Purpose:

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 the Clinical Centers (CC) of the Childhood Liver Disease Research Network (ChiLDReN).  The ChiLDReN Network was established with the merging of the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Consortium (CLiC) under RFA-DK-08-005.  The overarching research mission of ChiLDReN has been to improve our understanding of cholestatic and rare pediatric liver diseases that have included: Biliary Atresia; Alagille syndrome; alpha-1-antitrypsin deficiency; Progressive Familial Intrahepatic Cholestasis syndromes; Bile acid synthesis defects; Mitochondrial hepatopathies; Idiopathic Neonatal Hepatitis; and Cystic Fibrosis Liver Disease.  During the conduct of research activities under RFA-DK-13-011, the NIDDK charged the ChiLDReN Steering Committee to initiate clinical studies of pediatric primary sclerosing cholangitis owing to the alignment of this condition with the overarching research mission on the study of pediatric cholestatic liver diseases and more importantly, due to the common converging complication associated with all of the ChiLDReN liver diseases, the development of cirrhosis of the liver. 

Recently, the NIDDK sponsored a one day research workshop in June 2017 on the topic of biliary atresia with a focus upon the various mechanisms postulated to be pathophysiologic towards disease initiation and progression.  The meeting summary manuscript (Hepatology. 2018 Mar 31. doi: 10.1002/hep.29905. [Epub ahead of print]) concluded with a summary of clinical and scientific research challenges that would further the understanding of biliary atresia.  Several of the clinical and scientific challenges align with and may be amenable to be undertaken under the overarching research mission of the ChiLDReN Network moving forward into the next funding cycle.

In order to meet the future research challenges and opportunities in pediatric liver diseases, the ChiLDReN Network will need to prioritize those diseases currently being studied (including pediatric primary sclerosing cholangitis) that are optimally positioned to exploit the scientific opportunities available within or through collaborations with expertise outside of the Network that will translate into feasible and achievable advancement of the understanding of the pathogenesis or advancement in the clinical management of the various diseases.  Some of the Network priorities may require the further identification and enrollment of patients into one of the prioritized diseases; in others, the currently available collected data, biosamples, or previously identified patients may be sufficient to embark upon a scientific endeavor or clinical study or trial.

Organization of the ChiLDReN Network:

The ChiLDReN Network has been and will continue to be a cooperative research network composed of up to 13 Clinical Center (CC) grantees, one Scientific and Data Coordinating Center (SDCC) grantee (previously known as a Data Coordination Center), and the NIDDK/NIH through the Cooperative Agreement terms and conditions.  Steering Committee: The Steering Committee will be the main governing body of the ChiLDReN (see Terms and Conditions of Award).  Voting members of the Steering Committee will be the Principal   Investigator (PI) or designee for each U01 Clinical Center grant, the Scientific and Data Coordination Center PI, and the NIDDK. Executive Committee: An Executive Committee comprised of at a minimum of the Network Chair and Co-Chair who will be appointed by the NIDDK at the initiation of the new funding cycle; the Program Director/Principal Investigator of the SDCC; and the NIDDK Project Scientist and Program Official and other NIDDK personnel as deemed necessary by the Project Scientist and Program Official will be convened to effect management decisions required between Steering Committee meetings, that is needed for efficient progress of the Network scientific activities.  Other subcommittees, working groups, and task forces of the Steering Committee will be prioritized and operationalized as necessary, such as publications, ancillary, protocol, pathology and radiology.  Data Safety and Monitoring Board: An independent Data and Safety Monitoring Board (DSMB) has been 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 SDCC. All protocols or changes to protocols will be approved by 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 Program Officer. All face to face Steering Committee, DSMB, and other necessary face to face meetings requiring the presence of NIDDK personnel will be held in the Washington, DC/Baltimore metropolitan area or other suitable venue as appropriate for the operational efficiency of Network scientific activities and for the Programmatic oversight of cost efficient Network resource management. 

