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Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
Office of Rare Diseases, NIH (ORD, NIH) ( http://rarediseases.info.nih.gov/)
National Cancer Institute (NCI) (http://www.cancer.gov/)
National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov)
National Institute on Aging (NIA) (http://www.nia.nih.gov/)
National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov/)
National Institute of Allergy and Infectious Diseases (NIAID) (http://www3.niaid.nih.gov/)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (http://www.niams.nih.gov/)
National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov)
National Institute of Dental and Craniofacial Research (NIDCR) (http://www.nidcr.nih.gov/)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov)

Title: Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network (U54)

Announcement Type
This is a reissue of RFA-RR-03-008 which was previously released February 27, 2003. See companion FOA RFA-OD-08-002 for Data Management and Coordinating Center for the Rare Diseases Clinical Research Network.

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

Request For Applications (FOA) Number: RFA-OD-08-001

Catalog of Federal Domestic Assistance Number(s)
93.853, 93.273, 93.393, 93.394, 93.395, 95.846, 93.847, 93.848, 93.849

Key Dates
Release Date: February 8, 2008
Letter of Intent Receipt Date: July 20, 2008
Application Receipt Date: August 20, 2008
Peer Review Date(s): January-February 2009
Council Review Date: May 2009
Earliest Anticipated Start Date: July2009
Additional Information to Be Available Date (URL Activation Date): Not Applicable
Expiration Date: August 21, 2008

PRE-APPLICATION MEETING

The ORD anticipates holding a pre-application meeting in March, 2008 to which all interested prospective applicants are invited. Program and review staff will make presentations to explain the goals and objectives for the Rare Diseases Clinical Research Network and answer questions from the attendees. A Grants Management Specialist will be available to answer financial questions. A Notice with the date and time of the meeting will be issued in the NIH Guide for Grants and Contracts http://grants.nih.gov/grants/guide/index.html.

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

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

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

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

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

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

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

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

The NIH ORD, NIAMS, NIDDK, NICHD, NINDS, NIA ,NIAAA, NCI, NIDCR and NHLBI invite new and renewal applications (U54) for Rare Diseases Clinical Research Consortia (RDCRC) component of Rare Diseases Research Network (RDCRN). The purpose of this cooperative agreement research program is to facilitate clinical research in rare diseases through support for 1) collaborative clinical research in rare diseases, including longitudinal studies of individuals with rare diseases, clinical studies, and/or phase I, II and II/III trials; 2) training of clinical investigators in rare diseases research; 3) pilot and demonstration projects; 4) a test bed for distributed clinical data management that incorporates novel approaches and technologies for data management, data mining, and data sharing across rare diseases, data types, and platforms; and 5) access to information related to rare diseases for basic and clinical researchers, academic and practicing physicians, patients, and the lay public.

Each RDCRC will perform collaborative clinical research in rare diseases, train new investigators in rare diseases research, and provide content for an internet resource site on rare diseases. Each RDCRC will consist of a consortium of clinical investigators, institutions, and relevant organizations, including patient support organizations, focused on a subgroup of rare diseases. Use of the resources available at institutions with a Clinical and Translational Science Award (CTSA) or General Clinical Research Center (GCRC) should be incorporated into each RDCRC if available at the applicants institutions. The focus of each RDCRC can be on particular defects, e.g., lysosomal storage diseases, amino acid metabolism defects; particular organ systems, e.g., primary immune deficiencies, mental retardation syndromes; or other groupings. Since rare diseases are diverse, the nature of clinical research that is feasible varies. The application must describe the group of rare diseases to be included, the rationale for this grouping, and the relevant expertise available in the proposed RDCRC. The individual RDCRCs will be responsible for the design and implementation of their clinical studies. The Data Management and Coordinating Center (DMCC), formerly called Data Technology Coordinating (DTCC) will provide the data management and analysis infrastructure and support necessary for the RDCRCs to function optimally. The DMCC will work with each Consortium to integrate protocols, forms, and research tools into the Network.

This FOA allows RDCRC applications for all rare diseases research relevant to the mission of the NIH ICs listed on the first page of this FOA. Prospective applicants are urged to consult with the program staff of the NIH early in the preparation of the application (see Section VII. Agency Contacts or https://grants.nih.gov/grants/guide/rfa-files/RFA-OD-08-001.html.

Background

Approximately 25 million people in the United States are affected by an estimated 6,000 rare diseases or conditions leading to significant morbidity and mortality. 'Rare disease' is defined through an Amendment to the Orphan Drug Act of 1983 (Orphan Drug Act, P.L. 97-414; Health Promotion and Disease Prevention Amendments, P.L. 98-551) as a condition affecting fewer than 200,000 Americans or a disease with a greater prevalence but for which no reasonable expectation exists that the costs of developing or distributing a drug can be recovered from the sale of the drug in the United States.

An NIH ORD Special Emphasis Panel, composed of academic scientists, representatives of voluntary patient support groups, pharmaceutical, biotechnology and device industries, and other Federal agencies, made recommendations on the special research and health care issues posed by rare diseases. These recommendations encompassed four major areas: 1) Stimulating Research on Rare Diseases and Conditions with specific emphasis on clinical research and training of clinical research

scientists, establishing diagnostic and treatment centers with informatics support, and promoting the collaboration of the voluntary patient support groups, health care systems, and industry; 2) Utilizing

Research Resources with the NIH-supported GCRCs (now supported by Clinical and Translational Science Awards, CTSAs), the development of a centralized information database containing research resources, made available to research investigators, physicians, and patients for their use; 3) Coordination of Rare Diseases Research and Development Activities, with a primary responsibility of ORD to coordinate activities and act as a liaison between the rare diseases community and the NIH, including the public, and intramural and extramural investigators at the NIH ICs and other Federal agencies, manufacturers, and voluntary organizations; and 4) Identifying Emerging Opportunities in Rare Diseases Research, specifically through the establishment of specialized research and diagnostic centers to attract the interests of industry to promote advances and products for the prevention, diagnosis, and treatment of rare diseases. These recommendations are contained within the Department of Health and Human Services National Institutes of Health Report on Steps to Coordinate Rare Diseases Research Programs," January 2001 (http://rarediseases.info.nih.gov/html/reports/fy1999/SEP.html).

In November 2002, the Rare Disease Act of 2002 (Public Law 107-280) directed ORD, NIH to support regional centers of excellence for clinical research into, training in, and demonstration of diagnostic, prevention, control, and treatment methods for rare diseases. This law provides the legislated mandate for this FOA to address the needs of rare disease clinical research.

