- September 7, 2023 - This RFA has been reissued as RFA-DK-23-017
- November 19, 2018 - Notice of Correction to Cover Instructions for RFA-DK-18-501. See Notice NOT-DK-19-006.
No late applications will be accepted for this Funding Opportunity Announcement.
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
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.
To this end, the historical focus and prior accomplishments of this Network have been clinical in nature and have included the completion of the safety and efficacy of steroid use following hepatoportoenterostomy (HPE) in children newly diagnosed with biliary atresia (START); the cataloging of major birth anomalies associated with biliary atresia; the assessment of the effectiveness of fat-soluble vitamin supplementation in biliary atresia; the safety and feasibility of intravenous immunoglobulin for biliary atresia (PRIME); and a clinical trial under a CRADA to test the efficacy and safety of Intestinal Bile Acid Transport Inhibitor LUM001 in the treatment of Pruritus in Alagille Syndrome patients (ITCH); among many other accomplishments. Additionally, the ChiLDReN Network developed a robust biospecimen repository with over 1100 biliary atresia patient DNA specimens; frozen liver specimens from the range of liver diseases under study; and bile duct specimens from children undergoing hepatic portoenterostomy for biliary atresia. With these unique and well characterized biospecimens, the ChiLDReN Network was charged by the NIDDK to exploit the resources of the biosample repository through Network-wide translational science studies to further our understanding of the pathogenesis of these pediatric liver diseases. 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. As such, all applicants will be required to include a Pilot and Feasibility clinical trial research strategy with any of the rare pediatric liver diseases currently under investigation by the ChiLDReN Network within their application.
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 Clinical Center (CC) grantees, a 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 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 Projec 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.
Components of the ChiLDReN Network:
Composition of the ChiLDReN: The components of ChiLDReN will consist of the following: the NIDDK/NIH as the sponsor of the Network, up to thirteen CC grantees, and a single SDCC grantee, that will be operationalized by an Executive Committee, a Steering Committee and its subcommittees, Data and Safety Monitoring Boards (DSMB), and other committees as needed as noted above in: Organization of the ChiLDReN Network.
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. No deviations will be allowed. All individual CCs will be required to participate in a cooperative and interactive manner with one another, with the SDCC, and with the NIDDK 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 and procedures 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 Steering Committee approved ChiLDReN protocols.
Clinical Centers will be responsible for proposing protocols, participating in their overall development, conducting the research, and disseminating research findings. For each new investigational or therapeutic protocol, one Clinical Center will take the lead responsibility in conjunction with a protocol development subcommittee for drafting the protocol, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by all of the participating CCs. The Clinical Center PD/PI leading the development of the protocol will also provide protocol oversight and management if implemented as a ChiLDReN study. All clinical center PDs/PIs will be strongly encouraged to fully commit their center resources and efforts to the Network protocols. The SDCC will support protocol development, provide sample size calculations, statistical advice, questionnaires, and data analysis; coordinate implementation, training, and logistical support for the conduct of the studies; support manuscript preparation; organize committee meetings; and provide overall study coordination and quality assurance, including coordination of the logistical activities of the Data and Safety Monitoring Board(s), the Steering Committee and other standing committees; 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).
Cores in support of the research activities of ChiLDReN such as a diagnostic or the administrative core are headed by a Program Director/Principal Investigator 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.
Scientific and Data Coordination Center: A Scientific and Data Coordination Center will be integral to the operations of the ChiLDReN Network. The applicant for the Scientific and Data Coordination Center for the ChiLDReN is referred to RFA-DK-18-502 regarding Network related responsibilities and obligations in support of the scientific research activities of the ChiLDReN Network.
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 Network would accelerate clinical and translational research and progress in understanding the pathogenesis of rare pediatric liver diseases and treatment strategies with currently available or investigational therapeutic agents. ChiLDReN would thus facilitate the ability of the Network to discover new diagnostics, etiologic, pathogenic mechanisms, and treatment options for children with rare liver diseases and those who undergo liver transplantation as a result of these diseases. The specific objectives of 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. Transmit study data to the Scientific and Data and Coordinating Center in a timely and accurate manner;
9. Report all adverse events in accordance with procedures established by the Steering Committee and NIDDK and FDA 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 Executive or Steering committee or the NIDDK;
12. 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; 13. 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 ); 14. Accept the Cooperative Agreement Terms and Conditions of Award in Section VI.2 Award Administration Information ; 15. Agree to abide by the Network Duality of Interests Disclosure Policy.Renewal applications only for the awards supported under RFA-DK-13-011
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
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The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
1. Eligible Applicants
Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations
Applicant organizations must complete and maintain the following registrations as described in the 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.
