Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), (http://www2.niddk.nih.gov)|
National Institute of Child Health and Human Development (NICHD), (http://www.nichd.nih.gov/)

Title: Continuation, Expansion and Merging of the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Consortium (CLiC) to form the Childhood Liver Disease Research and Education Network (ChiLDREN) (U01)

Announcement Type
New

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

Request For Applications (RFA) Number: RFA-DK-08-005

Catalog of Federal Domestic Assistance Number(s)
93.848

Key Dates
Release Date: June 6, 2008
Letters of Intent Receipt Date: October 24, 2008
Application Receipt Date: November 25, 2008
Peer Review Date: February/March 2009
Council Review Date: May 2009
Earliest Anticipated Start Date: July 2009
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: November 26, 2008

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

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

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

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

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 National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health of the U.S. Department of Health and Human Services is seeking applications to continue, expand and merge the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Consortium (CLiC) to form the Childhood Liver Disease Research and Education Network (ChiLDREN). The BARC http://www.barcnetwork.org/index.html currently supported under RFA-DK-02-008 began in 2002 to study biliary atresia and idiopathic neonatal hepatitis. The purpose of BARC is to establish a database of clinical information and biological samples from children with biliary atresia and idiopathic neonatal hepatitis to facilitate and perform clinical, epidemiological and therapeutic research. It is also focused on conducting a clinical trial to determine the safety and efficacy of steroid use following the hepatoportoenterostomy (HPE) in children newly diagnosed with biliary atresia (START: STeroids in biliary Atresia Randomized Trial: A randomized, double-blinded, placebo-controlled trial of corticosteroid therapy following portoenterostomy in infants with biliary atresia). The CLiC http://rarediseasesnetwork.epi.usf.edu/clic/index.htm currently supported as a consortium of the Rare Disease Clinical Network under RFA-DK-03-008 was funded in 2004 with the major objective to study five genetic causes of intrahepatic cholestasis: Alagille syndrome, Alpha-1-antitrypsin deficiency, Progressive intrahepatic cholestasis, Bile acid synthesis defects, and Mitochondrial hepatopathies. The study of liver disease in cystic fibrosis has recently been undertaken by the CLiC. In addition to conducting clinical research in these rare liver disease of children, CLiC also has as its objective to fully participate in the Rare Disease Clinical Research Network (RDCRN) by providing opportunities within the CLiC for training of clinical investigators in these rare diseases; conducting pilot and demonstration projects; and providing and sharing information related to the diseases under study to basic and clinical researchers, academic and practicing physicians, patients, and the lay public. Presently, both the CLiC and BARC are comprised of 10 clinical centers and each has their own data coordinating center. The major objective of the newly formed ChiLDREN would be to combine the expertise and resources of the BARC and CLiC clinical centers and expand to up to 15 clinical centers and to establish one data coordinating center to study pediatric liver diseases. All functions and resources of both the BARC and the CLiC, including continued participation in the RDCRN, and the expansion to 15 clinical centers would enhance the ability and efficiency of the ChiLDReN to enroll sufficient numbers of children into the ongoing longitudinal studies and clinical trials. ChiLDREN would thus facilitate the ability of the network to discover new diagnostics, etiologic, and treatment options for children with liver disease and those who undergo liver transplantation and to train the next generation of investigators in rare pediatric liver diseases. The specific objectives of the newly formed ChiLDREN could include but are not limited to:

1) Completion of the steroid safety and efficacy clinical trial in biliary atresia

2) Continuation of the BARC and CLiC prospective longitudinal studies of children to continue to provide data and biospecimens for ancillary studies aimed at discovering new diagnostics, etiologic and treatment options for children both pre and post liver transplantation.

3) Continuation of the prospective longitudinal study of cystic fibrosis liver disease (CFLD) aimed at identifying predictors of development of liver disease in children with CF as well as predictors of outcome in children with CFLD.

4) Identification and validation of non-invasive markers of liver disease in CF patients including but not limited to new imaging modalities.

5) Phase I/II study of new agents to treat cholestasis in children.

6) Study of modifier genes in Alagille Syndrome and Alpha-1-antrypsin disease.

7) Expansion to include other diseases of cholestasis in children with industry and patient advocacy group support.

8) Continue to provide training opportunities for investigators in pediatric liver disease

9) Continue to provide support for small pilot and demonstration projects within the Network

10) Continue to provide education about pediatric liver diseases to the scientific and lay communities through publications and the website.