Investigations into rare diseases offer promising leads for scientific advancement. Many rare diseases represent single gene defects whose abnormalities in specific genes or proteins offer insight into normal biologic function. Other rare diseases are complex, resulting from the interaction of two or more genes. Understanding the pathogenesis of rare diseases may advance our understanding of more common medical disorders.

Despite the advances and opportunities for research in rare diseases, difficulties remain in clinical diagnosis and management. Diagnoses may be straightforward with well-described phenotypes or difficult with poorly defined criteria. There are insufficient characterizations of the courses of many rare diseases. Treatment can be equally challenging with many questions concerning appropriate and best clinical management. Rare diseases pose unique challenges to identification and coordination of resources and expertise for small populations dispersed over wide geographic areas. Rare diseases research requires collaboration of scientists from multiple disciplines sharing research resources and patient populations. Rigorous characterization and longitudinal assessment is needed to facilitate discovery of biomarkers of disease risk, disease activity, and response to therapy. In addition, systematic assessment could resolve controversies concerning current treatment strategies. Well described patient populations will be important to bring promising therapies to the clinic.

Purpose

This initiative will support the continuation of a collaborative and coordinated network of RDCRC comprised of investigators and patient support groups committed to investigation of rare diseases working in partnership with leaders in technology to enhance communication and sharing of resources in a multidisciplinary approach. The Rare Diseases Clinical Research Network (RDCRN) will focus on the collection of clinical information to develop biomarkers and new approaches to diagnosis, prevention, and treatment and promote the training of new clinical investigators in rare diseases research. The Network will support a comprehensive and integrated approach to data collection, storage, and management, and the integration of clinical data with other unique data, including genetic, imaging, pathologic, and laboratory data. This will incorporate new approaches to distributed computing and federated databases.

Each RDCRC within the Network must include a consortium of clinical investigators, institutions, CTSAs or GCRCs (if available at the applicants institutions), and relevant organizations, including patient support organizations, for the study of a subgroup of rare diseases that are relevant to the interests of the participating ICs. Each RDCRC must have a plan for identification and recruitment of patients for clinical studies. The development and maintenance of patient registries may be appropriate and necessary core activities of an RDCRC in some cases.The Data Management and Coordinating Center (DMCC), formerly called Data Technology Coordinating Center, DTCC, is collaboration between data base and computational/computer science innovators. It will provide a scalable coordinated clinical data integration of developed and publicly available datasets for data mining at RDCRCs, web-based recruitment and referral, and a user-friendly resource site for the public. The DMCC will provide a, management system for collection, storage, and analysis of RDCRC data as well as a portal and tools for research scientists and clinicians. In addition, the DMCC will provide logistical and administrative assistance for Network activities; produce and/or maintain Network Operating Policy and Procedures, documents, worksheets, and data collection forms; and monitor Network compliance while addressing privacy and confidentiality issues related to database management, distributed computing, and multi-level data sharing. The DMCC will serve as a Network resource, working with and providing expertise for the RDCRCs.

This initiative should facilitate identification of biomarkers for disease risk, disease severity/activity, and measures of clinical outcome appropriate for applicability to clinical trials and encourage development of new approaches to diagnosis, prevention, and treatment of rare diseases.

Organization of the Rare Diseases Clinical Research Network

The Rare Diseases Clinical Research Network (RDCRN) is a cooperative network composed of several Rare Diseases Clinical Research Consortia (RDCRC) and a single DMCC to facilitate clinical research in rare diseases carried out by the RDCRCs. A Steering Committee, composed at a minimum of the Principal Investigator (Director) of each RDCRC, the Principal Investigator (Director) of the DMCC, and the Office of Rare Diseases Program Coordinator will establish the procedures for the function of the RDCRN, as outlined in section "Steering Committee." The reissuance of the RDCRC RFA is open to new as well as existing RDCRCs.

The RDCRN will require cooperation among the ORD Program Coordinator, the participating IC Project Scientists, Directors of the RDCRC and their collaborators, and the Director of the DMCC to maximize their effectiveness. A number of issues need to be addressed in the cooperative agreement applications including those highlighted in Organization of the Rare Diseases Clinical Research Network and below under Cooperative Agreement Terms and Conditions.

Research areas of interest

See https://grants.nih.gov/grants/guide/rfa-files/RFA-OD-08-001.html for IC-specific rare diseases and research topics interests.

In summary, an RDCRC must include the following:

1. Clinical Research Projects for Observational/Longitudinal Studies and/or Clinical trials (At least two projects are required, one of which must be a longitudinal study)

2. Pilot/Demonstration Projects (At least one project is required)

3. Training (career development) Component

4. Website resource for education and research in rare diseases

5. RDCRC Administrative Unit

6. Collaboration with Patient Advocacy Group

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the NIH U54 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

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

The NIH U54 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award". Plans to continue the RDCRN beyond the current funding opportunity are indefinite.

2. Funds Available

The NIH ORD and participating ICs intend to commit approximately $8.75 million in FY 2009 to fund up to seven new and/or renewal grant applications in response to this FOA. If additional Institute funds become available, approximately 10 consortia may be funded. An applicant must request a project period for five years. In General, budget requests should be limited to $1.25 million in total cost (i.e., direct cost plus Facilities and Administrative (F&A) costs). Amounts above this level can be requested but will require prior approval from relevant NIH institute program staff (http:\\grants\guide\contacts\rfa-0D-08-001.htm).

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

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

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

For Foreign Institutions: Foreign institutions may not submit applications, but collaborating co-investigators and clinical research sites at foreign institutions are allowed as components of an RDCRC application. Consortium agreements with foreign institutions can be proposed as long as the appropriate federal-wide assurances for the protection of human subjects are in place (see http://www.hhs.gov/ohrp/) and the activities at the foreign site(s) do not exceed 49 percent of the direct costs of the overall budget. NIH provides limited facilities & administrative (F&A) costs (8 percent of total direct costs less equipment) to foreign institutions and international organizations to support the costs of compliance with NIH requirements, including, but not limited to, protection of human subjects, animal welfare, and research misconduct. See the NIH Grants Policy Statement (Revised December 2003) at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm.

1.B. Eligible Individuals

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

2. Cost Sharing or Matching

There is no requirement for cost sharing or matching.

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

3. Other-Special Eligibility Criteria

An applicant organization may submit only one application under this FOA.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

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

2. Content and Form of Application Submission

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

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Applicants are encouraged to contact the program staff of the relevant NIH ICs before submitting an application. A list of program staff and their contact information from the participating NIH institutes is included in Section VII. Agency Contacts and at http:\\grants\guide\contacts\rfa-0D-08-001.htm

Requirements for the RDCRC structure are provided below. Specific instructions for preparing the RDCRC application are provided in Section IV. 6. Other Submission Requirements.

