Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Allergy and Infectious Diseases (NIAID)

Funding Opportunity Title

Limited Competition: Continuation of the Clinical Islet Transplantation (CIT) Consortium Data Coordinating Center (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of RFA-DK-09-501

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-DK-12-501

Companion FOA

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.847, 93.855, 93.856  

FOA Purpose

This Funding Opportunity Announcement (FOA) is a Limited Competition announcement for continuing the Clinical Islet Transplantation (CIT) Consortium Coordinating Center.   This Consortium was begun in 2004 and has been conducting 8 clinical trials using human islets as a therapy for type 1 diabetes.   This funding will support ongoing Consortium activities and allow completion of current studies and the preparation of phase III study reports.  

Key Dates
Posted Date

January 13, 2012

Open Date (Earliest Submission Date)

February 14, 2012

Letter of Intent Due Date

February 14, 2012

Application Due Date(s)

March 14, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

June/July, 2012

Advisory Council Review

October, 2012

Earliest Start Date(s)

December, 2012

Expiration Date

March 15, 2012

Due Dates for E.O. 12372

Not Applicable.

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). 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.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose of this FOA

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Allergy and Infectious Diseases (NIAID) invite an application for a Data Coordinating Center (DCC) to participate in a consortium of investigators and institutions that will continue established clinical studies of islet transplantation in patients with type 1 diabetes mellitus (T1D).  The Clinical Islet Transplant Consortium (CIT), established in FY 2004 under RFA DK-04-004 and RFA DK-04-005 followed by RFA DK-09-501, has planned and initiated a program of single and multi-center clinical trials in pancreatic islet transplantation for individuals with type I diabetes, with or without a prior kidney transplant. These trials are accompanied by metabolic and immunologic mechanistic studies.  The successful applicant for the current funding opportunity (one DCC), will oversee the Clinical Islet Transplantation (CIT) consortium which includes the former Clinical Center (CC) grantees from RFAs DK-04-005 and DK-09-501.   This effort is intended to result in an improved treatment of T1D and licensure of the human islet product.   Two phase III clinical trials are currently underway, whose intent is to support licensure.

The CIT Data Coordinating Center (CIT-DCC) will provide a broad range of support services for the CIT, including statistical, monitoring, and operational support. It will also assist with the preparation of DSMB reports, regulatory submissions, scientific manuscripts, and other reports and documents as needed to support the work and goals of the CCs in the consortium and/or as required by the NIH.

The previously funded CCs together with the DCC will continue the current CIT scientific agenda and complete the CIT studies that are currently under way (a list of studies is available at http://www.isletstudy.org/).  Additionally they will share information and resources that will advance the field of islet transplantation.

Background

T1D is an autoimmune disease characterized by the destruction of the insulin-secreting beta cells of the pancreas.  T1D can be difficult to control with currently available therapies.  Life threatening and altering consequences are major problems for some patients with T1D including hypoglycemia, accelerated cardiovascular and peripheral vascular diseases, nephropathy, retinopathy, neuropathy, oral diseases and premature death.  The incidence of T1D appears to be increasing worldwide.  Although the disease may occur at any age, onset peaks prior to twenty years of age.  In some populations, approximately one percent of all newborns will develop T1D during their lifetime.

Islet transplantation as a therapy for T1D has been an important focus of NIH support, and significant progress has occurred in past years.  In particular, the success of the "Edmonton Protocol" for islet transplantation in freeing individuals with T1D from the need for insulin therapy has established islet transplantation as an alternative therapy for those T1D patients whose disease cannot be effectively managed with current methods of exogenous insulin administration. However, significant obstacles remain for development of islet transplantation as a treatment for T1D in the general population, most notably the toxicity associated with current regimens of immunosuppression and islet administration and the limited supply of human cadaveric islets, which is sufficient for only a small fraction of the people who could potentially benefit from this therapy.  The recent successes in islet transplantation provide additional impetus for research to develop methods to attain an unlimited supply of islets for transplantation; to improve methods for harvesting pancreata and isolating islets; to improve techniques for the administration of transplanted islets; and to develop approaches to minimize the toxicity of immunotherapy required for transplantation.  In addition, sufficient advances in islet transplantation have occurred to warrant phase III studies designed to support licensure of the human islet product.