This RFA is soliciting two types of applications: up to 15 clinical centers (CC), and a single data coordinating center (DCC). This is a one-time solicitation to form the ChiLDReN for a maximum of five years, contingent on satisfactory study recruitment and retention.

BACKGROUND INFORMATION:

Although a rare condition in children, chronic pediatric liver disease is a devastating condition that has high public health impact. Children with biliary atresia or any of the five genetic cholestatic liver diseases studied by CLiC account for the majority of the liver transplantations performed in the United States in children. In addition, liver disease in children with cystic fibrosis is the second or third leading cause of death in those with cystic fibrosis. Currently, the overlap in clinical sites of the BARC and CLiC is both considerable and predictable as they represent the major referral centers for pediatric liver disease. Including these clinical sites and adding a few additional pediatric clinical liver centers would enhance the capacity for unhindered flow of clinical information for the investigators as they study the disparate pediatric liver diseases and would vastly improve the efficiency with which the acquired data can be analyzed. The current situation with two separate consortia poses several procedural inefficiencies for the flow of patients, data, and collected specimens among each consortium. The separate, yet complimentary diseases, currently being studied by each consortia would benefit from the efficiency gained by a Childhood Liver Disease Research and Education Network (ChiLDREN) with the logical transition of patients from one study to another since some children are first entered in BARC and then are entered into a complimentary study in CLiC. Thus, the merging of the two consortia would allow for greater efficiency of NIDDK and clinical site resources and permit standardization of process, data, and specimen collection methodology. It will also allow the network to take advantage of available resources offered by lay organizations to expand the number of diseases studied efficiently and expeditiously. This is especially true for cystic fibrosis liver disease and may be true of other pediatric liver diseases. Also, the newly formed ChiLDREN will have the opportunity to expand the current studies to include follow-up of children who have undergone liver transplant for the diseases under investigation.

ORGANIZATION OF THE CHILDHOOD LIVER DISEASE RESEARCH AND EDUCATION NETWORK (ChiLDREN)

The ChiLDREN will consist of the following components: the NIH, up to fifteen CCs, a DCC, a Steering Committee and its subcommittees, a Data and Safety Monitoring Board (DSMB), and other committees as needed. In addition, the ChiLDREN will also have an administrative core and four biologic cores that support and are integrated into the Network: genetics, bile acid, histopathology and respiratory chain. All four of the biological cores are headed by a director and are funded as subcontracts through either the DCC or one or more of the CCs. The responsibilities of each component of the Network are described in the Terms and Conditions of Award.

The NIDDK will be responsible for organizing and providing support for the ChiLDREN and will be involved substantially with the awardees as a "partner," consistent with the Cooperative Agreement mechanism. A designated NIDDK Project Scientist, who will provide programmatic oversight, will monitor subject recruitment and study progress, ensure disclosure of conflicts of interest and adherence to NIDDK policies. The NIDDK will appoint the Chairperson(s) of the Steering Committee and all members of the DSMB. An additional NIDDK Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Ongoing Clinical studies. BARC and CLiC have current steering committee approved studies (described below) that will be integrated into the ChiLDREN as they are. It is anticipated that the studies will continue as written with no disruption once ChiLDREN is formed.

BARC DESCRIPTION. BARC is currently comprised of 10 clinical centers geographically spread across the United States. They have recently completed and published the results of a nine BARC center retrospective chart review on the outcome of children undergoing hepatoportoenterostomy (HPE) for treatment of biliary atresia seen at their clinical center. Four other actively enrolling studies are ongoing: 1) Prospective study of infants less than 6 months of age with cholestasis and biliary atresia epidemiology (PROBE). Extensive prospective data collection and biobanking of specimens along with genetic material is done from the children and their parents. 2) A histopathology study is being conducted to establish definitions, criteria, reproducibility, and potentially, a scoring system of liver histology derived from children with biliary atresia and/or other neonatal cholestatic conditions. 3) Prospective study of children with biliary atresia who are over the age of 1 year and who have not previously been enrolled in PROBE. This study is called Biliary Atresia Study in Infants and Children (BASIC). The BASIC study collects data and biospecimens and DNA for children with biliary atresia and their parents. 4) The START clinical trial is a randomized, placebo controlled, double-blinded trial of high dose corticosteroids for biliary atresia post-portoenterostomy. It is intended to evaluate the safety and efficacy of steroid use in children with biliary atresia. It includes intensive safety monitoring and data collection on growth and development. All of the BARC studies terminate data collection once a child undergoes a liver. The ChiLDREN would allow these studies to be modified, with steering committee approval, to include data after children undergo liver transplant.