Applicants are encouraged to discuss the scope of their proposed application and its responsiveness to the FOA with the relevant Program contacts listed in Section VII. Agency Contacts and at http:\\grants\guide\contacts\rfa-0D-08-001.htm

RDCRC

To accomplish the program goals of the RDCRN, each RDCRC application must include the following components and activities:

1) A description of Overall Clinical Research Program, Leadership & Resources: Describe the nature of the multidisciplinary team and approach for the consortium of clinical investigators, institutions, and relevant organizations, including patient support organizations, focused on a subgroup of rare diseases. Describe the institutional environments that are or would be relevant to the effective implementation of the proposed program. As appropriate, describe available resources, such as clinical and laboratory facilities, participating and affiliated institutions and units, rare diseases patient populations, geographic distribution of space and personnel, consultative and statistical resources. Each RDCRC must provide statistical and clinical support.

2) Clinical Research Projects for Observational/Longitudinal Studies and/or clinical trials (At least two projects are required and one of them must be a longitudinal study): Describe the rationale for the planned clinical studies and longitudinal assessment of subjects. Strategies for recruitment, retention, assessment, and analysis must be included. Depending on the state of knowledge of the particular diseases, the clinical studies could include strategies for assessing current therapeutic interventions, and phase I, II or II/III clinical trials.

Applicants must propose clinical research projects that can characterize and more completely define the disease and its course for the rare diseases that are encompassed in their consortium. These, in general, will be observational (non-interventional), such as longitudinal or natural history studies of patients with the given disease. The study design and objectives should take in to consideration what information regarding the rare disease population would be needed in order to pursue clinical trials for that rare disease. Applicants should approach a longitudinal study with the question: What knowledge/tools are needed regarding the rare disease in order to design efficient efficacy trials for this rare disease? Even if there are no treatments currently proposed for the rare diseases under study, a longitudinal study should be designed with the intention that if a treatment were suddenly available, what knowledge (outcome measures, features of disease course, markers of disease or subpopulations of the rare disease that may alter disease course, etc.) about the rare disease over time would be important to have to design an appropriate treatment (efficacy) trial.

3) Pilot/Demonstration Projects (At least one project is required): Describe and provide rationale for the planned pilot and demonstration projects. Examples of demonstration/pilot studies include development of novel laboratory assays and clinical instruments. Depending on the state of knowledge of the particular diseases, the pilot studies could include strategies for assessing current therapeutic interventions, phase I, II or II/III clinical trials.

4) Training (career development) Component: Describe a plan for training of new investigator(s) for clinical research in rare diseases within the RDCRC. The RDCRC should provide a unique environment for clinical research in rare diseases that will prepare new scientists for careers in this field and provide the opportunity for established scientists to re-orient their research careers toward rare diseases research.

5) Website resource for education and research in rare diseases: Describe resources to be included in a web site for education and research in rare diseases. These resources should include links or materials for lay public, patients, basic and clinical researchers, and clinicians. Examples include but are not limited to: contacts for animal models; availability of tissue, serum, specimens, DNA, etc; antibodies and research reagents; genetic resources; registries; education materials; and/or diagnostic flow charts. The actual design and implementation of the site will be a collaborative activity of the DMCC and all of the RDCRC through the Steering Committee (see below). Each RDCRC and the DMCC must agree to work cooperatively to develop the web site resource and provide content related to the RDCRC’s specific rare diseases.

6) RDCRC Administrative Unit: Include a description of RDCRC Administrative Unit. Describe in detail, the chain of responsibility for decision-making and administration. The purpose of a RDCRC is to expedite development and application of new knowledge in clinical research of specific importance to rare diseases. The RDCRC Administrative Unit will be responsible for the overall administration of the RDCRC. Also describe a plan for communication (meetings, conference calls etc) and participation of all personnel within the consortium.

3. Submission Dates and Times

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

3.A. Receipt, Review and Anticipated Start Dates
Letter of Intent Receipt Date: July 20, 2008
Application Receipt Date: August 20, 2008
Peer Review Date(s): January-February 2009
Council Review Date: May2009
Earliest Anticipated Start Date: July 2009

3.A.1. Letter of Intent

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

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

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

The letter of intent should be sent to:

Rashmi Gopal-Srivastava, Ph.D.
Office of Rare Diseases
National Institutes of Health
6100 Executive Boulevard, 3B-01
Bethesda, Maryland 20892 7518
Telephone: (301) 402 4336
Fax: (301) 480 9655
[email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package, including five identical CDs containing all appendix material must be submitted to:

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

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

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the ORD and participating NIH ICs listed on this FOA. Incomplete and non-responsive applications will not be reviewed.

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

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

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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

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

6. Other Submission Requirements

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in subsection 2.A. of Section VI. "Award Administration Information".

RDCRC applications must also have a description of the following elements:

1) Access to rare diseases patients

2) Clinical research projects

3) A training (career Development) Component

4) Website resource for education and research in rare diseases

5) An administrative Unit

6) Pilot/Demonstration Projects

7) Collaborative arrangements with patient support organizations

8) Institutional support

9) Budget documentation

10) Plan for sharing research data

Follow the instructions in PHS 398 application kit. Additional instructions and recommended formats for providing the information requested for this FOA are described below.

PHS 398 is required for all U54 applications. Each budget unit for project should be written in the style and within the page limitation described in the PHS 398 instruction kit. To assist in developing RDCRC grant applications and aid in the review of these applications, the applicant should assemble the component units following the format described below.

I. Abstract Page: Description, Performance Sites, Key Personnel (PHS 398 Form, page 2)

Describe the overall proposed clinical research program of the RDCRC indicating the goals and objectives of the individual clinical research projects.

II. Table of Contents (PHS 398 Form, page 3)

Discard this page from Form PHS 398 and create a Table of Contents appropriate for the RDCRC grant application. This is paginated to follow the list of Key Personnel. Do not use letters (e.g. 4a, 4b, 4c, etc.) The Table of Contents should specifically list the locations of the overall budgets, biographical sketches and various narrative sections. Also, list projects and components of the programs for which funding is sought with the title and project/program leaders. INCLUDE THE NUMBER AND TITLE FOR EACH PROJECT, for example, Project 1: Phase I clinical trial for the treatment of rare disease X. PI: John Doe, M.D.

III. Budgets and Supporting Form (PHS 398 Form, pages 4 and 5)

Justify and document all costs for current and future years throughout at the level of the individual component budgets.

The overall Consortium budget, "Summary RDCRC Budget," is to be presented first using PHS Form 398 page 4 entitled "Detailed Budget for First 12-Month Period using a composite summarizing all individual budgets (that is, under personnel, total the personnel costs for ALL components and continue for the other budget items.) No details need be given for the individual categories. To provide budget information in a format that is clear to reviewers and therefore provides the most positive review possible, present a consolidated budget for the first 12 months in a tabular form. Sample shown as Exhibit I (http://rarediseasesinfo.bps-lmit.com/html/Exhibit%20I.DOC) is suggested.