Objectives and Scope

The purpose of this FOA is to support a DCC for an established program of cooperative clinical trials (see http://www.isletstudy.org/.) including single/multi-center pilot studies investigating an innovative approach and multi-center pivotal (phase III) studies have been designed to evaluate/accomplish:

1. Increasing the efficiency of islet transplantation, with the goal of achieving successful single-donor islet transplantation. 

2. Improvements in immunotherapy to reduce toxicity, recurrent autoimmunity and allograft rejection.

3.  FDA licensure of the human islet product.

In association with ongoing clinical trials, the CIT has designed mechanistic studies to enhance understanding of rejection, engraftment and/or survival of islets in the setting of islet transplantation. 

The Data Coordinating Center for the consortium will continue providing support in the following areas:

1) Study Design, Conduct, Analyses, and Publications - The DCC will provide statistical leadership for the consortium. It will oversee implementation of the current  clinical trials and implement the statistical analysis plans that have been submitted to the FDA, and will also be responsible for  assisting with all updates to the protocols and manuals of operation; implementation and, where necessary, modification of the existing  data safety and monitoring plans; collaborating with the NIAID Regulatory and Medical staff to implement the existing procedures for reporting Serious Adverse Events; performing interim analyses of safety and efficacy for protocol teams, NIH, and the Data Safety and Monitoring Board (DSMB); generating executive summaries of  study results for use by the protocol team, NIH, and collaborators; conducting the final analyses and participating on publication writing teams; performing cross-protocol or cross study analyses utilizing data from multiple sources within and external to the consortium; producing study monitoring reports for the consortium and NIH; and conducting analyses and summaries for annual and interim reports for NIH-sponsored Investigational New Drug Applications, in cooperation with the NIAID Regulatory and Program staff or Support Contractor (see below).

2) Data Management – Provide central registration and randomization (as required by study protocols) for all study subjects; develop/modify case report forms and standardized criteria for clinical endpoint verification; maintain, design and implement as needed systems for the efficient tracking and transfer of clinical and laboratory data (including quality assurance and specimen tracking) to the central database; provide data management training to the clinical sites and laboratories; provide CRF notebooks to collaborators; provide for central storage, security, processing and retrieval of study results; and prepare selected public access databases.

3) Site Monitoring – Through a subcontract Clinical Research Organization(s) initiate, monitor, and close out clinical sites, pharmacies, and laboratories to assure Good Clinical/Laboratory Practice (GCP/GLP); together with NIAID regulatory staff, train site personnel on GCP/GLP/GTP compliance and on the policies and procedures established by the NIH, the Food and Drug Administration (FDA), and the Office of Human Research Protections (OHRP); audit clinical, pharmacy, and laboratory sites, as well as islet facilities, as necessary; and provide reports to the NIH and the Steering Committee on monitoring and audit findings and training activities.

4) Administrative Support – Organize meetings and teleconferences; provide core laboratory support and coordination, including specimen handling; distribute study drugs and supplies. 

5) Regulatory Requirements – The DCC will work in concert with the NIAID Regulatory Affairs Staff and/or Support Contractor and NIH staff by providing them with clinical study data, reports, and other support as required for Adverse Event Reporting and IND submissions.

It is expected that the successful DCC applicant will bring a range of experiences and perspectives to this consortium that will inform group decisions and accelerate the pace of progress toward general clinical applicability of islet transplantation for the treatment of T1D.

6) Provide financial support for the participating Clinical Centers who are no longer funded through their own grants including the clinical and infrastructure costs.

7) Develop a collaboration with the Collaborative Islet Transplant Registry (CITR) for providing CIT data to CITR and the obtainment of data from CITR.