2. Cost Sharing
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.3. Additional Information on Eligibility
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
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.
In the Introduction to Application, the PI/PD should state their willingness to comply with the Other Special Performance Requirements as noted in Section I.
All instructions in the SF424 (R&R) Application Guide must be followed.
Research Strategy: Applications for the CCs must include a scientific research strategy for the purposes of assessment of PD/PI knowledge and identification of current research challenges in the pediatric liver diseases studied by ChiLDReN. The Scientific research strategy must include a pilot and feasibility clinical trial. A scientific translational strategy is permitted, but is in addition to the pilot and feasibility clinical trial strategy, entirely optional, and may not be used in lieu of the required pilot and feasibility clinical trial strategy. The scientific research strategy should utilize the currently available ChiLDReN data, biospecimen repository, or enrolled patients. The scientific research strategy may encompass a range of analyses analogous to an ancillary study concept in scope that will exploit the vast data, biosample repositories and patient enrollees of the ChiLDReN Network. With over 100,000 serum/plasma/urine/tissue specimens collected by the ChiLDReN Network for these rare pediatric liver conditions, this repository of data and biosamples represents an abundant opportunity to utilize these resources for advancing our understanding of these diseases. In addition to the 1100 biliary atresia DNA samples, the Network also has within its inventory approximately 1700 DNA specimens from corresponding parents; 2200 frozen liver specimens across the liver diseases studied within the Network; and 340 biliary atresia bile duct specimens. Scientific research strategy should advance our understanding or fill a knowledge gap of the disease at either the clinical or translational level. Examples of topics may include but are not limited to: quality of life; defining risk factors for disease progression or regression; defining clinical risks for developing extra-hepatic complications; refining the natural history of cholestatic liver disease; biomarkers for liver fibrosis, liver function, and portal hypertension; defining micro RNA species associated with disease state or progression; defining the role of autotaxin in cholestatic liver disease; determining proteomic signatures for disease diagnosis or progression; determining the role of altered developmental signaling in disease pathogenesis.
Each CC must delineate how they will be able to submit data to the SDCC 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 SDCC 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 future plans for involvement with operational committees of ChiLDReN (e.g. Recruitment committee, Publications committee, etc.) and the establishment of uniform procedures and policies.
Clinical Centers that include a core as part of the application must describe the functions, capabilities and willingness of the core facility to carry out supportive roles in the conduct of ChiLDReN studies or administrative support as appropriate. The final decision on the acceptance of the core for ChiLDReN scientific activities will be at the discretion of the NIDDK based upon the availability of support.
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. Each CC application may consider the addition of other scientific personnel who must be fully justified. The additional scientific personnel must demonstrate the capability to provide substantial scientific expertise that is consistent with and aligns with the translational scientific objectives of the ChiLDReN Network. The final decision on the acceptance of the additional scientific personnel will be at the discretion of the NIDDK based upon the scientific value that the individual adds to the scientific objectives of the Network and upon the availability of support. The PD/PI should state his/her general support of collaborative research and interaction with the NIDDK, the other CCs, and the SDCC through the Network concept. Applicants should discuss their willingness, and that of the institutions involved, in pursuing a per patient basis (capitation) of operational costs.
CCs must be able to interact with the SDCC to transmit and edit data and should discuss their capability to participate in a distributed data entry system.
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
For the required Pilot and Feasibility clinical trial, 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.
For the currently ongoing ChiLDReN Network-wide clinical studies and trials that will continue into the next funding cycle, CC applications must describe detailed plans for future subject recruitment and retention related to each of the ongoing research studies that the Clinical Center is actively participating in and a description of the type of diseases and the number of children seen at their CC within the past two years who may be candidates to be enrolled in those ChiLDReN Network-wide studies. More importantly, each CC should describe future projections to recruit patients into the active Network-wide protocols at their site. 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 ongoing Network-wide protocols.
Inclusion Enrollment Report
For the required Pilot and Feasibility clinical trial , 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.
Section 4 Clinical Protocol Synopsis
4.3 Outcome Measures
For the required Pilot and Feasibility clinical trial , applications should indicate all timepoints when an outcome measure will be collected.