Page 5 of PHS Form 398, "Budget Estimates for All Years of Support Requested Direct Costs Only", should then follow, a composite summarizing all individual budgets (that is, under personnel, total the personnel costs for ALL components and continue for the other budget items). For the purpose of establishing future year budget requests, the applicant should not use cost escalations.

Both first 12 month and 5 year individual budgets should be included in the sections for each project. Details and justifications for all budget items must be part of the individual budgets. Read carefully pages 10 - 14 of the Instructions for PHS 398 on how to prepare budget pages and justifications.

Note that this grant mechanism is not intended for the acquisition of costly equipment which should be funded through other sources. Under unusual circumstances, where costly items of equipment are requested, the application must document available equipment within the institution and provide clear justification.

IV. Biographical Sketches

Biographical sketches are required for all professional level personnel who are listed with a measurable effort (including consultants) in the RDCRC application. The forms found in Form PHS 398 should be used. After the budget pages, put the Principal Investigator (PI) and Co-Principal Investigator (Co-PI) biographical sketches first, followed by the other individual biographical sketches in alphabetical order. These pages should not be duplicated in other components, projects, etc.

V. Overall Clinical Research Program, Leadership & Resources

Using continuation pages, substitute the following for the Research Plan instructions of Form PHS 398. It is important to provide a succinct, yet comprehensive overall research plan.

The section on Overall Research Plan, Leadership and Resources should not exceed 10 pages.

1. RDCRC Program Introduction and Statement of Objectives

Describe the group of rare diseases to be included, the rationale for this grouping, and the relevant expertise available in the consortium. Each RDCRC should include a group of at least three diseases. State the clinical research objectives of the proposed RDCRC and the research focus of the application. Describe the rationale for the proposed clinical research program on the proposed group of diseases, and explain the strategy for achieving the objectives of the overall program, how each project relates to the strategy, and how the diseases relate to one another. Describe the clinical research projects and the rationale for each within the RDCRC.

2. RDCRC Scientific and Administrative Leadership:

The emphasis in this section should be on the qualification of the RDCRC leadership. Describe the qualifications of the PI of the application (RDCRC Director) to lead the program. Qualifications and role of the Co-PI should also be included in this section.

3. Multidisciplinary Team Involving Patient Support Organizations and collaborations

Describe the nature of the multidisciplinary team and approach for the consortium of clinical investigators, institutions, and relevant organizations, including patient support organizations, focused on a subgroup of rare diseases. Include a plan to fully incorporate the patient support organizations representation in the organizational structure and consortium interactions (conference calls, meetings, etc). Describe advocacy participation across the planned objectives (e.g., in addressing clinical design, recruitment, and education).The proposed patient support organizations activities should be appropriate for the level of advocacy capabilities.

It is important to indicate prior collaborative arrangements between investigators in the group and patient support organizations, to emphasize the events that have led to the current application, and to predict the anticipated unique advantages that the research within the proposed RDCRC would gain. Describe how the RDCRC will utilize the members of the consortium fully within the confines of the resources and people engaged with the rare diseases to be studied, and how the scientific community and patient support organizations will be integrated within the consortium. Renewal applicants must demonstrate ability to collaborate by providing examples of previous and/or ongoing collaborations.

4. Environment and Resources

Each application must include a description of resources to be included in a web site for education and research in rare diseases. These resources should include links or materials for lay public, patients, basic and clinical researchers, and clinicians. Examples include but are not limited to: patient registries; contacts for animal models; tissue, serum, specimens, DNA, etc; antibodies and research reagents; genetic resources; registries; education materials; and/or diagnostic flow charts. The actual design and implementation of the site will be a collaborative activity of the DMCC and all RDCRC through the Steering Committee. The RDCRC and DMCC must agree to work cooperatively to develop the web site resource and provide content related to its focused rare diseases. Institutional and outside support for this program is encouraged.

Briefly describe the features of the institutional environment that are or would be relevant to the effective implementation of the proposed program. As appropriate, describe available resources, such as clinical and laboratory facilities, participating and affiliated institutions and units, rare diseases patient populations, geographic distribution of space and personnel, and consultative resources. Describe institutional capability for statistical and clinical support. Applicants from institutions which have a Clinical and Translational Science Award (CTSA) or General Clinical Research Center (GCRC) funded by the NIH may wish to identify the CTSA or GCRC as a resource for conducting the proposed research. Details of the interactions of the RDCRC staff with the staff and research personnel may be provided in a statement describing the collaborative linkages being developed. A letter of agreement from the Program Director of the GCRC or CTSA should be included with the application.

5. Institutional Commitment

Each RDCRC must provide a statement that addresses how the institutional commitment will be established and sustained, and how the RDCRC research effort will be given a high priority within the institution. The institutional commitment may be in the form of support for recruitment of scientific talent, provision of discretionary resources to the RDCRC Director, assignment of research space, cost sharing of resources, and/or other ways proposed by the applicant institution. The primary institution is strongly encouraged to demonstrate its commitment to RDCRC by providing financial support to the Training Component and Pilot/Demonstration Project Program on an awarded RDCRC, as well as other programmatic needs identified as high priority on the original application. Letters from a high-level institution official(s) (e.g., Dean of the School of Medicine, President, and Vice President for Research) should be attached confirming this commitment. For the consortium the institution that submits the U54 application must receive a formal written agreement(s) from the other participant organization(s). This agreement should clearly delineate the institutional commitment of the participating organization(s) (in the ways outlined above) to the RDCRC Program.

6. Rare Diseases Patient Population

Each RDCRC must document access to a substantial patient population in the rare diseases focus of the application and provide reasonable assurance that the patients and human specimens needed for clinical research are readily available. Each RDCRC must describe in detail how patients will be identified and recruited for study. The development and maintenance of patient registries may be appropriate and necessary core activities of an RDCRC in some cases.

Provide documentation for established consortium agreement with other institution(s) to provide adequate access to clinical specimens (e.g., tissues, blood, and urine) and/or patients at another site(s). Resources for outreach, recruitment and retention of these patients should be provided.

8. Data and Research Resources Sharing Plan

Applications for RDCRC grants are required to include a data and research resources sharing plan. The plan should outline how final research data will be shared among the RDCRC, as well as with the research community at large, or state why this is not possible.