Section II. Award Information
Funding Instrument

Cooperative Agreement

Application Types Allowed

Renewal
The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The total amount of funding that the NIDDK intends to commit for this FOA is $3.2 million in FY2012. The anticipated number of awards is one. Although the financial plans of the NIDDK provide support for the first two years of this program, awards pursuant to this FOA, particularly in years 3 to 5 of the awards, are contingent upon the availability of funds.

Award Budget

Application budgets are not limited, but need to reflect actual needs of the proposed project.

Award Project Period

 The maximum period for support of this project is 5 years. 

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

As this is a limited competition FOA, only the currently participating institutions are eligible.

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

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

For institutions/organizations proposing multiple PD(s)/PI(s), visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (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

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the 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.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

PHS 398 Research Plan Component

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

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS) as provided in the SF424 (R&R) Application Guide.

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (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.

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 SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD(s)/PI(s) Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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 Central Contractor Registration (CCR). 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 by the Center for Scientific Review and responsiveness by the NIDDK. Applications that are incomplete and/or nonresponsive will not be reviewed.  

In order to expedite review, applicants are requested to notify the NIDDK Referral Office by email at fc15y@nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

 1.  The DCC application should describe accomplishments, including its operational infrastructure (committees, procedures for coordination and communication, etc). It is expected that the PD(s)/PI(s) of the DCC will carry out a significant leadership role in the consortium

2.  The application must reflect adequate time commitment of personnel.  The minimum time commitment for the PD(s)/PI(s) is 2.4 person months.

3.  Budget Information:   The application should include budgets for five 12-month periods including any estimated carryover.  The total amount of funding that the NIDDK intends to commit for this FOA is $3.2 million in FY2012. The anticipated number of awards is one. Although the financial plans of the NIDDK provide support for the first two years of this program, awards pursuant to this FOA, particularly in years 3 to 5 of the awards, are contingent upon the availability of funds.

4.  Other responsibilities/requirements include:

a.  Participation in the biostatistical design (including sample size determinations) and analysis for the epidemiologic studies and clinical trial protocols conducted by the CIT;

b.  Maintenance, and any further required development for implementation and support of the CIT information management system;

c.  Maintenance and any further required development of study documentation, including data collection forms, electronic case report forms, manual(s) of operations for procedures and recruitment materials;

d.  Maintaining contract arrangements for distribution of study drugs and other study supplies;

e.  Coordination and monitoring of central laboratories and reading centers used to perform evaluations as defined in the CIT protocols;

f.  Coordination of meetings and conference calls of the Steering Committee (SC) and other groups and committee as needed;

g.  Preparation of data monitoring, performance and safety reports for interim monitoring by the DSMB for the CIT clinical trials;

h.  Development and implementation of quality assurance procedures;

i.  Ability to complete and submit necessary regulatory documents in support of the Food and Drug Administration (FDA)  Investigational New Drug Application (IND) or regulatory requirements of other involved countries in coordination with NIAID regulatory staff;

j.  Preparation of periodic technical and statistical reports for the DSMB, NIDDK, and FDA;

k.  Provision of biostatistical and scientific support for the publication and presentation of the study results;

l.  Clinical and infrastructure support for participating CCs;

Requirements and Responsibilities for the DCC and the grant/subcontract CCs:

The CIT will continue to be a collaborative effort that will require frequent interactions among the CCs, DCC and the NIH. The applicant must explicitly indicate a willingness to:

1. Participate in Steering Committee meetings (expected to occur in person at least once a year in or near the Bethesda, MD area and teleconferences at least monthly, as needed), site visits required by the NIH, and other CIT-related telephone conference calls;

2. Cooperate in the further 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 site specific and consortium-wide protocol for which the site is selected for participation;

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

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

7. Transmit study data to the DCC in a timely and accurate manner (grant/subcontract CCs);

8. Report all adverse events in accordance with procedures established by the NIH and CIT policies;

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

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

12. Accept the “Cooperative Agreement Terms and Conditions of Award” in Section VI.2 “Administrative and national Policy Requirements”. 

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

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.