CLiC DESCRIPTION. The CLiC is a consortium of the Rare Disease Clinical Research Network (RDCRN). It is made up of 10 clinical centers and includes four biologic cores that support the ongoing research conducted at the clinical centers. The four biological cores include genetics, histopathology, bile acid chemistry and respiratory chain. The data collection and management functions are handled locally by an administrative core as part of CLiC and a central Data and Technology Coordinating Center for the entire RDCRN. In addition, the CLiC includes a process and funds for small pilot demonstration projects, and for training/fellowship awards. CLiC maintains an active collaboration with patient support groups interested in the diseases that under study by CLiC. CLiC has three studies currently underway: 1) Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis will define the natural history of predictors of progression of Alagille syndrome, Alpha-1-antitrypsin deficiency, bile acid synthesis and metabolism defects, and progressive familial intrahepatic cholestasis. Data and biospecimens including DNA will be obtained from all persons with any of these diseases. In some instances, biospecimens will also be obtained from parents and sibling. As appropriate and indicated, specimens will be sent to and analyzed at one or all of the biologic cores as specified in the protocol. 2) The Longitudinal Study of Mitochondrial Hepatopathies will define the natural history and predictors of progression of mitochondrial liver diseases, specifically Respiratory Chain defects and Fatty Acid Oxidation defects. Data and biospecimens, including DNA, will be obtained from all persons with any of these diseases. In some instances, biospecimens will also be obtained from parents and siblings. As appropriate and indicated, specimens will be sent to and analyzed at one or all of the biologic cores as specified in the protocol. 3) The Longitudinal Study of Cystic Fibrosis Liver Disease will define the natural history and predictors of progression and development of liver disease in children with cystic fibrosis. Non-invasive markers of liver disease will also be sought. Data collection, collection of biospecimens and novel tests, including radiological assessments, will be done on children with cystic fibrosis and potentially their families. Close collaboration with the Cystic Fibrosis Foundation and sharing of data, as appropriate, is a hallmark of this study. In addition, the CLiC has awarded small pilot and feasibility studies and training fellowship grants every year to young investigators who study any of the aforementioned pediatric liver diseases.

CLINICAL CENTERS FOR CHILDREN. The Clinical Centers (CCs) will continue to recruit subjects into the approved BARC and CLiC studies described above and will conduct the clinical trials and longitudinal follow-up as described in the study protocols. No deviations will be allowed. All individual CCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the ChiLDREN (see Terms and Conditions of Award). Only investigators who wish to continue to carry out the protocols of the ChiLDREN and agree to be governed by the policies of the ChiLDREN and its steering committee should apply under this FOA. It should be noted however, that not all CCs will necessarily participate in all of the approved ChiLDREN protocols.

DATA COORDINATING CENTER FOR CHILDREN. The newly formed DCC will take on all of the administrative and data collection/analysis functions and will be responsible for all of the ongoing studies of the BARC and CLiC. Thus, they should include methodology and plans for transferring and capturing all data currently being collected by BARC and CLiC. In addition, the DCC will be responsible for supporting any protocol development or modifications; providing sample size calculations, statistical advice, questionnaires, and data analysis; supporting development, implementation, and maintenance of a data base of clinical information and blood samples; developing or modifying any data safety and monitoring plans; supporting manuscript preparation; and providing overall study coordination and quality assurance, including coordination of the activities and meetings (including conference calls) of the Data and Safety Monitoring Board (DSMB), the Steering Committee, and other needed committees. The DCC will prepare or modify protocols for submission to the DSMB and the Steering Committee for their approval prior to the implementation of any study protocols or protocol change. The DCC will be responsible for preparation of documents for submission to the Food and Drug Administration (FDA) in support of Investigational New Drug Applications (INDs) held by the NIDDK on behalf of ChiLDREN. The DCC will also prepare all reports including data reports for review by the DSMB at their meetings. The DCC will also be responsible for the logistics and planning of the meetings of the Steering Committee and the various operational committees of ChiLDReN. The Data Coordinating Center will be responsible for acquiring and administering subcontracts as needed. (See Terms and Conditions of Award). The NIDDK has established Central Biosample, Genetic, and Data Repositories for the ongoing and archival storage of data and biospecimens collected in large, multi-site studies funded by NIDDK. The DCC will work with the NIDDK Biosample, Genetic and Data Repositories and the CCs to coordinate procedures for coding, shipping, processing, receipt, and storage of study samples that are to be maintained in the Repositories and dispensed to steering committee approved ancillary study sites. In addition, the DCC will coordinate with the NIDDK Data Repository to prepare the collected data for eventual archiving and distribution. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the ChiLDREN Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time.

