BACKGROUND:

Primary glomerular diseases such as minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), immunoglobulin A nephropathy (IGAN), and membranous nephropathy (MN) are associated with significant morbidity and mortality in both adults and children. In addition to progressive loss of renal function [resulting in approximately 10% of all incident end stage renal disease (ESRD) cases in the US], primary glomerular disease can result in nephrotic syndrome leading to increased risk of infection, venous thromboembolism, hypercholesterolemia, cardiovascular disease, toxicities associated with immunosuppressive therapy, increased hospitalization rate, decreased quality of life, and mortality.

Despite the significant disease burden associated with these glomerulopathies, relatively little is known regarding their natural history, various underlying pathophysiologic process, predictors of outcomes and response to the existing limited arsenal of therapies. A major hurdle to studying these processes in depth has been the rarity of these conditions relative to diabetic or hypertensive-associated chronic kidney disease (CKD). This has accordingly made it challenging for independent investigators to acquire sufficient cases to comprehensively study these glomerulopathies.

To facilitate the advancement of our understanding of the course, cause, and treatment of glomerular diseases in adults and children, the NIDDK established the CureGN multi-center Study in 2013. The original aims of this multi-center, prospective, observational study were to:

• Recruit an observational multiethnic cohort of at least 2,400 adult and pediatric glomerular disease patients with biopsy-documented IgAN, FSGS, MN or MCD;
• Describe the disease trajectories;
• Estimate event rates for clinically meaningful outcomes and to identify clinical predictors of short- and long-term outcomes;
• Identify and characterize clinical, histological, molecular, and genetic biomarkers that are linked to glomerular disease, disease outcomes, or that might be used to improve disease classification, or response to therapy;
• Understand the genetic architecture of the four glomerulopathies, including epigenetic changes, and transcriptomic profile, and their impact on disease presentation and clinical outcomes;
• Devise systems-based "-omics" approaches to clarify pathogenesis;
• Describe the full range of the patient experience including, but not limited to Patient Reported Outcomes associated with primary glomerular diseases or disease progression and validate disease-specific instrument(s); and
• Facilitate the development of translational and clinical ancillary studies that will leverage the cohort to advance the diagnosis and care of patients with glomerular diseases.
  

An initial cohort of about 2,200 participants has been recruited between 2013 and 2018. At the start of the next project period, it is projected that approximately 2,400 participants with MN, FSGS, IgA and MCD will be actively followed. Continued follow-up of this cohort will permit progress toward achieving the initial aims.

The CureGN study is expected to foster many ancillary studies through investigator initiated (R01) grants, career development (K) awards and to foster careers in both basic and clinical research of glomerular diseases. The study group will also actively collaborate with ongoing studies supported by the NIDDK as well as other funding sources. The study will continue to pursue collaborations with industry (e.g., pharmaceutical companies), other government agencies (e.g., FDA), and advocacy groups as appropriate to achieve the overarching goal of advancing the diagnosis, understanding of pathophysiology, development of predictive biomarkers and treatments needed to meaningfully improve the care of individuals with glomerular diseases.

OVERALL GOALS:

The short-term objective of the next project period of the CureGN Study to be supported by this FOA is to better characterize the courses and consequences of MN, FSGS, IgA and MCD glomerulopathies over a longer period and in substantially greater depth than achieved over the first 6 years of the study. The in-depth characterization of the biological and behavioral aspects of these glomerulopathies will require careful and extensive assessment of the study participants by both traditional and novel markers. The longer-term goals are for the collected data to provide the needed information to allow a more refined pathophysiologic based re-classification of some the glomerulopathies and/or subtypes, a more precise prediction of individual level outcomes and to help identify novel targeted treatments for individual patients.

The major objectives of the next five years of the study are to:

1. Continue implementation of a common protocol to prospectively follow approximately 600 participants in each of the 4 disease groups: IGAN, FSGS, MCD and MN.
2. Retain enrolled participants and limit recruitment of newly-diagnosed participants to replace those who have withdrawn consent or have been lost to follow up. Follow-up of CureGN participants is anticipated to be ongoing until withdrawal from the study or death occurs.
3. Collect longitudinal phenotypic, clinical, patient-reported, genetic, biochemical, and tissue data.
   • Clinical data should include disease activity, associated non-renal outcomes, and transplant/graft survival outcomes.
   • Tissue data should include histopathological and molecular/"-omics" analyses facilitated by the banking of blood, urine, physical slides or digital whole slide images, and physical biopsy tissue blocks.
4. Analyze these samples and data with both traditional and innovative approaches that integrate high levels of data (e.g. data reduction based approaches) as well as systems biology approaches, with the goal of uncovering novel disease features for disease subgroup classification, prognosis, delineation of pathophysiologic pathways, response to therapy, and the identification of novel treatment targets.
5. Identify fixed and variable costs and establish procedures for negotiation of third party agreements or selection of subcontractors (i.e. clinical sites, clinical/investigational pharmacies, clinical/research laboratories, drug distribution centers, biospecimen repositories, etc.), and develop processes to efficiently administer and manage same throughout the project.
6. Promote applications for subsequent ancillary studies to identify disease targets, develop biomarker-therapy combinations, and establish and validate Patient Reported Outcomes (PROs) and surrogate outcomes for disease progression, treatment efficacy, treatment toxicities, and remission.
7. Engage and involve multiple foundations and Patient Advocacy Groups through a Patient Advocacy Council (PAC) to help accelerate recruitment and strengthen patient engagement and retention.
8. Foster productive collaborations with scientists outside of the CureGN network.
9. Propose plans for collaborations set up as public-private partnerships (http://ppp.od.nih.gov). Such collaborations must include close interaction with the FDA on biomarker and surrogate outcome development. Collaborations with industry on pre-competitive items are encouraged.

RESEARCH OBJECTIVES:

The CureGN PCC will serve as the primary contact with patient participants and their care givers. It will support consortial activities through the following:

Recruitment and Retention: The PCCs will be responsible for the completion and maintenance of the CureGN cohort. PCCs will develop and maintain strategies for efficient recruitment and effective retention of subjects in keeping with recommendations from the Patient Advisory Council, Observational Study Monitoring Board (OSMB) and External Evaluation Panel (EEP).

Study design and implementation: The PCCs will ensure execution of the study in keeping with the approved CureGN protocol. PCCs will work to address inefficiencies and limitations of the protocol with the development of protocol amendments. PCCs will communicate with the DCC site monitoring team to ensure protocol compliance and data integrity.

Sample collection and quality control: The PCCs will implement data collection and ensure data integrity. PCCs will work to address inefficiencies and limitations of sample collection with the development of protocol amendments. All data, whether derived through the central protocol or ancillary studies will be sent to the DCC for final quality control and analysis. All data collection and analyses (i.e., questionnaire results, biochemical measurements, pathological specimens, clinical data) will adhere to the standards of the Clinical Data Interchange Standards Consortium (CDISC) in order to facilitate biomarker, surrogate outcome, and therapy development in accordance with the FDA guidelines.

Biosample collection and quality control: The PCCs will work collaboratively with the DCC in the shipping and tracking of biological samples (e.g. blood, urine, glass slides, paraffin embedded biopsy tissue blocks, RNA, DNA) as they move from PCCs to internal or external sites for analyses or to the NIDDK Repository.

Community engagement: The PCCs will prioritize interactions and collaboration with outside scientists and third parties through the development of ancillary studies policies and oversight of an opportunity pool. The DCC will serve as the initial point of contact for public-private partnerships.

Only the current CureGN PCC awardees under RFA-DK-12-014 are 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.

Only the current UM1 Principal Investigators of the CureGN Participating Clinical Centers are eligible to apply under this limited competition FOA

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

Other Attachments: The application must include the following documents, uploaded as a separate pdf file with the names indicated below.

Specific names provided for Other Attachments must be no more than 50 characters including spaces.

1. Clinical Protocol Synopsis: The filename "Clinical Protocol Synopsis.pdf" should be used. The synopsis is meant to supplement the information provided in the Research Strategy and should include the following information:

• A description of the study population including CureGN subject eligibility, inclusion/exclusion criteria, and baseline characteristics
• A report on the performance toward implementation of the protocol including visit compliance, biosample collection, submissions to the digital pathology repository, and retention rates
  • for the study overall
  • for the individual PCC
• A description of key study outcomes
• A description of PCC network sites and local site leadership

2. Network Products: The filename "Network Products.pdf" should be used. The synopsis is meant to supplement the information provided in the Research Strategy and should include the following information:

• A Table of ancillary studies approved by the CureGN Ancillary Studies Committee including ancillary study PI, ancillary study title, status (i.e. complete, active, pending funding, rejected), encumbered sample types;
• A Table of publications and publication concepts approved by the CureGN Publications Committee including corresponding author, manuscript title, status (i.e. in development, submitted or in press);
• A timeline of completed and proposed network milestones.