For additional information on the NIH Data Sharing Policy, see http://grants.nih.gov/grants/policy/data_sharing/. The NIH also requires the timely sharing of biomedical resources by grant recipients. Therefore, the plan should also describe how unique research resources will be distributed, e.g., through the institution, a repository, or national coordinating center. For information regarding research resources sharing, see http://grants1.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc546000132 information regarding the sharing of model organisms can be found at http://grants.nih.gov/grants/policy/model_organism/index.htm.

9. Renewal Applications: Additional Material Required

All applications for renewal must provide information documenting the impact of the clinical research from the original application. See Section V. Application Review Information for the review criteria to be addressed.

VI. Clinical Research Projects for Observational/Longitudinal Studies or Clinical Trials

Using continuation pages from Form PHS 398, name and number each project sequentially so that it can be readily distinguished from other parts in the application. These projects should be numbered consecutively with use of only integers (i.e., Project 1, Project 2, Project 3, Project 4, etc.); projects numbers should not have suffixes (e.g., Project 1A or 1a, Project 1B or 1b, etc.). Each research project should be clearly identified by the same title as that provided in the Table of Contents.

Project 1 (Project 2; Project 3; Project 4; etc.)

1. Title Page with Project Leaders (This title page is not PHS 398 Face Page)

2. Abstract Page

3. Budget/Budget Justification Pages

4. Research Proposal (If an ongoing project, discuss scientific progress within the original 5-year time frame)

5. Human Subjects Research

a. Data Safety and Monitoring Plan

6. Women and Minority Inclusion

a. Targeted/Planned Enrollment Table (for each clinical research study)

b. Inclusion Enrollment Report Table (for renewal application)

7. Inclusion/Exclusion of Children

8. Literature Cited

9. Consortium/Contractual Arrangements

10. Resource Sharing

11. Consultants/Commercial Agreements

As outlined above, the project should begin with the abstract and budget pages and should follow the instructions for Form PHS 398. Items 1-4 should be limited to 15 pages. Describe the research section in enough detail so the scientific merit can be judged on the basis of the written proposal Begin each project with a short section that clearly states how that project contributes to the objectives of the RDCRC as a whole. The budget for each research project should reflect the instructions for Form PHS 398. A detailed budget is required for the first year; budget estimates are required for all subsequent years of support. Explicit and detailed budget justifications must be included for all years. Budget pages must be labeled so that they can be readily associated with the particular projects to which they apply. The project leader should devote at least 1.8 calendar months to the research. In the project, include the section for human subjects and carefully follow the detailed instructions the PHS 398 guidelines.

Applicants are required to submit clinical research projects that can characterize and more completely define the disease and its course for the rare diseases that are encompassed in their consortia. These, in general, will be observational (non-interventional) such as longitudinal or natural history studies of patients with the given disease. The study design and objectives should take into consideration what information regarding the rare disease population would be needed in order to pursue clinical trials in that rare disease. The applicants should approach the longitudinal study with the question: what knowledge/tools are needed regarding the rare disease in order to design efficient efficacy trials for this rare disease? Even if there are no treatments currently proposed for the rare diseases under study, the longitudinal study should be designed with the consideration that if a treatment were suddenly available for this rare disease, what knowledge (outcome measures, features of disease course, markers of disease or subpopulations of the rare disease that may alter disease course, etc.) about the rare disease over time would be important to have in order to design an appropriate treatment (efficacy) trial.

Depending on the state of knowledge of the particular diseases, the projects could include strategies for assessing current therapeutic interventions, Phase I, II or Phase II/III clinical trials. Each application must include a description and rationale for the planned clinical trials. Strategies for recruitment, retention, assessment, and analysis must be included.

Each application must include a description and rationale for the planned clinical studies and longitudinal assessment of subjects. Strategies for recruitment, retention, assessment, and analysis must be included. Evidence of the ability to conduct clinical studies as well as demonstration of successfully recruiting and retaining study participants should be provided.

A plan for a clinical research project must include provisions for rigorous data management, quality assurance, and safety monitoring. These monitoring activities are distinct from the requirement for study review and approval by an Institutional Review Board (IRB). For details about the Policy of the NIH for Data Safety Monitoring of Clinical Trials, see the PHS 398 Instructions (Rev. 09/2004; Part II, page 34). A general description of the data and safety monitoring plans should be included in the application (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Provide a general description of a monitoring plan to establish the overall framework for data and safety monitoring. This description should explain the rules and procedures for detecting, monitoring, and reporting any adverse drug reaction or event during a clinical study. A copy of a draft or IRB-approved clinical research protocol (Observational/Longitudinal Studies and clinical trails), along with informed consent forms and a specific data and safety monitoring (DSM) plan, should be included in the Human Subjects section (Section E) if the study is already underway or is anticipated to begin within in the first year of an award. Please note that a data safety and monitoring board (DSMB) is required for a multicenter clinical study and phase III clinical trials.

The NIH also requires that all investigators proposing research involving human subjects are educated on the protection of human research participants. For information relating to this requirement, see the NIH Guide Notices at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html, and also the answers to Frequently Asked Questions found at http://grants.nih.gov/grants/policy/hs_educ_faq.htm.

For renewal applications: applicants should outline the scientific accomplishments and discuss the potential impact on the rare disease for each clinical research project (study) completed in the last grant period. Publications should be restricted to those that cite support from the RDCRC grant. If a clinical trial(s) or longitudinal/Observational studies have been conducted as apart of a research project in your previous application, a table should be provided listing the following information for each trial: protocol number, protocol title, date trial opened, date trial closed and total number of accrual. With the exception of the publication list, this information should be incorporated into the Preliminary Studies/Progress Report of each clinical research project. Use no more than ten pages for the narrative portion of the Preliminary Studies/Progress Report. The publication list and/or any Target and Enrollment Reports/Tables are not included in the ten-page limit of the progress report.

VII. Pilot/Demonstration Project Program (PPP)

The presentation of this component is limited to 10 pages.

1. Title Page with Director(s)

2. Budget/Budget Justification Pages

3. Plan/Examples

Every RDCRC application must allocate a significant effort to support pilot/demonstration projects (for short term clinical studies) that take maximum advantage of new clinical research opportunities in rare diseases. Such projects may be collaborative among scientists within one or more RDCRC, or with scientists outside the RDCRC environment. In the application, the applicant RDCRC application should propose funding pilot projects that generate feasibility data and have the most promising clinical research potential. These funds are intended to remain flexible and to support studies of a limited duration, of 2 years or less. New applicants must include a description of eligible projects. Examples of pilot studies also include development of novel laboratory assays and clinical instruments. Phase I and Phase II clinical trials may be supported by this mechanism. Later phase trials (Phase II/III, Phase III) are not ruled out but may not be feasible for all rare diseases. At least one pilot/demonstration project must be included in the application.