STUDY GOVERNANCE

STEERING COMMITTEE. A Steering Committee will be the main governing body of the ChiLDREN (see Terms and Conditions of Award). An Executive Committee comprised of the Study Chair and Co-Chair, if appropriate; the Principal Investigator of the DCC; and the NIDDK Project Scientist also will be convened to effect management decisions required between Steering Committee meetings, as needed for efficient progress of the trial. Other subcommittees of the Steering Committee will be established and will operate as necessary, such as publications, ancillary, protocol, pathology and radiology.

DATA SAFETY AND MONITORING BOARD. An independent Data and Safety Monitoring Board (DSMB) will be established by the NIDDK to review protocols and monitor patient safety and performance of each study. As a part of its responsibilities, the DSMB will submit recommendations to the NIDDK regarding the continuation of each study. The DSMB will be responsible for final approval of the Data and Safety Monitoring Plan developed by the DCC. All protocols or changes to protocols will be approved by local Institutional Review Boards, the Steering Committee, the ChiLDREN Data and Safety Monitoring Board, and the NIDDK before initiation. Any specific collaboration involving the resources of ChiLDREN will require approval by the Steering Committee and the NIDDK Project Scientist.

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

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the U01 award mechanism.
The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

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

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

2. Funds Available

The estimated amount of funds available for support of up to fifteen clinical centers and one data coordinating center projects awarded as a result of this announcement is $5 million for fiscal year 2009. Because the nature, scope and availability and participation of qualified study participants will vary across clinical centers, it is anticipated that the size of each award for the clinical centers will vary but may not exceed $250,000 in direct costs. Direct costs for the data coordinating center may not exceed $800,000. Subcontracts for clinical sites, the biological cores or administrative core for the study chair may be added to the applications in excess of the direct cost limits cited above. Future year amounts will depend on annual appropriations.

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

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

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

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

1.B. Eligible Individuals

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

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Applicants are not permitted to submit a resubmission application in response to this FOA.

Renewal applications will be permitted for this FOA. However, only those applications funded under a U01 mechanism to the BARC are eligible.

Applicants may submit more than one application, provided each application is scientifically distinct.

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: GrantsInfo@nih.gov.

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 in item (box) 2 only of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times

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

3.A. Receipt, Review and Anticipated Start Dates
Letter of Intent Receipt Date: October 24, 2008
Application Receipt Date: November 25, 2008
Peer Review Date: February/March 2009
Council Review Date: May 2009
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 in Section IV.3.A.

The letter of intent should be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy Boulevard, Room 752, MSC 5452
Bethesda, MD 20892-5452
Courier use 20817
Telephone: (301) 480-8897
FAX: (301) 480-3505
Email: fc15y@nih.gov

3.B. Sending an Application to the NIH

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

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

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

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

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy Boulevard, Room 752, MSC 5452
Bethesda, MD 20892-5452
Courier use 20817
Telephone: (301) 480-8897
FAX: (301) 480-3505
Email: FC15Y@NIH.GOV

3.C. Application Processing

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

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

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

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

Applications for the CCs should demonstrate their accomplishments related to their participation in previous collaborative projects within BARC and CLiC (e.g., recruitment of subjects, committee membership or chairmanship, protocol development, publications, etc.). Applicants for the CCs who have never participated in BARC or CLiC studies or projects should demonstrate their experience and expertise in conducting collaborative clinical research studies in pediatric hepatology. They should also submit a plan for meeting the research objectives of the newly formed ChiLDREN.