Overall Impact

Reviewers will provide an overall impact/priority 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).

Scored Review Criteria

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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?  

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?  Are the expertise, training, and experience of the investigators and staff, including the administrative abilities of the Program Director(s)/Principal Investigator(s) [PD(s)/PI(s)] and co-investigators at the DCC, and the time they plan to devote to the effective coordination of the CIT appropriate? Have individuals from the applicant site made substantive contributions to achieving the aims of the consortium during the last 3 years of funding?   

Innovation

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?  

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Do the collaborative arrangements within the CIT enhance the productivity of the DCC? Are the facilities, equipment, environment and organizational structure of the DCC adequate to effectively coordinate the CIT activities in implementing the protocols, data collection and providing for specialized methodologies and plans for collecting and distribution of biospecimens to the central labs and NIDDK repositories adequate?    

Additional Review Criteria

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/priority score, but will not give separate scores for these items.

1.    Has the DCC demonstrated an understanding of the scientific, statistical, logistical, and technical issues underlying the CIT single and multi-center studies and knowledge necessary to lead in the areas of biostatistical study design, statistics, logistics, data acquisition and management, identification of and coordination with drug distribution centers and serum/tissue/data repositories, handling of laboratory specimens, quality control, data analysis, and consortium coordination?

2.    Are the proposed plans for acquisition, transfer, management, and analysis of data, quality control of data collection and monitoring, and overall coordination of the CIT adequate?

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

4.    Is there the ability to support the NIAID in preparing and filing the necessary regulatory documents? 

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

Not Applicable.

Renewals

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

Revisions

Not Applicable.

Additional Review Considerations

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/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s)convened by the NIDDK, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA

Applications will be assigned to the NIDDK. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the National Diabetes and Digestive and Kidney Diseases Advisory Council . The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

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 the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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.

Cooperative Agreement Terms and Conditions of Award

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

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

The PD(s)/PI(s) will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the FOA and for performing the scientific activity. Specifically, PD(s)/PI(s) have primary responsibility as described below.

The DCC and each grant/subcontract CC PD/PI will be voting members of the Steering Committee and will be required to participate in all Steering Committee activities and to follow the policies and procedures that are developed by the Steering Committee.  The grant/subcontract CC PIs will be required to provide primary study data to the Coordinating Center for management, quality control, and analysis.  Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.  The collaborative protocol and governance policies will call for the continued submission of data centrally to the CIT-DCC for a collaborative database; the submission of copies of the collaborative data sets to each PI upon completion of the study; procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data (if any) and records of individuals.  The NIH Program Directors, on behalf of the NIH, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee.

The DCC will be involved in collaborations with the NIH and grant/subcontract CCs during all phases of the trial and will maintain or contract with the NIDDK Biosample Repository for stored samples.  In addition, the DCC will ensure the timely and accurate transmission of study samples and data from the CCs to the DCC and coordinate with the NIDDK Data Repository to prepare the data for eventual archiving and distribution. Thus, the DCC awardee is expected to work cooperatively with grant/subcontract CCs and sponsoring organizations and oversee the implementation of and adherence to a common protocol, as well as assure quality control of the data collected as well as the transmission and storage of collected biologic specimens.  In addition to organizing and attending regular meetings (including conference calls), the CIT-DCC will be expected to maintain close communications with the NIH Scientific Coordinators, and the grant/subcontract CC PIs.

The DCC and grant/subcontract CC PD/PI are expected to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community and the NIH.  Support or other involvement of industry or any other third party in any study performed by the Consortium -- e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIH support; or special access to project results, data, findings or resources -- may be advantageous and appropriate.  However, except for licensing of patents or copyrights, support or involvement of any third party will occur only in the context of a Clinical Trials Agreement with the NIH.