A PPP, as a required component of RDCRC, must be maintained throughout the entire term of the grant. The NIH will monitor the activities of RDCRC sponsored PPP projects during non-competitive years to assure that there is adherence to the clinical research intention of the RDCRC program during the term of the award. PPP funds should be utilized for research activities and cannot be used for the purchase of any large equipment.

Note: A plan for a clinical trial must include provisions for rigorous data management, quality assurance, and safety monitoring. These monitoring activities are distinct from the requirement for study review and approval by an Institutional Review Board (IRB). For details about the Policy of the NIH for Data Safety Monitoring of Clinical Trials, see the PHS 398 Instructions (Rev. 09/2004; Part II, page 34). A general description of the data and safety monitoring plans should be included in the application (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Provide a general description of a monitoring plan to establish the overall framework for data and safety monitoring. This description should explain the rules and procedures for detecting, monitoring, and reporting any adverse drug reaction or event during a clinical trial. A copy of a draft or IRB-approved clinical trial protocol, along with informed consent forms and a specific data and safety monitoring (DSM) plan should be included in the Human Subjects section (Section E) if the trial is already underway or is anticipated to begin within the first year of an award. If the trial will be performed during the latter part of the grant term, submission of these items to NIH program staff is required prior to the initiation of the trial. Please note that a data safety and monitoring board (DSMB) is required for a multicenter clinical study and Phase III clinical trials.

The NIH also requires that all investigators proposing research involving human subjects are educated on the protection of human research participants. For information relating to this requirement, see the NIH Guide Notices at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html and at

http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html, and also the answers to Frequently Asked Questions found at http://grants.nih.gov/grants/policy/hs_educ_faq.htm

For renewal applications: describe any pilot or demonstration project funded during the last grant period and the outcome of the project relative to the RDCRC objectives, ongoing pilot and demonstration projects, and short descriptions of other potentially eligible projects. If a clinical trial(s) has been conducted as a part of a pilot project in your previous application, a table should be provided listing the following information for each trial: protocol number, protocol title, date trial opened, date trial closed and total number of accrual.

VIII. Training (Career Development) Component

The presentation of this component is limited to 5 pages.

1. Title Page with Director of Training Component

2. Budget/Budget Justification Pages

3. Plan/Examples

Each application must include a plan for training of new investigator(s) for clinical research in rare diseases within their RDCRC. RDCRC should provide a unique environment for clinical research in rare diseases that can be used to prepare new scientists for careers in this field and provide the opportunity for established scientists to re-orient their research careers toward rare diseases research.

The RDCRC must demonstrate a consistent and significant commitment to a Training (career development) Program in clinical research. Funds from this program may be used to support advanced post-doctoral or clinical fellows (who will be independent investigators within the next year), junior faculty, or established investigators who wish to develop or refocus their careers on clinical research in rare diseases. RDCRC Training Programs are not intended for predoctoral candidates or junior level post-doctoral fellows.

A minimum of $ $50,000 direct costs per year from the RDCRC budget must be dedicated to this program and be utilized to support the salary and research costs of candidates with outstanding potential. Institutional and outside support for this program is encouraged. Each junior level candidate (senior post-doctoral fellows, clinical fellows, and assistant professors/junior faculty) should have a mentor(s) and devote at least 3 calendar months of his/her effort to clinical research. The description of this program should include the policies, criteria, and processes for selecting candidates, including special efforts to recruit qualified women and minorities. The plan should include the number and types of positions (e.g., advanced post-doctoral fellows, junior faculty, and established investigators) that will be made available, the criteria for eligibility and selection of candidates, and a description of the selection process. New applicants should provide a list and short descriptions of potential candidates, as well as the names and research activities of mentors. Describe the plan to seek out and include qualified women and minorities for participation in the proposed program

A Training component, as a required element of a RDCRC, must be maintained throughout the entire term of the grant. Funds from the Training Program should be utilized to support clinical research activities, including partial salary support for the candidate, research personnel, supplies, travel, and/or other expenses. Training funds should not be used for the purchase of any large equipment. At least two trainees should be supported by this program.

For renewal applications: denote individuals supported during the last grant period, their scientific accomplishments while supported by the RDCRC, and how RDCRC support has advanced their clinical research careers in rare diseases. Provide the number of women and minorities trained and the number of calendar months devoted to clinical research.

IX. RDCRC Administrative Unit

The presentation of this component is limited to 5 pages.

1. Title Page with Director of Administrative Unit

2. Budget/Budget Justification Pages

3. Plan/Examples

The purpose of a RDCRC is to expedite development and application of new knowledge in clinical research of specific importance to rare diseases. The RDCRC Administrative Unit is responsible for the overall administration of the RDCRC. Describe in detail, and by diagram if appropriate, the chain of responsibility for decision-making and administration. Include to whom the RDCRC Director (Principal Investigator) reports and the administrative structure as it relates to the investigators responsible for the clinical research projects. If advisory groups will be used, indicate their specific functions, composition and to whom they report. Describe a sound plan for communication (meetings, conference calls etc) and participation of all personnel within the consortium.

The RDCRC Administrative Unit must include a clinical investigator who ensures a mutually supportive interaction between scientists conducting clinical research and those performing clinical investigation. The qualifications of the clinical investigator and the plan to promote clinical research should be described.

The RDCRC Director (PI of the cooperative agreement) is expected to make a commitment of at least 2.0 months to the overall administration of the program plus 1.2 months as a leader of a RDCRC project (if leading a clinical research project). RDCRC Administrative Unit support personnel may be budgeted in at no more than 12 calendar months which may be divided among one or more positions. This FTE must be fully justified. Note that the RDCRC Director is expected to send two RDCRC participants to three 2 day meetings in the first year to the Washington, D.C. area and biannually thereafter in Bethesda, MD with NIH staff, and should budget for these meetings.

Describe the biostatistical support for the RDCRC in this section. The biostatistician will provide statistical support for protocol development and assist in study designs. The biostatistician in collaboration with DMCC will also assist in the collection of epidemiologic information, data analysis, and quality assurance for database and statistical analyses of pooled data for the RDCRC. The description of the administrative unit of an RDCRC should detail how the activities and contribution of the collaborating investigators and institutions will be coordinated.

A Co-PI should be identified on the application who will be responsible for assisting the RDCRC Director (PI of the application) with the day-to-day administrative details, program coordination, and planning and evaluation of the program, and who would be in charge in the absence of the RDCRC Director. The Co-PI may be from a different Institution.