The CC application must provide detailed plans for future subject recruitment and retention related to the ongoing research studies of the BARC and CLiC and a description of the type of disease and the number of children seen at their CC within the past two years with biliary atresia, neonatal hepatitis, Alagille syndrome, Alpha-1-antitrypsin deficiency, progressive intrahepatic cholestasis, bile acid synthesis defects, mitochondrial hepatopathies and cystic fibrosis liver disease. Each CC submitting an application in response to this FOA must provide evidence of their ability to carry out the protocols already approved by the BARC and CLiC Steering Committees for each protocol in which their Center has been selected to participate.

Each CC must show how they will be able to submit data to the DCC and biospecimens to the NIDDK Repositories (supported by an independent contract from NIDDK) and to central laboratories and biological cores as approved by the Steering Committee. CCs must show how they will work in collaboration with the DCC to implement procedures for uniform data collection, handling and transmittal of data, as well as data audits and other data quality control procedures, as established by the study protocol. CCs must also provide information regarding past contributions to and future plans for involvement with operational committees of ChiLDREN (e.g. Recruitment, Publications, etc.) and the establishment of uniform procedures and policies.

Each CC application must describe their plans for retaining study subjects, so that a longitudinal assessment of pediatric liver disease can be accomplished according to the approved protocols. Plans for data collection beyond the transplant period should also be included in the application.

CC applications should provide a description of proposed pilot/feasibility type studies and opportunities for participation of junior investigators in a training fellowship to study pediatric liver disease. They must also state their willingness to submit applications to the Network and abide by the selection process approved by the steering committee for determination of the pilot/feasibility studies and training opportunities.

There should be evidence of strong institutional support for the CC, including adequate space in which to conduct clinical and research activities and office space for staff. Institutional resources for patient care and follow-up including personnel, space, and special laboratory facilities must be described in the CC application.

Clinical Centers that include one of the approved administrative or biological cores as part of the application must describe the functions, capabilities and willingness of the core facility to carry out all approved studies of CLiC and any future approved studies of ChiLDREN as appropriate.

An organizational structure for the CC should be set forth in the application, delineating specific personnel (e.g., pathologists, radiologists, etc.) available to carry out the approved protocols. The principal investigator should state his/her general support of collaborative research and interaction with the NIDDK, the other CCs, and the DCC through the Network concept. Applicants should discuss their willingness, and that of the institutions involved, pursuing a per patient basis (capitation) of operational costs.

CCs must be able to interact with the DCC to transmit and edit data and should discuss their capability to participate in a distributed data entry system.

Supplemental Instructions for Data Coordinating Center (DCC)

The application for the DCC must demonstrate experience in the area of coordination of multi-center clinical trials and epidemiological studies in all phases from start up (e.g., protocol development, manual of operation) through analysis and publication preparation and submission. The DCC applicant should describe any previous interactions with either the BARC or CLiC and their role in the development of policies, procedures, protocol development and publications for BARC or CLiC. In addition, the DCC must state their willingness and ability to transfer data from and support ongoing studies in both BARC and CLiC. The DCC must interact with the leadership of the BARC and CLiC so they can briefly describe all the protocols that have been approved by the BARC and CLiC steering committees that will be continued once the ChiLDREN is formed and how the transformation into one DCC will be accomplished.

It is expected that the PI of the DCC will carry out a significant leadership role in the network. A description of past and future participation in the leadership role must be included.

The DCC applicant must also address the following regarding responsibilities and requirement for the DCC.

1. Participation in the design of all research studies and the development or updating of the manual of operation, data collection forms, and questionnaires;

2. Development and implementation of systems for communication among Steering Committee members and among study sites;

3. Data collection, editing, processing, analysis and reporting utilizing the latest technology to assure timely reporting to the NIDDK, the investigators and the DSMB;

4. Monitoring of adherence to the research plan and of data quality;

5. Establishment of procedures that insure the safety and confidentiality of all records.

6. Procedures for coordinating submission of biospecimens from the CCs to the NIDDK Repositories, central laboratories, and biological cores and to ancillary study participants.

7. Ability to fill out necessary regulatory documents in support of the Food and Drug Administration Investigational New Drug Application (IND).