Upon completion of the project, the DCC is expected to put all study intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NIDDK/NIAID, for the conduct of research at no charge other than the costs of reproduction and distribution.  As much of the data will be used to support licensure applications(s), public release of information needed for licensure will be done after licensure applications have been met.  In the event that a non-CIT CC requires, as determined by the FDA, a CIT pivotal study report to support licensure, this will be provided at the cost of duplicating the report.   Indeed, NIH policy requires that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication [Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources:  Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html)].  It is expected that the specimens and data collected in projects funded by this RFA will eventually be made available to the broader scientific community, after a proprietary period.

The DCC and grant/subcontract CC PD/PI acknowledge in their approved "Sharing Plan" that they will share the specimens and data collected with the wider scientific community, through eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or through another mechanism determined by NIH. Evaluation of the Non-competing Grant Progress Report (PHS 2590) will include assessment of the effectiveness of research resource release.

The DCC and grant/subcontract CC PDPI responsibilities regarding Steering Committee membership, protocol development and conduct, and data coordination and management are described under Collaborative Responsibilities.

The awardee will retain custody of and have primary rights to the data and software developed under this award, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

NIH Program Directors will be assigned to perform normal program stewardship responsibilities for this award.   The Government, via the NIH Program Directors, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports.  NIH Staff may use information obtained from the data for the preparation of internal reports on the activities of the study.  However, awardees will retain custody of and have primary rights to all data developed under these awards.

Program Review

The NIH Program Directors, together with the CIT-DCC and the Steering Committee, will review the progress of each participating institution through consideration of the annual reports, site visits, patient logs, etc.  This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.

Monitoring Study Performance

The NIH Program Directors and the CIT-DCC will assist the Steering Committee in the development of mechanisms and procedures for monitoring study performance.  This includes participation in periodic on-site monitoring of compliance with protocol specifications, quality control and accuracy of data recording, and patient accrual.  The monitoring plan will incorporate any relevant regulatory requirements.

The NIH reserves the right to terminate or curtail any study or any individual award in the event of (a) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (b) substantive changes in the consensus protocol to which the NIH does not agree, (c) reaching a major study endpoint substantially before schedule with persuasive statistical significance, (d) human subject ethical issues that may dictate a premature termination, (e) evidence of study lack of efficacy, or (f) budgetary insufficiency.

Organizational Changes

Certain organizational changes require the prior written approval of the NIH Program Directors.  These changes include the addition or replacement of a physician, scientific investigator, affiliate, component, or research base that is associated with this study.  A change in the PD(s)/PI(s), or in any key personnel identified on the Notice of Award, must have the prior written approval of the NIH Grants Management Specialist in consultation with the NIH Program Director.

The NIH Program Director may also serve as the NIH Scientific Coordinator.

NIH Scientific Coordinator

NIH staff assistance as NIH Scientific Coordinators will be provided by the Clinical Islet Transplantation Program Director, DDEM, NIDDK, and the Chief of the Clinical Transplantation Section, DAIT, NIAID or their designees.  These NIH Scientific Coordinators and/or their designees will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. 

During performance of the award, the NIH Scientific Coordinators, with assistance from other scientific program staff who are designated based on the research topic and their relevant expertise, may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources (e.g., determining where a particular reagent can be found, or assay performed); coordinating or participating in the collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications.  The Scientific Coordinators and NIH Regulatory Staff will serve as a liaison/facilitator between the PI, pharmaceutical and biotech industries, and other government agencies (e.g., FDA, USDA, CDC) and will serve as a resource of scientific and policy information related to the goals of the PI’s research.  However, the role of the NIH will be to facilitate and not to direct the activities.  It is anticipated that decisions in all activities will be reached by consensus, and that the NIH Program Directors will participate in this process. The NIH Scientific Coordinators will serve as voting members of the Steering Committee and will participate in all Committee activities.

Regulatory Affairs

The NIH Regulatory Affairs staff, assisted by the staff of the CIT-DCC and the NIAID Regulatory Contractor, will be responsible for preparing all regulatory documents required by the Food and Drug Administration, and will provide to the PD(s)/PI(S) the guidance and assistance necessary to ensure that compliance with FDA regulations is maintained. The NIH regulatory affairs staff will initiate and participate in all communication with FDA representatives. 