X. Appendix Material(s)

If there is appendix material it must included with the submission of the application. Five identical copies of all appendix material, along with all required copies of the application, must be sent to:

Center for Scientific Review

National Institutes of Health

6701 Rockledge Drive, Room 1040, MSC 7710

Bethesda, MD 20892-7710 (for U.S. Postal Service express or regular mail)

Bethesda, MD 20817 (for express/courier delivery; non-USPS service)

Do not use the appendix to circumvent the page limitations of the Research Plan. Graphs, diagrams, tables, and charts should be included in the body of the Research Plan unless a PDF file is necessary to show detail. Not all grant mechanisms allow publications to be included in the appendix. When publications are allowed, a limit of 3 publications, which are not publicly available, will be considered in the initial peer review. A summary listing all of the items included in the appendix is encouraged, but not required. When including a summary, it should be the first file on the CD. Applications that do not follow the appendix requirements may be delayed in the review process.

Five identical CDs containing all appendix material must be submitted in the same package with the application. When preparing CDs:

Use PDF format. Where possible, applicants should avoid creating PDF files from scanned documents. NIH recommends producing the documents electronically using text or work-processing software and then converting to PDF. Scanned documents are generally of poor quality and difficult to read.

Appendices: Applicants must follow the instructions in recent NIH guide notices about what is allowable in appendix material: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-06-051.html and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html.

Resource Sharing Plan(s)

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

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

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

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

Section V. Application Review Information

1. Criteria

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

The following will be considered in making funding decisions:

2. Review and Selection Process

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

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

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

Clinical Research Projects

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is the proposed research plan appropriate for the state of knowledge, current capabilities and resources for the rare diseases or group of diseases? Are the questions being asked for the rare disease(s) and objectives outlined most likely to advance knowledge in rare disease(s)? Is the clinical design appropriate to address the objectives of the research plan?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area? Are there novel methods for recruitment and outreach to health professionals?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Do they have experience in conducting clinical research? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Are the investigators committed to collaborative and cooperative nature of this program?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support? Is there active participation of relevant patient support organizations? Will the proposed administrative plan, infrastructure, and resources provide appropriate support for the clinical research to be undertaken by the RDCRC?

Training (Career Development) Component

Is the plan for training new investigators adequate and appropriate?

Pilot/ Demonstration Projects Program

RDCRC Administrative Unit

Are the plan(s) for overall administration of RDCRC, coordination of clinical research and collaborations presented and sufficient for the requirements of the proposed RDCRC? Is the plan for communication and participation of all personnel within the consortium well described?

Overall Clinical Research Program Organization and Capability

Leadership:

Are the scientific qualifications and involvement of the Principal Investigator (RDCRC Director) and Co-Principal Investigator as well as his/her scientific and administrative leadership capabilities and time commitment presented and sufficient for the requirements of the proposed RDCRC?

Rare Diseases Patient Population:

Is the access to rare diseases patients and populations for conducting current and projected clinical research adequate to ensure likely success of the goals of the program? (For renewal applications, documentation of accomplished clinical research goals, including evidence of human subjects enrollment on clinical research studies during the past funding period should be provided.)

Institutional Commitment:

Is there institutional commitment to establishing the RDCRC as an integral part of its overall clinical research environment? Will the institution align or adjust incentives and rewards to promote the academic mission of collaborative rare diseases research? Is there commitment from the institutional leadership to protect the time of the investigators to pursue clinical research and mitigate the demands of providing patient care? Will clinical researchers/trainees training be supported? Is the institutional leadership committed to this program and its goals in terms of providing specific assets specifically for the program, such as faculty support, specific equipment, dedicated space, or financial support as a few examples? Do the plans for integrating the activities of RDCRC clinical research projects, as well as integrating rare diseases research with existing institutional resources (e.g., use of clinical data and safety management systems, biostatistical support, etc.), give confidence and sufficient evidence that such efforts are likely to be effective?

Multidisciplinary Team Involving Patient Support Organizations Collaborations:

Is there a plan to fully incorporate the relevant Patient Support Organization within RDCRC structure and interactions (conference calls, meetings etc)? Is Patient Support Organization participation described across the planned objectives (e.g. in addressing clinical design, recruitment and education)? Are proposed activities appropriate for the level of the Patient Support Organizations? Is there evidence of tangible interactions with Patient Support Organizations and other institutions? Are the abilities and availabilities of the investigators to interact with other participating sites and with the NIH in sharing information, participating in committees, and collaborating on activities of mutual interest evident and sufficient? (For renewal applications, contributions and outcomes from RDCRN meeting, Workshop and other related RDCRC meetings during the term of the award.)

Progress for Renewal Applications:

NIH considers the following in evaluating Center grant applications:

2.A. Additional Review Criteria:

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

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

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

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

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

2.B. Additional Review Considerations

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

2.C. Resource Sharing Plan(s)

When relevant, reviewers will be instructed to comment on the reasonableness of the following Resource Sharing Plans, or the rationale for not sharing the following types of resources. However, reviewers will not factor the proposed resource sharing plan(s) into the determination of scientific merit or priority score, unless noted otherwise in the FOA. Program staff within the IC will be responsible for monitoring the resource sharing.

3. Anticipated Announcement and Award Dates

N/A

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator (RDCRC Director) will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

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

2.A. Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the multiproject cooperative agreement (U54), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator of RDCRC will have the primary responsibility for defining the details of the project within the guidelines of the RFA-OD-08-001and for performing the scientific activity, and agree to accept close coordination, cooperation, and participation of the NIH staff in those aspects of the scientific and technical management of the project described below. Specifically, awardees have primary responsibility as described below.

RDCRC Director and the DMCC Director (formerly DTCC Director)

The Rare Diseases Clinical Research Consortium Directors (RDCRC Directors) and Data Management and Coordinating Center Director (DMCC Director) are the persons responsible for the overall management of their RDCRC (Consortium) and coordination with the other Consortia. The relationship between the Consortia and the Data Management and Coordinating Center (DMCC) should be one of equal partners in the Rare Disease Clinical Research Network (Network). Each Consortium Director must devote at least 2.4 months/calendar year to this program.

Collaboration and Coordination

The collaboration of investigators between Consortia is highly encouraged based on shared interests and complementary talents. The planned collaborating sites within the Consortium must be ongoing and active. Plans for evaluating and removing or replacing non-productive members of a Consortium must be in place for each Consortium.

Steering Committee Membership and Meeting Attendance

Each Consortium Principal Investigator will be designated the Consortium Director. Each Consortium Director will be a voting member of the Network Steering Committee and participate in all Committee activities and decisions including, but not limited to, conference calls and special subcommittees as may be necessary. The Steering Committee shall be responsible for determining the frequency of meetings and scheduling the time and location. The Steering committee will establish the procedures for the function of the Consortia network, as outlined in section "Steering Committee."