4.4 Statistical Design and Power
For the required Pilot and Feasibility clinical trial , 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
For the required Pilot and Feasibility clinical trial : Milestone Plan. The filename "Milestone Plan.pdf" must be used for this attachment.
The Milestone Plan attachment is separate and distinct from the Study Timeline attachment. For the required Pilot and Feasibility clinical trial , applicants 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.
Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
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)
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.
Applicants to this FOA have been required to provide the following:
- A Pilot and Feasibility clinical trial focused on a scientific issue with one or more of the rare pediatric liver diseases currently being studied by the ChiLDReN Network. The standard review criteria noted in this FOA should be applied to the research strategy of the Pilot and Feasibility clinical trial.
- A description of the CC’s patient population that may contribute to the recent conduct of the currently ongoing clinical studies or trials in the ChiLDReN Network and potentially into the future. The description of the patient population at each CC should be assessed independently from the patient population being studied in the proposed Pilot and Feasibility clinical trial.
An optional translational science research strategy may be included in the application. The translational science research strategy should focus upon methods to gain a better understanding of the pathogenic mechanisms that lead to liver disease or liver injury with one or more of the rare pediatric liver diseases being studied by the ChiLDReN Network. Standard review criteria should be applied if an optional translational science research study strategy is included in the application.
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?
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?
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?
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?
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?
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?
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?
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?
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?
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
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?
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.
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.
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.
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.
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).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
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
- Will receive a written critique.
- Scientific and technical merit of the proposed project as determined by scientific peer review.
- Availability of funds.
- Relevance of the proposed project to program priorities.
3. Anticipated Announcement and Award Dates
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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
1. Award Notices
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
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 and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
1. Developing the research design and study protocol, including definition of objectives and approaches, sample size and power calculations, and establishing procedures for participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.
2. Establishing a Steering Committee to implement, coordinate and manage the project(s). Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.
3.Designating Protocol Chairs. The Program Directors/Principal Investigators (for studies involving multiple protocols) shall designate a single Protocol Chairperson (if the Program Director/Principal Investigator does not assume this role) for each protocol to be carried out by the study group. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Significant modifications to approved protocols must be approved by the Steering Committee.
4. Implementing collection of data specified by the study protocol. For a multi-center study, each awardee/site is required to ensure that data will be submitted expeditiously to the Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.
5. Establishing procedures for data quality and completeness. 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 facilitate cooperation/referral of study participants by physicians to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple sites, a plan for analysis of pooled data will be developed by the Steering Committee.
6. Submitting interim progress reports, when requested or agreed upon by both parties, to the NIDDK Program Official including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the NIDDK Program Official may require additional information from individual awardees/sites. Such reports are in addition to the required annual noncompeting continuation progress report.
7. Reporting of the study findings. Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. The awardee must also be adherent to Study Publication and Presentation Policy. The NIDDK will have access to and may periodically review all data generated under an award. NIDDK staff may co-author publications of findings with awardees consistent with NIH and study policies.
8. Agree that any third-party (including both industry and academia) collaboration should be governed by a research collaboration agreement (e.g. Clinical Trial Agreement, Research Collaborative Agreement, Memorandum Of Understanding, etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH/NIDDK policies and procedures. The NIDDK Program Official may consult with others at NIH including the NIDDK Technology Advancement Office.
9. Any involvement of a third party (including both industry and academia) in the study, including access to any study data; study results; using the name of the study; or the name of the NIH or NIDDK, is permitted only after written concurrence by the NIDDK Program Official who may consult with others at NIH including the NIDDK Technology Advancement Office.
10. Study investigators are required to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and steering committee policies on publications.
11. Maintaining confidentiality of information: The awardee(s) will maintain the confidentiality of the information developed by the investigators (i.e., protocols, data analysis, conclusions, etc.) as well as proprietary information of a company collaborating with the study.
12. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. Prior to enrolling participants, the PI or his/her designee will coordinate with the NIDDK Central Repository to develop a Data Sharing Plan and prepare the collected data for eventual archiving and distribution. In addition, if applicable, the PI or his/her designee will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, storage, and sharing of study samples that are to be maintained in the Repository. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study’s Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing (http://grants.nih.gov/grants/policy/data sharing/ and,
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm ), as well as the NIDDK policy for data sharing in multi-center and large single-center clinical studies
http://www.niddk.nih.gov/research-funding/process/human-subjects research/Documents/PublicversionNIDDKdatasharingpolicy2013July2013.pdf.