Site Support

NIH Scientific Coordinators and DCC staff will meet at least monthly, by teleconference, with the site coordinators for each study, to discuss recruitment issues and study operations.  After completion of a study, NIH Scientific Coordinators or their designees and/or CIT-DCC staff (or contractors) will conduct a close-out visit. 

Protocol Implementation

As members of the Steering Committee, the NIH Scientific Coordinators will serve as a resource with respect to the implementation of the protocols and will, along with the CIT-DCC, assist the Steering Committee in protocol implementation.

Data Coordination and Management

The NIH Scientific Coordinators and the CIT-DCC will provide technical assistance and data management services to the participating institutions with respect to quality control, uniformity of data collection, management of the collective database, and data analyses.

Publication and Presentation of Study Findings

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

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

Areas of Joint Responsibility include:

Steering Committee

A Steering Committee serves as the main governing body of the cooperative research program. The Steering Committee will review all concepts for scientific merit and feasibility; review all protocols prior to implementation; review all public presentations of CIT results and manuscripts, posters, and abstracts prior to publication; review compliance with protocol requirements; define subcommittees; develop study policies; receive and act upon reports of subcommittees; and review matters relevant to administrative, financial, medical, legal, and ethical considerations of studies. The Steering Committee will maintain surveillance of the CIT performance and, together with the NIH, is responsible for the addition or deletion of CCs.

The Chairperson of the Steering Committee is responsible for the overall administration and science of the CIT activities by providing leadership for the steering committee activities described above. He/she will, together with the leadership of the DCC and the NIH Scientific Coordinators, schedule steering committee and investigator meetings; establish the agenda for those meetings; and monitor the work of the subcommittees.

At a minimum, the Steering Committee will be composed of the following individuals: the PI of the grant/subcontract CCs; the PI of the CIT-DCC; the chair of the Mechanistic Studies Subcommittee (see below); and the NIH Scientific Coordinators (the Clinical Islet Transplantation Program Director, DDEM, NIDDK; and the Chief of the Clinical Transplantation Section, DAIT, NIAID or their designees).  Additional members, voting or non-voting, may be added to the steering committee by majority vote of the Steering Committee; non-voting members may be added at the discretion of the NIH Scientific Coordinators. All major scientific decisions will be determined by the Steering Committee, with each grant/subcontract CC PI, the NIH Scientific Coordinators, and the PI of the CIT-DCC having one vote. 

The Steering Committee will meet in person at least once annually and by teleconference at least monthly.  Additional meetings by teleconference will be scheduled as needed, with need determined by the Steering Committee Chair and the NIH Scientific Coordinators.  The Steering Committee elects a Chairperson from among the Steering Committee members; the NIH Scientific Coordinators and the PI of the CIT-DCC are not eligible to be the Steering Committee Chair. Each Steering Committee member will be expected to participate in all Steering Committee activities, e.g., meetings, conference calls, special subcommittee activities, etc. as may be necessary.

The Steering Committee will have primary responsibility for implementing the clinical protocols, approving the design and implementation of all mechanistic studies (via the Mechanistic Studies Subcommittee), facilitating the conduct and monitoring of all clinical trials and mechanistic studies, analyzing and interpreting study data, and reporting study results. Studies will not be approved if the NIH or the Steering Committee determines that it will not be feasible to accrue patients within the specified time frame. 

Executive Committee

An Executive Committee comprised of the Steering Committee Chair, the PI of the CIT-DCC, and the NIH Scientific Coordinators will be convened to effect management decisions required between Steering Committee meetings, as needed for efficient progress of the studies.

Investigational Protocols

One PI or subcommittee will take the lead responsibility for implementing each individual protocol, with the assistance of the CIT-DCC and NIH Scientific Coordinators.  The Steering Committee will provide input and will be responsible for oversight of protocol development.  Any decision to discontinue a protocol will be determined by the NIH, a vote of the entire steering committee and/or review by the DSMB.

