the part of all Clinical Sites as they become operational.  Applicants should also describe plans for Memoranda of Understanding or other sharing agreements potentially needed for data and sample sharing within the Network.   
• Applicants should describe their experience and plans for data collection at all levels of patient involvement including inquiries, medical chart reviews and formal, detailed evaluations.  The four- year average annual IRP-UDP flow of inquiries, chart review and formal evaluation noted above might serve as a basis for estimating patient flow.  Assuming a six-month start-up (July-December 2014) and  success on the part of all 6 new sites,  anticipated recruitment by 6 new clinical sites in calendar year 2015 might be approximately 175 thoroughly evaluated patients (25-30 per site), given the burden of start-up and solution of problems identified.

The NIH Clinical Center could, based upon 4 year averages, add an additional 120 patients per year for each year of network operation.  It is anticipated that there will be little data collected centrally on the inquiries, more on the chart reviews and much more on evaluated patients. It is anticipated that in the subsequent years, each site might add as many as 50 to 125 evaluated patients each year. 

Variation in performance of the selected Clinical Sites is likely; applicants should describe their approach to monitoring site performance, anticipating and resolving start-up issues, and assisting any poorly-performing sites. 

Applicants should discuss their plans to collect data on environment, genotype and phenotype and describe plans to work with the National Center for Biotechnology Information (NCBI), which maintains the NIH databases, to optimize data analysis and public access to the data.

Applicants should describe their plans for collection, storage and analysis of these diverse data and samples across multiple disease syndromes, submitted by multiple Clinical Sites of initially varying expertise and experience.  Plans for back-up systems robust enough to prevent loss of data following diverse natural and human causes should be described.

Network Design (November 2013 – June 2014)

Within the Research Strategy, applicants should describe how they will work closely with the IRP-UDP investigators and program officials to design protocols and operating guidelines to standardize Network approaches to inquiries, chart review, detailed evaluation, collection and submission of data.

Applicants should describe plans to work with IRP-UDP investigators to anticipate and provide potential solutions to problems in the creation of new Clinical Sites.  These might include, but are not limited to central collection and distribution of inquiries across sites, sharing of chart review, potential use of special patient evaluations in the new Clinical Sites to take advantage of local expertise, creation of sites with specific organ disease interests and skills and transfer of patients among clinical sites based upon expertise and interest and geographic proximity to the patient.

A major focus during this design phase will be to create an environment that leads to success of the new Clinical Sites and the Network as a whole including: early identification and mitigation of problems encountered in the new sites, use of NIH and other Network experts in problem solving and participation in training programs led by the IRP-UDP and other groups.  Applicants should present their plans to assist in this effort.

Progress Monitoring - Network Start-up (July 2014 - December 2015) and Full Operation (January 2016 - June 2017):

Within the research strategy, applicants should describe plans for participating with Network investigators in identifying and solving start-up problems including recruitment, data collection, quality assurance and refinement of protocols and manual of operations.  Applicant should suggest plans that will assist in developing collaboration between clinical and laboratory scientists both within and outside the Network.  The CC’s plan to implement and continue to refine data management strategies should be clear in the application.

Applicants should describe plans to provide timely process and substantive data to the Network leadership to permit early identification of problems and to report progress on an annual basis to an External Scientific Panel (ESP).  Applications should include plans to work with the Network leadership in conducting site visits to the Clinical Sites on an as needed basis to monitor record keeping, timeliness and accuracy of data entry.  

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 SF424 (R&R) Application Guide, with the following modification:

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

Appendix

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

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

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness 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.  

In order to expedite review, applicants are requested to notify the NHGRI Referral Office by email at nakamurk@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

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

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

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? How will this project improve the approach to patients who suffer from rare diseases or yet to be described diseases? How will this project improve the understanding of the etiology of these diseases and lead to their mitigation?

Investigator(s)    

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

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? Will this research advance the use of genomics, related technologies and the use of common data elements/protocols in clinical care of patients with rare or as-yet-undescribed diseases?

Approach

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

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?  

Environment

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

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

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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

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

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

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Human Genome Research. 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.