Other Special Performance Requirements

With the merging and expansion of the BARC and CLiC the ChiLDREN will continue to be a collaborative effort that will require frequent interactions of awardees among themselves and with the NIDDK. Applicants must explicitly indicate their willingness to:

1. Participate in Steering Committee meetings (expected to occur in person 3-4 times a year at rotating sites of the CCs and the DCC, and as monthly teleconferences, or as needed), site visits required by the NIDDK, and regular telephone conference calls;

2. Cooperate with other awardees in the development and design or modification of research protocols, and cooperate with other awardees in carrying out approved research protocols;

3. Abide by common definitions; common methods for patient selection and enrollment; and common protocols, procedures, tests, and reporting forms as chosen by majority vote of the Steering Committee;

4. Actively seek to implement each consortium-wide protocol approved by the DSMB and the NIDDK that the site is selected for participation;

5. Comply with all study policies and quality assurance measures approved by the Steering Committee;

6. Agree to oversight of the study by a Data and Safety Monitoring Board (DSMB),

7. Accept awards for the support of research based on per-patient (capitated) rates and the actual numbers of subjects enrolled, followed, and completing the study (Clinical Centers only);

8. Transmit study data to the Data and Coordinating Center in a timely and accurate manner (Clinical Centers only);

9. Report all adverse events in accordance with procedures established by the Steering Committee and NIDDK policies;

10. Cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources;

11. Serve on and chair subcommittees and protocol committees as assigned by the steering committee or the NIDDK;

12. Accept the Cooperative Agreement Terms and Conditions of Award in Section VI.2.A Award Administration Information .

Research Plan Page Limitations

The text portion of the research plan should not exceed 20 pages. However, up to an additional 5 pages of tables may be used to describe relevant information about a CC’s capabilities, such as the number and types of patient populations treated at their institution or enrolled into the BARC or CLiC studies, may also be included. Applications that include one or more of the biological or administrative cores may use an additional 5 pages for each core.

Appendix Materials

All paper PHS 398 applications submitted for May 25, 2008 and subsequent due dates must provide appendix material on CD only, and include five identical CDs in the same package with the application. Paper applications submitted for due dates prior to May 25, 2008 may voluntarily provide the appendix on five identical CDs; if submitting CDs it is not necessary to include a paper appendix. (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.)

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

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this 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/.

The DCC application should include an overall sharing plan for data generated during the funding of ChiLDREN. CC applications need not cite this plan in detail, but applicants should indicate their willingness to participate fully in it. The plan should indicate specifically what will be shared, with whom it will be shared (including the NIDDK Data Repository), when it will be shared, by what means it will be shared, and what conditions will apply to recipients of shared data. This plan must be approved by the NIDDK before awards will be issued under this RFA.

Section V. Application Review Information

1. Criteria

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

2. Review and Selection Process

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 NIDDK and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

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

The following will be considered in making funding decisions:

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 meritorious 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

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? Does the research plan specifically describe how the ongoing studies will be implemented at each site? Have the biological core(s) described how they intend to support the ongoing studies and future studies likely to be undertaken?

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 it likely that the goals of the research plan will be achieved? What is the scientific and technical merit of the approach to meeting the requirements of the integration of the currently approved studies or the research plan of the biological cores?

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?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? 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)? Additionally, do the specific competence and previous experience of the professional, technical and administrative staff of the CC or the DCC increase the likelihood the goals of the research plans will be achieved?

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 evidence of adequate facilities, space, and resources for the work proposed including evidence of an appropriate organizational structure and institutional support? Do the collaborative arrangements within the proposed Network enhance the productivity of the CC or DCC?

In addition to the above review criteria, the following criteria will be applied to applications

COMMITMENT: Is there evidence of commitment to continue to conduct the approved studies of the BARC and CLiC and to support the merger of the two consortia?

Review of the CC applicants will also be based on the following specific criteria:

Recruitment and Retention: Is there evidence that the CC sees enough patients with pediatric liver disease to be able to meaningfully contribute to the ongoing BARC and CLiC studies. Have they demonstrated their willingness and ability to recruit and retain these patients in clinical trials and epidemiological studies?

Data and Sample Management: Is there an adequate plan to ensure the timely and accurate transmission of study data to the DCC and patient samples to the NIDDK repositories and approved central laboratories or biological cores?

Cooperative Experience: Is there evidence of a strong willingness to work cooperatively and to participate in all aspects of a cooperative network including service on subcommittees and authoring publications and proposals?

Review of the DCC application also will be based on the following specific criteria:

Is there understanding of the scientific, statistical, logistical, and technical issues underlying the BARC and CLiC multi-center studies and knowledge necessary to lead in the areas of study design, statistics, logistics, data acquisition and management, identification of and coordination with central laboratories and serum/tissue/data repositories, handling of laboratory specimens, quality control, data analysis, and consortium coordination?