Mechanistic Studies Subcommittee

The Steering Committee shall appoint a Mechanistic Studies Subcommittee to review and approve or modify proposed mechanistic studies. Each PI shall select one representative from his/her consortium as voting members of the Mechanistic Studies Subcommittee.  In addition, the NIH Scientific Coordinators or their designees, shall serve as voting members.  The Mechanistic Studies Subcommittee may ask the Steering Committee to appoint additional Mechanistic Studies Subcommittee members if additional expertise in a specific area is needed.  The Mechanistic Studies Subcommittee shall elect a Chair from among its non-Federal members. The Chair shall serve as a voting member of the Steering Committee.  The Subcommittee will meet at least twice yearly and its members will be expected to participate in all meetings, conference calls, and other Subcommittee activities.

Data and Safety Monitoring Board (DSMB)

An independent DSMB, appointed by the NIDDK, will review CIT studies at least annually and report their findings to the NIH Program Directors.  Clinical protocols and mechanistic studies will be subject to review by the DSMB, in an advisory capacity, prior to implementation. The DSMB review will focus on the safety, ethics, and scientific and statistical integrity.

Data Coordination and Management

Data Coordination and Management will be carried out by the CIT-DCC.  Each participating institution will be responsible for providing primary study data to the NIH via the CIT-DCC for management, quality control, and analysis, using procedures and standards determined by the Steering Committee and the CIT-DCC. The NIH will provide, via its program staff and the CIT-DCC, the following: technical assistance and data management services to the participating clinical institutions with respect to quality control, uniformity of data collection, management of the collective database, and data analysis; centralized data collection and management; and quality assurance.  Specific analyses to be performed will be directed by the Steering Committee or the NIH Scientific Coordinators. The results of those analyses will be delivered to the Steering Committee. The Steering Committee is responsible for determining how the results are interpreted, whether the results should influence ongoing data collection, and how the findings should be disseminated.  In the event of a specific safety concern, the DSMB may request specific analyses from the DCC. All participating sites will have access to all data originating from their sites. The awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. 

Publication and Presentation of Study Findings

Timely publication of major findings is encouraged.  Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of the participating institutions and NIH support.  Policies for directing analyses of aggregate and site-specific data will be developed by the Steering Committee. Review and approval by the Steering Committee will be required for all analyses prior to publication or presentation according to criteria that will be developed by the Steering Committee.  

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

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described 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. 

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.      

Application Submission Contacts

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Thomas L. Eggerman, M.D., Ph.D.
Director, Clinical Islet Transplantation Program
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
6707 Democracy Boulevard, Room 697 (MSC 5460)
Bethesda, MD 20892 (overnight delivery 20817)
Telephone: 301-594-8813
Email:eggermant@mail.nih.gov

Guillermo Arreaza-Rubin, M.D.
Director, Clinical Immunology Program
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
6707 Democracy Boulevard, Room 6101 (MSC 5460)
Bethesda, MD 20892 (overnight delivery 20817)
Telephone: 301-594-4724
Email:arreazag@mail.nih.gov

Nancy D. Bridges, M.D.
Chief, Transplantation Branch
National Institute of Allergy and Infectious Diseases (NIAID)
6610 Rockledge Drive Room 6325
Bethesda, MD 20817
Telephone: 301-594-4724
Email: NBridges@niaid.nih.gov

Peer Review Contact(s)

Francisco O. Calvo, Ph.D
Chief, Review Branch  
6707 Democracy Boulevard, Room 752      
Bethesda, MD20892-5452
(For express/courier service: Bethesda, MD 20817
Telephone: 301-594-8897
Email: fc15y@nih.gov

Financial/Grants Management Contact(s)

Christina Coriz
Grants Management Specialist
Grants Management Branch, NIDDK
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
6707 Democracy Boulevard, Room 709B (MSC 5460)
Bethesda, MD 20892 (overnight delivery 20817)
Telephone: 301-594-8848
Fax: 301-594-9523
Email:corizc@niddk.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

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 Parts 74 and 92.


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