Scientific and Data Coordination Center: The SDCC will take on the administrative and data collection/analysis functions and will be responsible for the conduct of all of the ongoing and future studies of ChiLDReN.  Thus, they should include methodology and plans for transferring and capturing all data currently being collected by ChiLDReN.  In addition, the SDCC will be responsible for supporting any protocol development or modifications; coordinate implementation, training, and logistical support for the conduct of the studies; 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; exploring the integration of web based data entry, digital data storage, automated electronic medical record downloads of data to a centralized database; coordinate implementation, training, and logistical support for the conduct of the studies; and providing overall study coordination and quality assurance, including coordination of the activities and meetings (including conference calls or face to face meetings) of the Data and Safety Monitoring Boards (DSMB), the Steering Committee, and other needed committees. The SDCC 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 SDCC will be responsible for preparation of documents to the Food and Drug Administration (FDA) in support of Investigational New Drug Applications (INDs) held by the NIDDK on behalf of ChiLDReN.  The SDCC will also prepare all reports including data reports for review by the DSMBs at their meetings. The SDCC will also be responsible for the logistics and planning of the meetings of the Steering Committee and the various operational committees of ChiLDReN. The Scientific and Data Coordinating Center will be responsible for acquiring and administering subcontracts as needed or as directed by the NIDDK for the operational aspects of carrying out the management of Network protocols. (See Terms and Conditions of Award). The NIDDK has established a 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 SDCC 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; coordination of the biospecimens, tracking, distribution, and eventual depositing of both data and biospecimens into the NIDDK Data and Biospecimen Repository as per NIDDK policy (https://www.niddkrepository.org/niddk/home.do); and dispensing biospecimens and data to steering committee approved ancillary study sites.  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 as per NIDDK policies.  Applicants for the SDCC should also propose a subcontract selection process that may be utilized to develop additional services in support of the scientific activities of the ChiLDReN Network that may include but are not limited to a Bioinformatics Core; digital pathology services; a DNA extraction service; analytic genomics services among other possible services in the support of the Network scientific activities. Ultimately, the specific activities of any core or services in the conduct of the scientific activities of ChilLDReN will be dependent upon the scientific priorities of the Steering Committee.

Clinical Centers for ChiLDReN: The Clinical Centers (CCs) will continue to recruit subjects into the newly prioritized and Steering Committee approved as well as the currently ongoing ChiLDReN studies and will conduct the clinical trials and longitudinal follow-up as described in the study protocols. An overview of currently active protocols may be found at the ChiLDReN website: http://www.childrennetwork.org. 

Cores or other services in support of the research activities of ChiLDReN such as a diagnostic or the administrative core are headed by a lead or a director and are funded as a cooperative agreement or as subcontracts through either the SDCC or one or more of the CCs. The responsibilities of each entity of the Network are described in the Terms and Conditions of Award.

NIDDK: The NIDDK/NIH 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 scientific oversight, will monitor subject recruitment and study progress, ensure disclosure of conflicts of interest and Network 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.

Objective of this Research Program:

To promote clinical and translational research on pediatric liver diseases focusing upon elucidating the pathogenesis and natural history and developing means of treatment and clinical management, the NIDDK proposes to continue the ChiLDReN Network.  The specific research objectives that the SDCC may assist in the newly formed ChiLDReN could include but are not limited to:

1. Completing the current genomic screens underway or are currently planned by the Genomics Working Group that are of a discovery based research in nature.  Furthermore, to undertake when feasible initial validation studies of genomic screen candidates in order to improve the understanding of the etiologies, gene interactions, and modifiers of disease phenotype.  In certain situations, this endeavor should strongly consider partnering with expertise that is likely to reside outside of the newly formed ChilLDReN that will provide time efficient and cost effective approaches to achieve these scientific objectives.

2. Complete the FORCE study and associated biomarker assays that are underway or currently planned by the FORCE Working Group. 

3. Continue the IMAGINE II study.

4. Utilize the findings of the START and PRIME studies that may shed additional insights on the pathogenesis of biliary atresia via mechanistic based studies with the collected biospecimens and data.