Are the proposed plans for acquisition, transfer, management, and analysis of data, quality control of data collection and monitoring, and overall coordination of the ChiLDREN activities including the transfer in of data, studies, and protocol materials from either the BARC, CLiC or both consortia DCCs adequate?

Is the expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator and co-investigators at the DCC, and the time they plan to devote to the effective coordination of ChiLDREN adequate?

Are the administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to work cooperatively with the principal investigators of the CCs and the NIDDK clearly defined.

Are the facilities, equipment, environment and organizational structure to effectively coordinate the ChiLDREN activities in implementing the protocols, data collection and providing for specialized methodologies and plans for collecting and distribution of biospecimens to the NIDDK repositories, biological cores, ancillary study investigators adequate?

Is there ability to develop or modify the Data Safety and Monitoring Plan, Manuals of Operations and Case Report Forms for the Networks multiple sites and studies?

Is there ability to support the NIDDK in filing the necessary paperwork for INDs to the Food and Drug Administration?

Is there expertise in setting up, monitoring and managing databases?

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 rating:

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 on Human Subjects in the PHS 398 instructions).

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 on Human Subjects in the PHS 398 instructions).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five points described in the Vertebrate Animals section of the Research Plan 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

Not Applicable

Section VI. Award Administration Information

1. Award Notices

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

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

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (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 cooperative agreement an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2. A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for: all aspects of the protocols, including any modification of study design; conduct of the study including participant recruitment, safety and follow-up; assuring quality of patient care and protocol adherence; data collection; quality control; data and safety monitoring, data analysis and interpretation; preparation of publications; and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee. Awardee(s) agree to the governance of the study through a Steering Committee. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee, the NIDDK and the Data and Safety Monitoring Board.

All applicants will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of ChiLDREN.

Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The collaborative protocol and governance policies will call for the continued submission of data centrally to the DCC for a collaborative database; procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data and records of individuals. The NIDDK Project Scientist, on behalf of the NIDDK, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee.

All awardees will be responsible for implementing the clinical trials and studies according to the protocols and methodologies decided upon by the Steering Committee. For a study involving multiple institutions, it is the responsibility of each awardee/site to ensure that data will be submitted in a timely manner to the central Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.

Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple awards, strategies for the analyses of pooled data will be developed by the Steering Committee. No site may publish or share data collected at their own individual site while following a ChiLDREN protocol in accordance with policies, including the data sharing plan, approved by Steering Committee.

Awardees are responsible for submitting interim progress reports, when requested, to the NIDDK Project Scientist including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the NIDDK may require additional information from individual awardees/sites. Such reports are in addition to the annual awardee noncompeting continuation progress report

Awardees are responsible for establishing procedures, where applicable, for all participating institutions in coordinated awards to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children.

The Data Coordinating Center will be involved in collaborations with the NIDDK and the Clinical Centers during all phases of the study. Thus, the DCC awardee is expected to work cooperatively with Clinical Centers and sponsoring organizations in multicenter studies and oversee the implementation of and adherence to a common protocol, as well as assure quality control of the data collected and storage of collected specimens. In addition to organizing and attending regular meetings, the Data Coordinating Center will be expected to maintain close communications with the NIDDK Project Scientist and the Principal Investigators of the Clinical Centers.

Awardees are encouraged to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community and the NIDDK. In additional they will adhere to the steering committee approved publication/presentation policy.

Support or other involvement of industry or any other third party in any study performed by the Network -- e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIDDK support; or special access to project results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification to, and concurrence by the NIDDK.

Upon completion of the project, the DCC is expected to transfer all study intervention materials and procedure manuals into the NIDDK Central Repository, which in accordance with current NIDDK and NIH policies, will make them available to the scientific community for the conduct of research at no charge other than the costs of reproduction and distribution.

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 will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

A The NIDDK Project Scientist responsibilities include:

1. Retaining overall programmatic responsibility for the award, and will clearly specify to the awardee the name(s) and role (s) of any additional individuals with substantial involvement in the project and the lines of reporting authority.

2. Interacting with the principal investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the principal investigator and staff, periodic site visits for discussions with awardee research teams, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data safety and monitoring board, and related meetings. The NIDDK retains the option of periodic external review of progress.