The NIDDK Technology Advancement Office must be consulted early in the process when an NIDDK-funded study enters into a collaboration agreement and the NIDDK Regulatory Specialist consulted early in the process when a protocol may be required to operate under an IND/IDE.

All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Specific Aims: Briefly describe the Specific Aims for the CureGN Participating Clinical Center (PCC). The CureGN PCC Specific Aims should be congruent with those of the re-competing CureGN Data Coordinating Center (DCC) and should address opportunities to improve care for individuals with glomerular disease related to improving individual level disease trajectory and response to treatment, and implementing precision medicine approaches.

Research Strategy: This section should propose plans for organization and management of the CureGN network. Divide the Research Strategy into the following sections:

1. Progress Report: document progress toward goals in prior funding period.
2. Study administration and design
   • Provide a statement of willingness by the Center to fully participate in the cooperative nature of the CureGN network as outlined in Section VI, "Cooperative Agreement Terms and Conditions of Award".
   • Describe administrative structure of the PCC and support of network activities (e.g. development of policies and protocols, working groups, study website, etc)
   • Discuss oversight and training to ensure adherence to the highest ethical, research and clinical standards, and any required regulatory standards.
   • Describe the engagement of a Patient Advocacy Council with wide representation from relevant stakeholders (including patients and their care givers, patient advocacy groups and foundations) willing to inform CureGN research objectives, protocol development and participant retention and to serve as CureGN ambassadors to the larger community.
   • Describe engagement of junior investigators in the conception, execution, and presentation of network activities.
   • Describe the strategy for enrollment completion and ensuring adequate representation of minority ethnic groups.
   • Describe the strategy to ensure maximum retention and continued follow-up of the enrolled participants, including type and frequency of measurements as well as relevant outcomes.
   • Discuss potential approaches to enhance the collection of important non-renal function-based outcomes such as cardiovascular events and immunosuppressive-related morbidity.
   • Describe approaches to capture outcomes of participants lost to follow up (e.g. use of USRDS records and/or death records).
3. Data administration
   • Describe how the PCC will ensure data integrity. Elaborate on collaborative approaches with the DCC to collect, manage, and clean study data.
   • Describe the type of data to be collected and the timing of transfer to the DCC for ultimate deposition to the NIDDK Repository. Describe any processing that will occur prior to submission to the DCC.
4. Biorepository (organization and management of physical biological samples and maintenance of digital pathology repository)
   • Describe approaches for organization, management and tracking of biosamples between sites and to the NIDDK Repository.
   • Describe the type, frequency, and estimated amounts of biological samples to be sent to the DCC for ultimate deposition to the NIDDK Repository during the next project period.
   • Describe the PCC contributions to the Digital Pathology Repository including maximizing sample contributions (biopsy slides), data sharing, scoring and analyses.
     1. Describe the number of cases existing within the PCC.
     2. Describe the number of cases shipped to the Digital Pathology Repository.
   • Describe the number of tissue biopsy blocks available for future molecular studies and the process for their acquisition and storage.
5. Ancillary studies
   • Describe how investigators outside the current grantees will be brought into the study group to meaningfully supplement expertise to inform study design, data analysis and interpretation.
   • Discuss how ancillary studies, including those related to career development, will continue to be promoted and implemented consistent with study policies.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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. All instructions in the SF424 (R&R) Application Guide must be followed. Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy. Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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 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?

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?

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?

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?

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

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.

Not Applicable

For Renewals, the committee will consider the progress made in the last funding period.

Not Applicable

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

Not Applicable

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).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

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.

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 (https://grants.nih.gov/policy/sharing.htm, http://grants.nih.gov/grants/policy/data_sharing/,

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.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267 Cindy N. Roy, PhD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8805
Email: cindy.roy@nih.gov

Afshin Parsa, MD, MPH
National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK)
Telephone: 301-827-1375
Email: afshin.parsa@nih.gov

Jason Hoffert, PhD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-496-9010
Email: jason.hoffert@nih.gov ?

Norma DeGuzman
National Institute of Diabetes and Digestive, and Kidney Diseases (NIDDK)
Telephone: 301-480-1810
Email: norma.deguzman@nih.gov

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.