Data Coordination and Management and Sharing

The awardees will have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS and NIH policies. The DMCC will develop a data management system with the input of the Steering Committee. All Consortia will place their data at the DMCC which will also offer analysis expertise for Network investigators. The intention of the NIH is that the data collected within this Network will be become a resource for the Rare Disease Community and be available to the scientific community. Criteria and mechanisms for data sharing among investigators within the Network and with the scientific community will be developed by the Steering Committee.

Publication and Presentation of Study Findings

Early publication of major findings is encouraged. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of the Rare Disease Clinical Research Network and NIH support. The Steering Committee will establish unifying procedures and criteria for presentation and publication of data developed within the Rare Disease Clinical Research Network so that these procedures and criteria are consistent across the Network.

Federally Mandated Regulatory Requirements

Each institution participating in the Rare Diseases Clinical Research Network is required to meet DHHS regulations for the protection of human subjects and FDA requirements for the conduct of research using investigational agents. At a minimum, these include:

o methods for assuring that each institution at which Rare Diseases Clinical Research Network investigators are conducting clinical studies has registered with the Office of Human Research Protections (OHRP; http://www.hhs.gov/ohrp/) and has a Federal wide Assurance; that study protocols are reviewed and approved by the responsible Institutional Review Board (IRB) prior to patient entry; that active protocols are reviewed at least annually by the IRB, and that amendments are approved by the IRB.

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

2.A.2. NIH Responsibilities

An NIH Project Scientist from each participating IC will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

One representative from ORD will be designated to serve as the Program Coordinator for this cooperative agreement. The ORD Program Coordinator and one Project Scientist from each participating ICs will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below.

Steering Committee Membership and Meeting Attendance

The ORD Program Coordinator and one Project Scientist from each participating IC will serve on the Steering Committee and will participate in all Committee activities, including, but not limited to,

meetings, conference calls, subcommittees, and special committees. They will assist in development of operating policies, quality control procedures, and policies that require cooperative action. However, while the ORD Program Coordinator and participating IC Project Scientist will attend Steering Committee Meetings, their cumulative votes may never exceed 40 percent.

Monitoring Performance

The ORD Program Coordinator and IC Project Scientist will assist the Steering Committee in the development of procedures for monitoring the performance of the clinical studies. This includes participation in periodic on-site monitoring with respect to compliance with protocol specifications, quality control and accuracy of data recording, and accrual. The NIH will also provide assistance to the DMCC in identifying technology resources, provide oversight of activities, including security and privacy issues.

Publication and Presentation of Clinical Studies Findings

The NIH staff may contribute, through review, comment, analysis, and/or co-authorship, to reporting results of the clinical studies and trials/studies to the investigator community and other interested scientific and lay organizations. Co-authorship by the NIH staff will be subject to approval in accordance with the NIH policies regarding staff authorship of publications resulting from extramural awards.

The Government, via the ORD Program Coordinator, IC Project Scientists and Program Officials, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. Information obtained from the data may be used by NIH staff for the preparation of internal reports on the activities of the clinical studies. However, awardees will retain custody of and have primary rights to all data developed under these awards.

Program Stewardship

The assigned Program Officials from participating NIH ICs will be responsible for normal programmatic stewardship and monitoring of this award and approval of new pilot studies. The Program Officials will not serve as the substantively involved IC Project Scientists. They may receive input and recommendations from other NIH staff in monitoring the awards.

2.A.3. Collaborative Responsibilities

All investigators within each Consortium and the DMCC must be willing to work cooperatively and collaboratively both within their Consortium and with other Consortia. Each Consortium is expected to send two Consortium participants to three 2 day meetings in the first year to the Washington, D.C. area and biannually thereafter.

Steering Committee

A Steering Committee will be established to serve as the main governing body of the cooperative network. At a minimum, the Steering Committee will be composed of one representative from each of the Consortia, one representative from the DMCC, the ORD Program Coordinator, and other participating IC Project Scientists. All members are expected to actively participate in all Steering Committee activities. The combined vote of NIH membership may never exceed 40 percent.

The Chairperson of the Steering Committee will be selected by the Steering Committee from among the non-Federal members during one of the early meetings of the Committee to be convened by the NIH Program Coordinator. All major decisions will be determined by the Steering Committee. The Committee will meet at least three times during the first 12 months of the program and at least semi-annually thereafter. As needed, the Steering Committee may establish subcommittees for special purposes. It is expected that most of the work of the Steering Committee will be performed in these subcommittees. All Consortia and DMCC must abide by decisions of the Steering Committee.

The Steering Committee will have responsibility for facilitating the conduct of the clinical studies, promoting trans-Consortium collaboration, establishing and updating the content of the web resource site, and establishing procedures for reporting results of Consortium studies. The Steering Committee will provide scientific and technical assistance and guidelines with respect to quality control, uniformity of data collection, management of the collective rare diseases database, and data analysis.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Copies (paper or electronic) of publications (in press or in print) that are developed as a result of this support must be provided to NIH (ORD and relevant institute). NIH must be acknowledged by the awardee (via inclusion of grant number) as the source of support for the work in all publications and presentations.

NIH encourages all grantees to submit to the NIH National Library of Medicine's (NLM) PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported, in whole or in part, from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process (http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-05-022.html). The Public Access website (http://publicaccess.nih.gov/) provides instructions on submitting manuscripts.

Section VII. Agency Contacts

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

1. Scientific/Research Contacts:

Applicants should direct inquiries regarding scientific/research and programmatic matters for this RFA to the appropriate NIH IC Program Official listed at the website below:http:\\grants\guide\contacts\rfa-0D-08-001.htm

Issues that remain after consultation with NIH IC program staff that are not addressed in this FOA may be addressed to:

Rashmi Gopal-Srivastava, Ph.D.
Office of Rare Diseases
National Institutes of Health
6100 Executive Boulevard, 3B-01
Bethesda, Maryland 20892 7518
Telephone: (301) 402 4336
Fax: (301) 480 9655
Email: [email protected]

2. Peer Review Contacts:

J. Fernando Arena, M.D., Ph.D.
Division of Clinical and Population Based Studies
Center for Scientific Review, National Institutes of Health
6701 Rockledge Drive Room 3135, MSC 7770
Bethesda, MD 20892-7770 (20817) for overnight mail)
Telephone: (301) 435-1735
FAX: (301) 480-3692
Email: [email protected]

3. Financial or Grants Management Contacts:

Grants Management contacts for participating ICs are listed at http:\\grants\guide\contacts\rfa-0D-08-001.htm

Section VIII. Other Information

Required Federal Citations

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

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

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

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

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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

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

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

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

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

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

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

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicine’s PubMed Central (see http://www.pubmedcentral.nih.gov/), an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html). For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

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

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

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

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

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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

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

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