3. Reviewing and approving protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. The NIDDK Project Scientist will monitor protocol progress, and may request that enrollment in a protocol study be terminated for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure (except for patients already on-study).

4. Making recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.

The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NIDDK cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination.

The NIDDK will name additional scientific advisors as necessary from within the National Institutes of Health whose function will be to assist the NIDDK Project Scientist and the Steering Committee in carrying out the goals and aims of the approved studies. NIDDK will have one vote for all key study group subcommittees, regardless of the number of NIDDK personnel involved.

The Project Scientist will have substantial scientific programmatic involvement in quality control, interim data analysis, safety monitoring, and final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The dominant role and prime responsibility for these activities resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientist.

Other NIDDK Project Scientist responsibilities and levels of involvement in the project, as described below.

1. For multi-institutional protocols, participation in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or designee will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.

2. Serves as a resource with respect to other ongoing NIDDK activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort.

3. Has substantial involvement in assisting in the design and coordination of research activities for awardees as elaborated below:

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

2.A.3. Collaborative Responsibilities

The Steering Committee, composed of each of the Principal Investigators of the CC and the DCC, the Biological Core Directors, and the NIDDK Project Scientist will be the main governing board of the studies. Only the principal investigators, biological core directors and the NIDDK Project Scientist or designee will be voting members of the Steering Committee and all major scientific decisions will be determined by a majority vote. This committee will have the primary responsibility for approval of the common protocols, facilitating the conduct of participant follow-up, monitoring completeness of data collection and timely transmission of data to the DCC, and reporting the study results. It will also be responsible for establishing Network policies in such areas as access to patient data, ancillary studies, publications and presentations, and performance standards.

A Chairperson or Chairpersons will be chosen from among the Steering Committee members by the NIDDK from among the principal investigators (but not the NIDDK Project Scientist or Data Coordinating Center Principal Investigator) or alternatively, from among experts in an appropriate scientific field who is not participating directly in the study. In collaboration with the PI of the DCC and the NIDDK Project Scientist, the Chairperson is responsible for coordinating the Committee activities, for preparing meeting agendas, and for scheduling and chairing meetings.

Subcommittees will be established on topics such as ancillary studies, publications and presentations, quality control, recruitment, protocol adherence, among others. Both PIs and Co-PIs may serve as chairs of the subcommittees.

An Executive Committee comprised of the Study Chair(s), the Principal Investigator of the Coordinating Center, and the NIDDK Project Scientist will be convened to effect management decisions required between Steering Committee meetings, as needed for efficient progress of the trial.

Each CC Awardee and the DCC Awardee agree to the governance of the study through the Steering Committee. Meetings of the Steering Committee will ordinarily be held by telephone conference calls or at rotating sites of the CCs and the DCCs.

The NIDDK Project Scientist (and the other cited NIDDK scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., issues of recruitment, intervention, follow-up, quality control, standards and methods, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. Regardless of the number of NIH staff participating in technical advisory roles, the NIDDK will be limited to one vote on the Steering Committee.

An independent Data and Safety Monitoring Board (DSMB) will be established by the NIDDK to review protocols and monitor patient safety and performance of each study. As a part of its responsibilities, the DSMB will submit recommendations to the NIDDK regarding the continuation of each study. The DSMB will be responsible for final approval of the Data and Safety Monitoring Plan developed by the DCC. Because the DSMB serves as an independent group advisory to the NIDDK, study investigators will not communicate with the Board members regarding study issues, except as authorized by the Board s Executive Secretary or the NIDDK Project Scientist.

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

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

Section VII. Agency Contacts

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

1. Scientific/Research Contacts:

Patricia R. Robuck, Ph.D, M.P.H.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 659
Bethesda, MD 20892-5450
Telephone: 301-594-8879
FAX: 301-480-3505
Email: pr132q@nih.gov

2. Peer Review Contacts:

Francisco O. Calvo, Ph.D.
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
Telephone: (301) 594-8885
FAX: (301) 480-3505
Email: fc15y@nih.gov

3. Financial or Grants Management Contacts:

Ms. Sharon Bourque
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 719
Bethesda, MD 20892-5456
Telephone: (301) 594-8846
FAX: (301) 594-9523
Email: sb114m@nih.gov

Section VIII. Other Information

Required Federal Citations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 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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