13. The Food and Drug Administration Amendments Act of 2007 (FDAAA or US Public Law 110-85) was passed on September 27, 2007. The law requires mandatory registration and results reporting for certain clinical trials of drugs, biologics, and devices. If trials conducted under this grant are applicable clinical trials subject to FDAAA, the sponsor or his/her designee will perform the mandatory study registration and reporting of study results to ClinicalTrials.gov. For more information about this law and requirements for sponsors and/or investigators, visit the PRS and U.S. Public Law 110-85 Information Page at http://prsinfo.clinicaltrials.gov/fdaaa.html. In addition, grantees should be aware that clinical trials not covered by FDAAA may still require registration in an approved registry in order to be published, according to the guidelines issued by the International Committee of Medical Journal Editors (http://icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial registration.html).
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
An NIDDK Project Scientist with substantial involvement will:
1. Serve as the contact point for all facets of the scientific interaction with the awardee (s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK staff to provide advice to the awardee on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Project Coordinator, who will provide direct technical assistance to the awardees to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.
2.For multi-center studies, participate in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or Project Coordinator will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.
3. Serve as a resource to study investigators with respect to other ongoing NIDDK activities that may be relevant to the study to facilitate compatibility with the NIDDK missions and avoid unnecessary duplication of effort.
4. Have substantial involvement assisting in the design and coordination of research activities for awardees as elaborated below:
a. Assisting by providing advice in the management and technical performance of the investigations, coordinating required regulatory clearances for investigational agents used in the study, which are held by NIDDK. The NIDDK may reserve the right to cross file or independently file an Investigational New Drug Application or an Investigational Device Exemption form with the FDA.
b. The NIDDK Project Scientist or Project Coordinator may coordinate activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results.
c. Reviewing procedures for assessing data quality and study performance monitoring.
d. The NIDDK Project Scientist or Project Coordinator may be co-authors on study publications. In general, to warrant co-authorship, NIDDK staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results and (d) preparation and authorship of pertinent manuscripts.
The NIDDK Program Official identified in the Notice of Award will:
1. Interact with the Program Director(s)/Principal Investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the Program Director/Principal Investigator and staff, periodic site visits, 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, as an option, periodic review of progress by researchers not involved with the study.
2. Review and approve protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.
3. The NIDDK Program Official will monitor protocol progress, and may request that a protocol study be closed to accrual 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; (f) low likelihood of showing a benefit of the intervention (futility); and (g) 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 as specifically approved by the NIDDK.
4. Make 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.
5. Appoint an independent Data and Safety Monitoring Board (DSMB) as appropriate for Phase III clinical trials or other high-risk studies, or an Observational Study Monitoring Board (OSMB) for observational/epidemiologic studies; these Boards will review study progress, safety data, and interim results, as appropriate, and provide guidance to the NIDDK. The NIDDK Program Official or their Project Coordinator will serve as the Executive Secretary and/or NIDDK program representative on the DSMB/OSMB.
Areas of Joint Responsibility include:
In addition to the interactions defined above, NIDDK Project Scientist and Awardees shall share responsibility for the following activities:
Steering Committee:
A Steering Committee organized by the study investigator(s) will be the main governing body of the study.
The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among awardees, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIDDK Program Official, and will provide periodic supplementary reports upon request.
The Steering Committee will be composed of all Program Director(s)/Principal Investigator(s), (including those of data coordinating /statistical centers, if any) and co-investigators as deemed necessary, and the NIDDK Project Scientist. The final structure of the Steering Committee and voting procedures will be established at the first meeting. The NIDDK Project Scientist will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.
A Chairperson of the Steering Committee, other than the NIDDK Project Scientist, will be selected by the NIDDK, in consultation with the Steering Committee. The Chairperson provides leadership to the Committee by conducting the Steering Committee meetings, representing the study group to the External Oversight Committee established by the NIDDK and by interacting closely with the awardees during protocol development and implementation.
Dispute Resolution:
Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to dispute resolution. A dispute resolution panel will be composed of three members --one selected by the awardee (or the Steering Committee, with the NIDDK member not voting), a second member selected by NIDDK, and the third member elected by the two prior selected members. These special dispute resolution procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CR Part 16.
3. Reporting
When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.
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