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable 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 the UDN 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:

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Participating in group activities, including a study-wide Steering Committee and working groups as needed. 
• Scheduling, convening, and documenting Steering Committee and working group meetings.
• Implementing Steering Committee recommendations for designing, implementing, evaluating, and disseminating network data and general information, as appropriate and feasible.
• Facilitating and monitoring progress of working groups.
• Identifying quickly any problems in recruitment, timely and accurate submission of data and resolving these issues expeditiously.
• Implementing Steering Committee recommendations following NIH Working Group approval, for designing, implementing, evaluating, and disseminating the UDN approaches and successes.
• Work with Network leadership in developing and providing protocols, reports and data in a timely fashion as agreed upon by the Steering Committee. 
• Disseminating protocols, consent materials, methods, developed for the UDN within and outside the Network.
• Disseminating detailed process, outcome and evaluation data derived from the Network.
• Working with Network investigators to determine needs for additional consent and Institutional Review Board approval.
• Working with Network investigators to develop and implement appropriate educational materials for patients and clinicians.
• Cooperating with other awardees in the development and design of research methods, protocols, tools and strategies.
• Sharing results according to the data sharing policy agreed to between the NIH Working Group and the applicant.
• Adhering to policies regarding data access, publication, and intellectual property established by NIH and the Steering Committee for the UDN.
• Abiding by common definitions, protocols, procedures, as chosen by majority vote of the Steering Committee.
• Accepting and complying with study policies established by NIH, and with additional non-conflicting policies approved by the Steering Committee.
• Organizing the publication and dissemination of UDN findings. 
• Scheduling and attending regular meetings (in person or by phone) with the Steering Committee and relevant working groups.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and NIH Working Group.
• Attending and participating in Steering Committee meetings and accepting and implementing decisions by the NIH Working Group, as appropriate.

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

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

The Project Scientist is a scientist of the NIH Working Group who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination.  However, the role of NIH staff will be to facilitate and not to direct the activities.  It is anticipated that decisions in all activities will be reached by consensus of the UDN and that NIH staff will be given the opportunity to offer input to this process.  The Project Scientist will participate as a member of the Steering Committee and will have one vote.  The Project Scientist will have the following substantial involvement:

• Participating with the other Steering Committee members in addressing issues that arise with UDP planning operation and analysis.  The Project Scientist will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the awardees. The Project Scientist will also help coordinate the efforts of the UDN with other groups conducting similar efforts.
• Attending all Steering Committee meetings as a voting member and all Working Group meetings, assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist will be responsible for working with the grantee as needed to manage the logistic aspects of the resource.
• Reporting periodically on Network progress to the NIH Working Group and through it to the NIH Common Fund and to the National Advisory Council of Human Genome Research Institute.
• Serving on subcommittees of the Steering Committee, and Working Groups as appropriate.
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.  
• Participating in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the program.  
• Other NIH Working Group staff may assist the awardee as designated by the Program Official. 

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned Program Official may also serve as an NIH Working Group Project Scientist.

Collaborative Responsibilities

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to develop the UDN. The awardee and the Project Scientist will meet in person with the program Steering Committee on a quarterly schedule during the first year of Network operation and subsequently three times per year and monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. PDs/PIs, key co-investigators and pre- and post-doctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, are eligible to attend these meetings.

The Steering Committee will serve as the main scientific body of the program.  The Steering Committee will be responsible for coordinating the activities being conducted by the program.  The Steering Committee membership will include the Principal Investigators, other CC staff as needed (ex-officio) and the NIH Project Scientist.  The Steering Committee may add additional members, and other government staff may attend the Steering Committee meetings as desired. 

The Steering Committee may establish working groups as needed to address particular issues, which will include representatives from the program and the NIH and possibly other experts. The UDN SC will have the overall responsibility of assessing and prioritizing the progress of the various working groups and other needed subcommittees.

The Coordinating Center (CC) Awardee agrees to work collaboratively to:

• Share statistical experience and expertise across the UDN and provide advice on design.
• Participate with the current IRP-UDP investigators to refine and adapt current single center activities to the requirements of the Network.
• Assist in refining a common approach to patients with Undiagnosed Diseases. 
• Work collaboratively with other UDN investigators to provide for secure, accurate and timely data submission.
• Participate in presenting and publishing new processes and substantive findings.
• Participate in the governance of the UDN as a member of the Steering Committee.
• Interact with other relevant NHGRI and NIH activities, as needed, to promote synergy and consistency among similar projects.

Dispute Resolution:

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

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

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

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

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Carson R. Loomis, Ph. D.
National Human Genome Research Institute
Telephone: (919) 541-7592
Email: loomisc@mail.nih.gov

Rudy O. Pozzatti, Ph. D.
National Human Genome Research Institute
Telephone: (301) 402-0838
Email: pozzattr@mail.nih.gov

Cheryl Chick
National Human Genome Research Institute
Telephone: (301) 435-7858
Email: chickc@mail.nih.gov

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

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