5. Prioritization of the various prospective longitudinal studies of ChiLDReN and of the data elements to be collected that will provide data and biospecimens that will better inform disease modeling, end-point verification, natural history, and for ancillary studies aimed at discovering new diagnostics, etiologic and treatment options for children both pre and post liver transplantation.

6. Complete the PUSH study in 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.

7. Identification and validation of non-invasive markers of liver disease activity, stage, or portal hypertension in pediatric patients including but not limited to new imaging modalities and serum biomarkers.

8. Conceive, develop, and initiate Phase I/II studies of new or currently available agents to treat cholestatic liver disease or liver fibrosis or other aspects of significant morbidity associated with the various liver diseases undertaken by this Network.  The NIDDK will negotiate on behalf of the ChiLDReN Network with any potential industry partners for which mutual scientific interests have been established in order to move forward with formalizing a private public partnership.

9. Ongoing Clinical studies:  It is anticipated that current studies and those being developed will continue as written or as planned with no disruption once ChiLDReN is continued. 

10. Conceive, develop, and initiate pilot and feasibility translational studies based upon the data and findings generated from the ongoing Network-wide translational studies led by the Genomics and FORCE Working Groups.  The NIDDK will reserve up to $50,000 per year from the allocated set aside for this FOA on an annual basis to support meritorious pilot and feasibility translational studies that will be administered through the administrative core of the Network or for other translational science objectives that are meritorious in the advancement of the overarching scientific objectives of the Network.

This is a one-time funding opportunity to continue the ChiLDReN for a maximum of five years, contingent on satisfactory study recruitment, patient retention, progress of translational studies, and availability of funds.   

Other Special Performance Requirements:

ChiLDReN will continue to be a collaborative effort that will require frequent interactions of awardees among themselves and with the NIDDK in order to operate efficiently and effectively. Applicants must explicitly indicate their willingness to:

1. Participate in Steering Committee meetings (expected to occur in person 2-3 times a year in the Washington DC/Baltimore metropolitan area or other suitable meeting venue as appropriate, and on 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 Network and study policies, procedures, and quality assurance measures approved by the Steering Committee;

6.  Agree to oversight of the studies 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;

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

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

10.  Serve on and chair subcommittees and protocol committees as assigned by the Executive or Steering committee or the NIDDK;

11. Engage a broader set of investigators external to the immediate study group to provide opportunities to analyze the data and participate in the parent study by means of ancillary studies;

12. Develop opportunities for local analysis of data by study investigators and other qualified researchers at their institutions, and investigators outside the study group (“disseminated data analysis”);

13. Accept the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2. "Award Administration Information";

14. Agree to abide by the Network Duality of Interests Disclosure Policy.

1. Eligible Applicants

Only the current ChiLDReN DCC under RFA-DK-13-011 is eligible to apply under this FOA.

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

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

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

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

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

“Only the current awardee ChiLDReNs DCC from RFA-DK-13-011 is eligible to apply under this FOA.

2. Cost Sharing

3. Additional Information on Eligibility

Number of Applications  

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

All instructions in the SF424 (R&R) Application Guide must be followed.

With respect to this FOA, the SDCC applicant should address the following points in the application:

Research Strategy:

• The PI/PD should state their willingness to comply with the Other Special Performance Requirements as noted in Section I.
• It is expected that the PD/PI of the SDCC will carry out a significant leadership role in the network. Describe the future participation of the SDCC PD/PI in a leadership role in the ChiLDReN Network.
• Discuss the applicant's familiarity and experience with various aspects of study design in rare pediatric diseases that would be important in developing clinical protocols, for example: eligibility criteria; baseline and outcome measures; methods of randomization; important considerations for making sample size and power calculations; methods and frequency of data collection and entry; monitoring accuracy of data collection; quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously; managing labeling and handling of serum and tissue samples (see below); and plans for statistical analysis.
• Discuss the progress that they have made to achieve the goals of the consortium in the prior funding period.
• Discuss the applicant’s participation in the design of all research studies and the development or updating of the manual of operation, data collection forms, and questionnaires.
• Discuss development and implementation of systems for communication among Steering Committee members and among study sites.
• Discuss data collection, editing, processing, analysis and reporting utilizing the latest technology to assure timely reporting to the NIDDK, the investigators and the DSMB.
• Describe the establishment of procedures that ensure the safety and confidentiality of all records.
• Describe procedures for coordinating submission of biospecimens from the CCs to the NIDDK Repositories, central laboratories, and biological cores and to ancillary study participants.
• Discuss the ability to fill out necessary regulatory documents in support of the Food and Drug Administration Investigational New Drug Application (IND).
• Discuss accomplishments in encouraging ancillary studies, and approaches for engaging the broader research community, data sharing, and fostering future research collaboration.
• Provide documentation of the investigators` involvement in the activities of the consortium, and a clear commitment of participation in data analyses and dissemination.
• Propose unique or novel analysis strategies.
• Describe how the SDCC will coordinate a strategy across the consortium to ensure a robust and unbiased scientific approach.
• Describe plans to respond to others who request data and plans to send out limited datasets.
• Provide data quality measures, clinical visit retention rates and performance of procedures from prior study phases, and a description of the processes for ensuring high quality and complete data collection and resources available to support electronic information handling.
• Provide a description of how the Scientific and Data Coordination Center will coordinate with the Clinical Centers to ensure the consistent implementation of the study protocols in all currently enrolled study participants in each of the study protocols.
• Provide proof of institutional support, and description of the organizational and administrative structure of the Scientific and Data Coordinating Center.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data and Resource (Biological Sample) Sharing Plan.

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Please include a discussion of the availability of potential participants for the proposed study and anticipated yield from recruitment and screening efforts. The plan should also include a discussion of past experience in recruiting and retaining similar populations, expected challenges to recruitment and retention, and possible contingency plans. Provide plans on how high rates of follow-up will be maintained over the course of the study.

Inclusion Enrollment Report

If there is more than one site, please provide a table showing the expected number and demographics of the population to be recruited at each site and overall.

3.3 Data and Safety Monitoring Plan

Describe their plans for managing the Data and Safety Monitoring Board meeting materials.

Section 4 – Protocol Synopsis

4.3 Outcome Measures

Applications proposing clinical trials should indicate all timepoints when an outcome measure will be collected.

4.4 Statistical Design and Power

This should be submitted only by applications proposing clinical trials. The sample size and statistical power calculations should contain enough detail, including a description of any assumptions made, so that a reviewer can readily duplicate the sample size. The power analysis should include a discussion of the anticipated level of adherence to the intervention and rates of follow-up (i.e., drop out/lost to follow up) during key outcome collection contacts. There should be a discussion of how missing data will be handled. Any planned interim analyses should also be described.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

Milestone Plan. The filename "Milestone Plan.pdf" ( appended with 1, 2, 3, etc. if needed) must be used for this attachment. The Milestone Plan attachment is separate and distinct from the Study Timeline attachment.

Applicants proposing clinical trials are required to provide detailed interim performance measures and timelines for completing key objectives and administrative functions for the proposed clinical trial(s), as applicable. Milestones should be easily measurable and realistic. Milestones may include, as applicable, but are not limited to:

• Finalization of the clinical trial protocol(s) and informed consent/assent forms (with program director agreement, if applicable) and establishment of a single IRB and provision of IRB approval
• Registration of the clinical trial(s) in ClinicalTrials.gov
• Completion of all required regulatory approvals (e.g., Investigational New Drug Application or Investigational Device Exemption from the Food and Drug Administration)
• Contracts/third party agreements, including intervention product supply
• Training of study staff
• Anticipated date of enrollment of the first participant
• Randomization of 25%, 50%, 75% and 100% of the target sample size
• Follow-up visit completion, if applicable, of 25%, 50%, 75% and 100% of the enrolled or randomized study population, including women, minorities and children
• Expected drop-out or lost-to-follow-up rate overall, or by treatment arm
• Anticipated rate of adherence to the intervention(s)
• Completion of data collection
• Completion of primary endpoint and secondary endpoint data analyses
• Completion of final study report and manuscript submission
• Closeout plans/communication of results to participants
• Reporting of results in ClinicalTrials.gov.

These milestones will be negotiated at the time of the award, as appropriate. If milestones are not achieved fully, NIDDK may request development of a remedial plan and more frequent monitoring of progress, or take other remedial actions.

Applications that propose a clinical trial that lack the Milestone Plan are considered incomplete and will not be peer reviewed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NIDDK, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies.  CDEs are data elements that have been identified and defined for use in multiple data sets across different studies.  Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records.  NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository).  NIH has established a “Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection.  The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research.  Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects. 

1. Criteria

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

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Significance  

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

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)  

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

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

With respect to this FOA:

• Do the descriptions of the future participation of the SDCC PD/PI in the ChiLDReN Network indicate leadership and guidance roles?
• Are the descriptions of the applicant's familiarity and experience with various aspects of supporting clinical and translational research and data management in support of a large network setting for rare diseases well suited to the anticipated tasks?
• Has the progress that they have made to achieve the goals of the consortium in the prior funding period been successful?
• Are the applicants’ participation in the design of all research studies and the development or updating of the manual of operation, data collection forms, and questionnaires been appropriate in support of the consortium research activities?
• Has the documented involvement by the SDCC investigators in the activities of the consortium demonstrated a clear commitment of participation in data analyses and dissemination?

Innovation  

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

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach  

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods ? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

With respect to this FOA:

• Has the implementation of systems for communication among Steering Committee members and among study sites been efficient and appropriate?
• Are the data collection, editing, processing, analysis and reporting utilizing the latest technology to assure timely reporting to the NIDDK, the investigators and the DSMB?
• Are the established procedures that insure the safety and confidentiality of all records appropriate?
• Are the procedures for coordinating submission of biospecimens from the CCs to the NIDDK Repositories, central laboratories, and biological cores and to ancillary study participants appropriate and efficient?
• Are the capabilities of the SDCC applicant to fill out necessary regulatory documents in support of the Food and Drug Administration Investigational New Drug Application (IND) adequate?
• Have the approaches to encourage ancillary studies, and approaches for engaging the broader research community, data sharing, and fostering future research collaboration been effective?
• Are the unique or novel analysis strategies applicable in the rare diseases and study designs in this consortium?
• Are the SDCC’s strategies to coordinate a robust and unbiased scientific approach appropriate?
• Are the plans to respond to others who request data and plans to send out limited datasets time efficient and adequate?
• Are the data quality measures, clinical visit retention rates and performance of procedures from prior study phases, and a description of the processes for ensuring high quality and complete data collection and resources available to support electronic information handling appropriate to the research and analytic needs of the consortium?
• Are the plans on how high rates of follow-up will be maintained over the course of the study adequate?
• Are the plans on how the Scientific and Data Coordination Center will coordinate with the Clinical Centers to ensure the consistent implementation of the study protocols in all currently enrolled study participants in each of the study protocols appropriate and adequate?
• Are the plans for managing the Data and Safety Monitoring Board meeting materials sufficient for the efficient conduct of Board meetings?
• Is there evidence of institutional support, and is the description of the organizational and administrative structure of the Scientific and Data Coordinating Center appropriate in the management of the consortium research activities?

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

Environment  

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

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Milestone Plan 

Are the proposed milestones appropriate for the study?  Will they allow meaningful tracking of study performance and are they feasible for the work proposed?

Protections for Human Subjects  

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

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

Inclusion of Women, Minorities, and Children  

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

Vertebrate Animals  

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards  

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

Resubmissions  

Renewals  

Revisions  

Applications from Foreign Organizations  

Select Agent Research  

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

Resource Sharing Plans  

Authentication of Key Biological and/or Chemical Resources:  

For networks involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support  

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

2. Review and Selection Process